s A STUDY OF METABOLISM IN SEVERE DIABETES £■.§,2 §ni ^S^^Ste S:2. fl S oti J2-T-) o.S^J^S rt ft I ° ££ "^ c2°§^ So .a -2 "•2_c .a a ^s^-a-a ss « a £ § S *x «££^| ^S •§ g C O eo 5P2 n o-p O m-^ 5503O- X Fj"2 -1-3 o3T3m«2a^3.S ^QJ-^^ a^T, ^lli Sill" si's iln^ni I Ch © bfiJ2 ,-'.S'^eo3«2l=lo3-^P ~ «o „S „m 'O fl O • - **- "5 to *0 a>^-3 > SP °o ®* °i ^ ®* ^^^•^s* to *-i^ ©i ©» ■I. +_. Bh On ft. ft* ft, ft. ASHINGTOX A STUDY OF METABOLISM IN SEVERE DIABETES BY FRANCIS G. BENEDICT and ELLIOTT P. JOSLIN WASHINGTON, D. C. Published by the Carnegie Institution of Washington 1912 Carnegie Institution of Washington Publication No. 176 / & z PRESS OF GIBSON BROTHERS WASHINGTON, D. C. PREFACE. The researches in this book are an amplification of the investigation on the metabolism of diabetes mellitus instituted in this laboratory in 1908. The experimental evidence has reached such a point that certain fundamental questions can be adequately discussed; many others are still in the process of investigation. The complicated nature of calorimetric experiments, the urine analyses, and the respiration experiments have made this study possible only through the active and hearty cooperation of our associates. Most of the respiration and calorimeter experiments were made either by Mr. Thorne M. Carpenter or Mr. L. E. Emmes. The urinary analyses were made in part in the Nutri- tion Laboratory and in part in the private laboratory of one of us (E. P. J.), with frequent determinations in both places as controls. As before, the deter- minations of /5-oxybutyric acid were made by Dr. F. H. Stanwood in the Lab- oratory of Biological Chemistry of the Harvard Medical School. The routine clinical urinary examinations were made by Miss Elsie Newman, while the total nitrogen determinations and the sugar determinations by the copper- reduction method were made in the Nutrition Laboratory by Miss Alice Johnson and Miss E. B. Babcock. For the determinations of the "retention of alkali" by the kidneys in the case of a normal individual studied in connection with this report we are indebted to Dr. Gerald Blake. Nutrition Laboratory of the Carnegie Institution of Washington, Boston, Mass., June 14, 1912. hi CONTENTS. Page. Part I. — Introduction 3 Plan of research 4 Apparatus and methods 7 Determination of gaseous tensions of aveolar air 7 Ventilation of the lungs 7 Determination of sugar in the urine 8 A copper-reduction method of sugar analysis (A. W. Peters) 8 The heating power 8 The process of reduction 9 The determination of reduced copper 10 The control of all of the conditions 11 Calorimetric measurements 12 Part II. — Statistics of experiments on the metabolism of diabetics 15 Classification of cases 15 Diet 16 List of experiments with diabetics 16 Case A 17 Case B 18 Case G 19 Case H 19 Case 1 21 Case J 23 Case K 24 Case L 25 Case M 27 Case N 29 Case O 36 Case P 41 Case Q 51 Case R 55 Case S 61 Case T 63 Case U 66 Case V 75 Case W 76 Case X 79 Part III. — Discussion of results and general conclusions 85 Pulse-rate 85 Body-temperature 87 Body-weight 89 Nitrogen excretion of diabetics without food 102 Gaseous metabolism 104 Carbon-dioxide excretion in diabetes 104 Oxygen consumption in diabetes 107 v VI CONTENTS. Page. Discussion of results and general conclusions — Continued. Gaseous metabolism — Continued. Respiratory quotient 110 Indirect calorimetry 113 Composition of the alveolar air of diabetics 114 Comparison of the metabolism of diabetics with that of normal individuals. ... 117 Selection of controls 118 Evidence of the kymograph record 118 Detailed comparison of normals and diabetics 119 Comparison of the metabolism of diabetics with varying degrees of severity. . . 122 A comparison of the metabolism of fasting diabetics under varying conditions as to the intensity of the acidosis 123 The influence of a normally induced acidosis upon metabolism 125 Experiments with H. L. H 126 Statistics of experiments with H. L. H 126 Results of experiments with II. L. H 127 Experiments with H. H. A 128 Statistics of experiments with H. H. A 129 Results of experiments with H. H. A 132 Relations between a normally-induced acidosis and the observed increase in the metabolism in severe diabetes 134 A STUDY OF METABOLISM IN SEVERE DIABETES BY FRANCIS G. BENEDICT and ELLIOTT P. JOSLIN PART I. INTRODUCTION. It is acknowledged by all clinicians that the most satisfactory treatment of diabetes mellitus is obtained by a careful and intelligent regulation of the diet. The use of drugs has invariably met with but transitory success ; modern clinicians are therefore relying less and less upon such remedies and are turning their attention more definitely toward a careful dietetic regime. Accordingly it is of fundamental importance that all the knowledge possible should be care- fully accumulated regarding the uses made by the diabetic patient of the diet, the demands of the body for nutriment, and the best kinds of food to be ingested. It is of further importance that the reaction of the healthy indi- vidual to the narrow diet of the diabetic should be investigated, and this espe- cially because the studies upon acidosis have shown that the metabolism of health may be made to closely approximate that of disease by simple external influences, such as the withdrawal of all carbohydrate and the excessive admin- istration of fat. In our earlier investigation1 we endeavored to study the energy transfor- mations of diabetics without giving particular attention to the influence of the intake of food. It was believed that the energy transformations without food should first be clearly established, and then a study should be made of the influ- ence of various foods upon the metabolism of diabetics, with particular refer- ence to the effect of the so-called "oatmeal cure," which has received much attention in recent years. Although the method of study has not been materially modified in our later observations now to be recorded, our experience in the first series has enabled us to plan to better advantage each individual experiment with the purpose of making it an improvement upon those preceding. Careful atten- tion to experimental details, a most scrupulous regulation of the diet, and the technical experience acquired in the last three years in numerous experiments of this type with both normal and pathological individuals have all helped to raise somewhat the standard of accuracy and give us increased confidence in the correctness of the plan of procedure. In the earlier investigation as many individuals as possible were studied in order to determine their general energy requirement for comparison with the energy requirement of normal individuals; in the later series of observations the attempt was made to study systemati- cally and completely the individual subjects rather than to make a large number of less detailed observations on a variety of subjects. At least three of the cases reported herewith have been most carefully studied over a considerable period of time. Benedict and Joslin, Metabolism in Diabetes Mellitus, Carnegie Institution of Wash- ington Publication No. 136, 1910. 3 4 METABOLISM IN SEVERE DIABETES. The fundamentally vital conclusion of our first report, i. e., that the metabolism of diabetics was increased above normal somewhat over 15 per cent, was not readily accepted, as was, perhaps, natural, and criticisms of the methods, particularly of the method of comparison of diabetics with normals, were freely made. While we believe that the earlier results showed definitely that our conclusion was well founded, the fact that the criticisms raised were made by a number of excellent workers in the field of metabolism justified our continuing the accumulation of experimental evidence. As a result of this later work, we find ample confirmation of the conclusion drawn from our ear- lier investigations, namely, that the metabolism of diabetics was increased (about 15 per cent) above normal. The criticisms raised by a number of writers with regard to this general thesis are discussed in Part III. In our first report the principal subjects considered were the energy trans- formations and gaseous exchange of diabetics. Incidentally evidence was presented regarding the dextrose-nitrogen ratio and the ingestion of food. In discussing the influence of the ingestion of beefsteak upon the metabolism of one of the subjects we were entirely at fault in our statements regarding the dextrose-nitrogen ratio — an error that has been clearly pointed out by Lusk.1 On the other hand, we see no reason to alter our opinion there expressed that with diabetics the dextrose-nitrogen ratio is at best a very uncertain factor, and unless a rigidly strict carbohydrate-free diet be adhered to for several days, the dextrose-nitrogen ratios have little, if any, significance. Neither do we see any reason for changing our belief that the adherence to a strictly carbohydrate-free diet in severe diabetes during a period of several days is a procedure very much to be questioned. This being the case, the significance of the dextrose-nitrogen ratio for diagnostic purposes has not, we believe, the importance that has been ascribed to it by other writers. Plan of Research. The original plan of research involved the study of a number of different problems. Of these, the first was the accumulation of further evidence with regard to the increase in metabolism noted with practically all of the diabetics previously studied. The difficulty incidental to a satisfactory comparison of diabetics with normal subjects was pointed out in great detail in the first report, and while we firmly believe that the evidence there set forth showed that on the average there was an increase in metabolism of 15 per cent in diabetes over health, nevertheless plausible arguments could be brought forward indicating that the comparison of diabetics with normal subjects might not be scientif- ically sound or correct. The disproportion between the body-weight and the body-surface of the two classes of subjects, the differences in the kinds of food eaten, the possibility of a larger protein katabolism with diabetics, and the error of drawing deductions from one individual as normal and another indi- vidual as a diabetic are by no means convincing arguments against our thesis; 'Lusk, Science, Si, p. 433. INTRODUCTION. 5 nevertheless they remain as possible and plausible criticisms of the conclusion drawn from our earlier work. The later experiments were therefore planned further to clarify the situation and to remove cause for criticism. It also became necessary to secure additional data with regard to nor- mal individuals. During the progress of this investigation a large number of normal subjects have been studied in connection with the respiration researches in this laboratory, and hence the data are continually increasing. They will here be presented in abstract to show normal metabolism under conditions of experimentation similar to those used with the diabetics studied. Furthermore, a study of the influence of the ingestion of carbohydrates upon the metabolism of diabetics was deemed of great importance. The early investigations of Nehring and Schmoll,1 Magnus-Levy,2 and Leo3 indi- cated that with the ingestion of carbohydrates there was frequently no increase in the respiratory quotient. Similarly there was apparently no great increase in the sugar excreted in the urine; at least the increase was not sufficient to off- set the excess carbohydrate ingested; and while there may have been a posi- tive carbohydrate balance on that particular day, the respiratory exchange did not indicate a combustion of carbohydrates, since it was not materially higher than during fasting. This presented an anomalous situation in that while carbohydrate was ingested in large amounts, it apparently was neither burned nor excreted, and the question therefore immediately arose as to where this carbohydrate had disappeared. For the purpose of throwing light upon the problem a number of experiments were made in this laboratory in which vari- ous carbohydrates were ingested, chiefly levulose and oatmeal, the latter being used particularly on account of the great interest in the so-called "oatmeal cure" for diabetes. Under these conditions the metabolism was studied very exactly in short periods following the ingestion of various amounts of carbo- hydrates in order to determine whether there was an increase in the metabolism or a variation in the respiratory quotient which would indicate a difference in the character of the metabolism as the time progressed. In this way it was hoped that some light would be thrown upon the character of the metabolism and the apparent storage of carbohydrate. In at least one or two of the earlier experiments we found an apparently abnormal reaction to the ingestion of protein. With normal individuals the ingestion of protein, particularly in the form of beefsteak, shortly produces a rise in metabolism, i. c, the "specific dynamic action" of the protein. With one of the cases previously reported (Case A) this rise in metabolism did not appear; it was therefore suggested that possibly when the body was extremely glycogen-poor the non-nitrogenous portion of the protein molecule split off when the steak was ingested and was deposited as glycogen instead of being burned, and that the specific dynamic action of the protein might be due to the rapid combustion of the non-nitrogenous parts of the protein molecule. It •Nehring and Schmoll, Zeitschr. f. klin. Med., 1897, 31, p. 59. 2Magnus-Levy, Zeitschr. f. klin. Med., 1905, 56, p. 86. "Leo, Zeitschr. f. klin. Med., 1891, p. 101. 6 METABOLISM IN SEVERE DIABETES. seemed important to verify this observation, if possible, by further evidence; hence a number of experiments are here included in which beefsteak was ingested. Our earlier experiments also suggested that during severe acidosis, when the patients were clinically in the worst condition, there was a higher meta- bolism. The relationship between the acidosis and metabolism was by no means clearly established or, indeed, recognized in our earlier report, but as these investigations progressed, it became desirable to make a particular study of the relationship between the degree of acidosis and the total metabolism. This has been given a special and prominent part in the later research, and the relationship between the degree of acidosis and the total metabolism has proved to be one of the most interesting points in this study. It was possible so to adjust the diet of the diabetics as to secure with the same subject degrees of acidosis varying from very severe to very light; hence we have here an opportunity of comparing the metabolism of a diabetic with a severe acidosis with his metabolism when without an acidosis. This has proved to be a great advantage, since the results obtained are more strictly comparable than those obtained when comparing the metabolism of a diabetic with a severe acidosis with that of a normal subject without acidosis. The general plan of the research as outlined in the preceding pages was that upon which the year's work was based, but it became clear as time went on that the program must be so restricted as to settle absolutely one or two fundamentally important points rather than to attempt to secure conclusive evidence on so many different phases of the question as are here outlined. While it was thoroughly practicable to secure evidence with regard to the increased metabolism during different degrees of severity of diabetes, and while the relationship between the severity of diabetes and the metabolism began to be strikingly apparent, nevertheless, for experiments on the ingestion of oat- meal, carbohydrates, and beefsteak, both a certain type of case and a certain type of experimental plan were necessary. For this reason it was more diffi- cult to secure patients for this series of experiments than for a study of the gen- eral and broader questions ; hence, while a considerable amount of data has been accumulated on the points here raised, we do not presume in this report to discuss in any way the questions with regard to the influence of the inges- tion of food, the dextrose-nitrogen ratio, the influence of the ingestion of car- bohydrates and sugars upon the positive carbohydrate balance, and similar questions, except in a very general way incidental only to their effect upon the question of the relation between the severity of the diabetes and the general metabolism. On the other hand, it seems desirable to present in this report all of the statistical data for the experiments thus far made, so as to make them available for clinicians and for scientists interested in metabolism during dia- betes. A complete discussion of the data, together with additional material, will be given in a subsequent publication. Consequently the final plan of work considered in this report will be first, the evidence with regard to the increased metabolism during diabetes; second, INTRODUCTION. 7 the relationship between the severity of diabetes and the degree of increased metabolism; and third, the influence of a carbohydrate-free diet upon the total metabolism of normal individuals. Incidentally the accumulated data jus- tify the discussion of the factors affecting body-weight. In connection with the research a modified method for the rapid quantitative determination of sugar in the urine has been elaborated which is described at some length. Apparatus and Methods. The apparatus and methods used in the conduct of this research are essen- tially those described in the earlier publication.1 The bed calorimeter has been more extensively employed than has the chair calorimeter, the latter being used for only three experiments in this connection. On the other hand, the respiration apparatus, which has continually undergone minor modifica- tions in methods of technique and facility of operation, though not in principle, has been extensively used.2 In most instances it has been found that observa- tions made with this apparatus are fully as valuable and essentially the same as are the more time-consuming and expensive observations with the respi- ration calorimeter; hence we have no doubt of the wisdom or propriety of com- puting the energy transformations from the gaseous metabolism as determined on the respiration apparatus. The respiration apparatus has the special advantage in that with it experiments can be made rapidly, and thus the time relations of the metabolism, particularly after the ingestion of food, can be more exactly and rapidly studied than in experiments with the respiration calorimeter, with the longer periods of 45 minutes. DETERMINATION OF GASEOUS TENSIONS OF ALVEOLAR AIR. Owing to the interesting observations of Beddard, Pembrey and Spriggs,3 it seemed advisable in certain instances to determine the composition of the alveolar air in severe cases of diabetes. Accordingly, with three subjects (I, N, and Q) observations were made of the carbon-dioxide tension, and at times the oxygen tension, of the alveolar air, these being in large part carried out through the kindness of Mr. H. L. Higgins, of the laboratory staff, who used the Haldane gas-analysis apparatus4 and both the Haldane and the Plesch methods for determining the alveolar air.5 VENTILATION OF THE LUNGS. Using an Elster meter of the type employed by Zuntz, and a pair of Zuntz valves, the ventilation of the lungs per minute was also occasionally deter- mined with one of the subjects (N). Benedict and Joslin, loc. tit., p. 15. 2 A detailed description of the apparatus, showing its use and technique, has just been published in the Deutsch. Archiv. f. klin. Med., 1912, 107, p. 156. 3Beddard, Pembrey and Spriggs, Proc. Physiol. Soc, Journ. Physiol., 1908, 37, p. 39. 4Haldane, Methods of air analysis, London, 1912. 6Haldane and Priestley, Journ. Physiol., 1905, 32, p. 225; Plesch, Zeitschr. f. Exp. Pathol, u. Ther. 1909, 6, p. 380. 8 METABOLISM IN SEVERE DIABETES. DETERMINATION OF SUGAR IN THE URINE. General dissatisfaction with the methods commonly used for the estima- tion of reducing sugars was expressed in our first report and it was there pointed out that the newly-introduced Citron method, Avhile of value from the clinical standpoint, was of little value from the standpoint of exact scientific research. In our new experiments the Citron method was used for only the earlier deter- minations of sugar. Those made in the private laboratory of E. P. J. wrere for the most part carried out by a method suggested by Dr. Stanley R. Benedict,1 of the Cornell University Medical College. For the more recent analyses, especially those made in connection with the best experiments, a highly improved method wras used which was devised by Dr. A. W. Peters, of the Nutrition Laboratory. After a most careful study of the conditions affecting reduction, temperature conditions, and concentration, Dr. Peters developed a method using the old Fehling or Allihn solution of copper sulphate and the alkaline tartrate, and has determined the amount of unreduced copper remain- ing in the solution by a titrimetric method. By this means the most accurate determinations of sugar are possible, this being without doubt the most exact method of sugar determination that has thus far been devised. While the method may be readily used in hospital laboratories, it will probably never be acceptable for private practice. Inasmuch as it represents the most scientific attempt to study quantitatively the method of sugar reduction, it is given herewith in considerable detail. For this presentation of the method we are indebted to its author, Dr. A. W. Peters. A COPPER-REDUCTION METHOD OF SUGAR ANALYSIS (A. W. PETERS). The construction of this method of sugar analysis is based upon precedi ng developments for (1) the accurate volumetric determination of copper in alka- line tartrate liquids; (2) the standardization of the heating power used; and (3) the determination of constant and controllable conditions for the reduction. For more detail reference must be made to the original descriptions.2 When the apparatus and reagents have once been prepared a single determination occupies from 12 to 15 minutes. The Heating Power. A heating apparatus should be set up of such power that it will heat 60 c.c. of distilled water under described conditions through the temperature interval of 35° to 95° C. in 120 seconds =•= 5 seconds. The water is placed in an Erlenmeyer flask of the best Jena glass, with a capacity of about 200 cm. and a basal diameter of about 6 cm., so that the depth of the liquid will be about 18 mm. The flask is partially closed with a two-hole stopper, one hole of which xDr. S. R. Benedict's method is based upon the reducing action of sugars upon an alkaline sulphocyanate solution of copper.. See Benedict, Journ. Biol. Chem., 1911, 9, p. 57. 5Peters, Amos W., The sources of error and the electrolytic standardization of the iodide method of copper analysis, Journ. Am. Chem. Soc, 1912, 34, pp. 422; and A critical study of sugar analysis by copper-reduction methods, Journ. Am. Chem. Soc, 1912, 34, p. 928. INTRODUCTION. 9 carries a thermometer. The thermometer should not have a greater error at the boiling-point of water than ± 0.5° C. when the barometric pressure is taken into consideration. The lower end of the thermometer should be placed at a distance of about 2 mm. from the bottom of the flask and the region of the stem above 35° C. should extend above the upper surface of the stopper so as to be plainly visible. This flask should be placed in the center of a plate of unper- forated asbestos gauze carried by a ring-stand so that it can be raised or low- ered. The distance between the burner and the asbestos should always fall within the limits of 3 to 5 cm., thus avoiding a long flame which would be easily affected by air-currents. Room-temperature and freedom from drafts should prevail. If the latter condition can not be provided the heating apparatus may be wholly or partially protected by a cylindrical hood of sheet metal or asbestos. The flask as above described containing 60 c.c. of distilled water is placed on the asbestos and the time observed that is required for the mer- cury to rise from 35° to 95° C. The rough adjustment to 120 seconds is made by regulating the flow of gas so as to change the power of the flame with the position of the asbestos constant at 4 cm. The finer adjustment is made by moving the asbestos plate toward or away from the burner within the limits of 3 to 5 cm. The conditions are not properly adjusted until repeated determina- tions of the time give constant results within limits of error of only a few seconds. At 120 seconds the standard heating power here adopted has been established. The Process of Reduction. The reduction mixtures should be placed in the same kind of flasks, with the same stopper, thermometer, etc., and with the same conditions of heating power as were used for the standardization of the latter. The volume of the reduction mixture is always 60 c.c. It consists of 20 c.c. of Allihn's alkaline tartrate solution plus 20 c.c. of Fehling's copper sulphate solution plus 20 c.c. of distilled water for a blank determination, or, in the case of sugar analysis, of an aqueous sugar solution with enough distilled water added to make a final volume of 60 c.c. The Fehling-Soxhlet solution contains 34.639 grams of pure crystallized copper sulphate in a volume of 500 c.c, but the purity of the copper sulphate is more important than its exact weight. Since its correct copper content can not with reliability be deduced from the formula CuS04.5H20, this value is found by means of standardized thiosulphate as described on page 11 for the "basis titration." The Allihn alkaline tartrate solution contains 173 grams of sodium-potassium tartrate (Rochelle salt) and 125 grams of potassium hydrox- ide in a volume of 500 c.c. For a determination of sugar the flask containing the reduction mixture is placed on the heating apparatus and the time is observed, but in this case the reckoning begins only when the thermometer reaches 95° C. The flask should stand undisturbed in the center of the asbestos gauze until the expiration of 20 seconds after the temperature of 95° C. has been reached. It is then promptly removed, with the stopper and thermometer still in place, and twirled for a few 10 METABOLISM IN SEVERE DIABETES. seconds under the tap in order to cool the mixture rapidly, but only to a few degrees under the boiling-point, since the mixture is to be filtered hot without delay. A Gooch crucible should have been previously prepared with a very heavy filter, so that suction will draw water through it only slowly. Avery close and satisfactory filter may be made by placing a layer of pure talcum powder between two layers of asbestos in the Gooch crucible. A good filter may also be made by substituting for the crucible a calcium-chloride drying-tube car- ried by a one-hole rubber stopper. This is packed first with glass-wool and upon this is made, in the bulb of the tube, a very heavy mat of asbestos, which may also be made as close as desired by means of talcum. The same filter is used many times, the precipitate being removed from it by nitric acid (original specific gravity of 1.42) which has been diluted with, one-half of its volume of distilled water. This requires less time than making a new filter for each deter- mination. The suction-flask should have a capacity of about 200 c.c, so that a titration on the filtrate can be performed in the suction-flask, thus avoiding a transfer of the liquid. Not more than 15 to 20 c.c. of wash- water should be used, as it all remains as part of the final volume at the end of titration. This volume should not exceed 120 c.c, to which volume the concentration of the reagents used for the determination of copper has been adjusted. For the inexperienced it is recommended to make a rough measurement of the final volume of the liquid obtained at the end of titration. The Determination of Reduced Copper. The amount of copper that has been reduced under the above conditions is a quantitative index of the amount of sugar originally present. The reduced copper may be determined directly upon the precipitated cuprous oxide or residually by the determination of the amount of copper still remaining un- reduced in the alkaline filtrate. The amount of copper in the filtrate may be determined either electrolytically for control or volumetrically by the iodide method. For rapidity combined with accuracy the iodide method is recom- mended, but only when it has first been controlled for the conditions under which it is to be used. For the alkaline tartrate copper solutions which are here used (i. e., Allihn's alkaline tartrate, etc.) this control has been satisfac- torily made. The residual method for the determination of the reduced copper may therefore be regarded as certainly the most rapid as well as accurate when the iodide method is applied as described in the previous references and under the following provisions : (1) The thiosulphate solution should have a value between 12.5 and 13 mg. of copper per cubic centimeter. It should be standardized preferably against the same stock solution of copper which is to be used in the sugar analyses, and the true copper value of this solution should be determined elec- trolytically. If , however, the stock solution is made of chemically pure copper sulphate there will be no appreciable difference between the standard value of the thiosulphate determined by this electrolytically controlled solution, and the value obtained by the nitric-acid-talcum procedure above referred to, using INTRODUCTION. 11 pure metallic copper, which procedure may then be substituted for electrolytic determination on the stock solution. The standardization may appropriately be made on 20 c.c. of the stock solution, which is the same volume as will be used in sugar determinations, and with a final volume at the end of titration in no case exceeding 120 c.c. This volume should contain 20 c.c. of concentrated acetic acid and about 7 c.c. of saturated solution of pure potassium iodide. The thiosulphate value of 20 c.c. of the stock solution of copper sulphate deter- mined in simple acetic-acid solution is designated as the "basis titration," and is of fundamental importance for subsequently testing the constancy of solu- tions and of conditions even when it is not used for the purpose of standardi- zation. A solution of pure copper sulphate will remain at a constant standard value, but the thiosulphate will change somewhat if much exposed to air and especially to light. (2) The alkaline filtrates from sugar determinations, whose volume must not exceed 75 c.c, should be acidified with concentrated sulphuric acid. The amount of acid used should be such that the thiosulphate value of a blank determination, in which the unheated reduction mixture of 60 c.c. previously described contains all the reagents but no sugar, will be identical with the "basis titration." This amount has been found by experiment, as described in the previous references, to be 4 c.c. of concentrated sulphuric acid, but should be verified or changed if necessary. After the mixture has been acidified and cooled to 20° C, potassium iodide is added to the amount of 6 to 7 c.c. of an aqueous solution that is saturated at room-temperature. The iodine which is evolved is titrated at once with thiosulphate, using a solution of soluble starch as an indicator near the close of the titration. The end point should be determined by the "spot test," espe- cially in the presence of urinary or other coloring matter, and may be verified by immediate back titration with a drop of iodine solution of about the same concentration as the thiosulphate. (3) For the residual method a blank determination is always necessary. The assumption that there is no self-reduction of reagents may lead to error, although by the present method pure and especially freshly prepared reagents show a negligibly small self-reduction. The blank value is obtained with the reduction mixture of 60 c.c. previously described but without the presence of sugar. This is heated and filtered and treated in all respects as when a deter- mination of sugar is made. From the thiosulphate value of the copper thus found unreduced is subtracted the value found in the same way in a subsequent sugar analysis. This thiosulphate difference evidently shows the amount of reduced copper due to the action of the sugar. The difference may be con- verted into milligrams of copper by means of the standard value of the thiosul- phate previously obtained, and the corresponding amount of sugar may be found from a table of reduction values. The Control of All of the Conditions. All of the conditions of this method and the technique of the operator can be controlled by the use of a standard solution of pure dextrose. The results 12 METABOLISM IN SEVERE DIABETES. thus obtained are a standard of comparison to determine whether in a given case the conditions have been correctly adjusted for the use of the values for dextrose which are recorded in table 1. From these controls the values for 50 and 100 mg. obtained from a 0.5 per cent or 1 per cent standard solution of pure dextrose were usually selected for the first tests. The quantities to be Dextrose compared should be the qq ratios, as the limits of error of these are evi- dent from the table. er Table 1. — Reduction values for dextrose. I. II. III. Dextrose- I. II. III. Dextrose- Dextrose. Copper. copper ratio.1 Dextrose. Copper. copper ratio.1 mg. mg. mg. mg. 1 1.2=1=0.13 0.833 60 115.5 0.520 2 2.8±0.1 .714 70 134 4 .521 5 8.2=«=0.14 .610 80 152.9 .523 8 13.8±0.1 .580 90 171.0 .514 10 17.4±0.3 .575 100 191.6±0.35 .522 IS 27.7±0.5 .542 110 208.9==0.15 .527 20 37.1±0.2 .539 120 228.1 .526 25 4S.1±0.4 .520 135 255.0 .529 30 57.3==0.05 .524 150 280.8±0.6 .534 35 67.6=1=0.13 .518 165 306.8 .538 40 76.2±0.1 .525 180 330.5±0.1 .545 45 S6.0==0.1 .523 200 349.6 .572 50 96.0±0.5 .521 'Average factor between 4S and 192 mg. copper, 0.522. This abbreviated table is to be used by means of its ^ " ratios, which are factors for converting the reduced copper to its corresponding amount of dextrose. The most important property of these ratios from a practical standpoint is that they change their value slowly in comparison with the amounts of reduced copper to which they pertain. For amounts of reduced copper between 48 and 192 mg. no table is necessary, as the ratios fluctuate about a mean common factor of 0.522. In all other regions of the table it should be observed that the slow change of the ratios will enable the operator to interpolate mentally the required ratio for any amount of reduced copper lying between two adjacent values of column n. For the very small amounts of dextrose the third decimal place has no practical significance. CALORIMETRIC MEASUREMENTS. It is a matter of much regret and no little chagrin that during the greater part of the time the new experiments on diabetics were being carried out the results obtained with the bed calorimeter were vitiated by some then unknown factor, so that the accuracy of the heat measurement in about two-thirds of the experiments is seriously questioned. In about one-third of the experiments we know the results to be satisfactory and accurate, but we have discarded all of the data rather than select arbitrarily one-third of the material for presen- tation. The index of this inaccuracy is to be found in abnormal relations between the carbon-dioxide production, the oxygen consumption, and the heat produc- INTRODUCTION. 13 tion. As has been pointed out in the earlier report,1 the relationship between the oxygen consumption and calories and the carbon-dioxide production and calories was a relatively constant one for diabetics, that is, approximately 3.3 calories for every gram of oxygen consumed or carbon dioxide produced. On the completion of the later experiments it was ascertained that these ratios were abnormally low, both for oxygen and for carbon dioxide, while the respiratory quotients as finally determined were in full accordance with the earlier work. A further examination of the results, together with a series of control experiments, showed that the apparatus measured the heat radiated from the body most accurately, and the error was finally found to be in the determination of the water-vapor. It was just at this time that fundamental alterations in the method of determining the water-vapor were being intro- duced, and unquestionably the errors in heat measurement can be directly ascribed to this. Under these conditions, therefore, we deem it inexpedient to discuss in this report the heat as measured, but as all of the control experiments point toward the highest degree of accuracy in the measurement of the carbon dioxide and oxygen, we can confidently base our discussion upon these two factors. Since in an earlier publication the relationships between oxygen con- sumption, carbon-dioxide production, and heat production were so thoroughly studied, and since these well-known relationships play an important role in so-called "indirect calorimetry," the data for the gaseous exchange in this new series of experiments have an increased significance. 'Benedict and Joslin, loc. cit., p. 219. PART II. STATISTICS OF EXPERIMENTS ON THE METABOLISM OF DIABETICS. These experiments were all made with patients from the private practice of one of us. Frequently the patients were placed in the New England Deaconess Hospital, within a short distance of the laboratory, and the diet strictly controlled. Others lived in or near Boston and made periodic visits to the laboratory for experimental purposes. CLASSIFICATION OF CASES. The cases were divided into groups with particular reference to severe, moderately severe, and light diabetes. The basis for this classification has been essentially that outlined in our previous publication, namely, under severe diabetes were classed all those who failed to become sugar-free, even though all carbohydrates except the green vegetables were excluded from the diet, or those who became temporarily sugar-free upon vegetable days which were fol- lowed by a low quantity of protein in the diet. The cases in this group invari- Table 2. — Description of cases used in the studies on diabetes. No. of case. Desig- nation of case. Sex. Age at onset. Onset. Present condition. Duration. 220 2S3 246 319 373 201 235 310 295 289 210 228 177 281 194 441 371 344 336 381 332 320 333 317 A B C D E F G H I J K L M N O P Q R S T U V w X M. F. M. M. M. M. M. F. M. M. M. M. M. M. F. M. M. M. M. M. F. M. F. M. 39 39 28 31 17 22 31 17 13 18 44 21 47 12 13 16 13 40 46 41 35 35 16 32 Gradual, 1900 Gradual, Dec. 1908. Acute, Sept. 1908.. . Mar. 1909 Sept. 1907. Died, Aug. 24, 1910 Died, coma, Apr. 13, 1910. Died, coma, Dec. 8, 1909. Died, coma, Jan. 13, 1910. Died, coma, Oct. 13, 1909. yrs. mos. 10 .. Jan. 1908 Died, pneumonia (?), Feb. 1910 {^lSS&&Jaa:.190.1:. }D-d. coma, May 4, 1910... 1889 1900 Feb. 1908 Nov. 1907 July 1908 1900 Julvl909 Feb. 1908 Dec. 1910 Sept. 1909 Nov. 1903 Died, coma, May 3, 1910 Died, May 1912 Died, Sept. 17, 1912 Died, coma, Nov. 4, 1910 Active work, Nov. 11, 1912 Active work, Nov. 11, 1912 Died, coma, Feb. 16, 1911 Died, coma, Dec. 10, 1910 Died, coma, Nov. 5, 1911 Died, coma, Mar. 14, 1911 Died, pulmonary tuberculosis, Mar. 14, 1912 Died, coma, Oct. 19, 1910 Died, coma, Mar. 5, 1911 . 1899 Sept. 1908 Apr. 1909 ] Died, coma, Aug. 11, 1911 July 1909 Died, Feb. 6, 1911 Nov. 1908 Comfortable, Nov. 11, 1912 July 1903 Comfortable, May 8, 1912. . 5 21 12 4 3 4 12 1 2 11 2 2 1 4 3 4 3 10 1 1 4 7 10 11 6 6 4 7 10 ably showed a minus carbohydrate balance when the diet was considerably restricted. The second criterion for determining the severity of the case was the presence of an acidosis. Under moderately severe diabetes were classed those who became sugar-free and showed a positive carbohydrate balance, or with whom the acidosis was either very slight or absent. Only one case of light diabetes was included in the study. This was a fat man, Case M, who 15 16 METABOLISM IN SEVERE DIABETES. was able to assimilate at least 100 grams of carbohydrate per day. The num- ber of cases of moderately severe and light diabetes are so few as to make them a secondary consideration in this discussion. A brief description of the cases is given in table 2. DIET. The diet of the patient was arranged in accordance with that described in the previous report.1 By strict diet is meant foods containing no carbo- hydrates such as meat, fish, eggs, and their derivatives, oil, butter, coffee, and tea. The vegetables used contained varying amounts of carbohydrates, ranging between 5 and 10 per cent; but the total amount of carbohydrates given during the day in the form of cooked and uncooked vegetables closely approximated and is estimated at 10 grams. LIST OF EXPERIMENTS WITH DIABETICS. The experimental data from which the deductions in this book are drawn were obtained from a large number of cases with a considerable number of experiments. A list of the experiments in the second series, together with the number of periods, is given in table 3. Table 3. — -List of experiments with diabetics lying in bed, 1910-1911. Case. Calorimeter. Respiration apparatus. Without food. With food. Without food. With food. No. of experi- ments. No. of periods. No. of experi- ments. No. of periods. No. of experi- ments. No. of periods. No. of experi- ments. No. of periods. A H I K L M N o P Q R s T U V vv x Total. . T i Y 7 r 2 1 2 2 13' '3' 2 '3' 21 Y 6 2 '4' 6 '"9 Y 2 Y 3' Y 6 '4' 1 Y 1 1 Y 5 Y Y 1 2 1 3 7 3 4 Y 14 Y io' 5 7 3 Y Y 2 6 Y 1 '7' Y Y 8 27 Y 4 31' 21 62 6 19 23 65 21 78 1 These experiments with Case X were made with the subject sitting in the chair calorimeter. As an indication of the amount of experimental material available for deductions, a summarized list of all our experiments to date is also given in table 4. 1 Benedict and Joslin, loc. cit., p. 29. STATISTICS OF EXPERIMENTS. 17 Table 4. — Experiments with diabetics, 190S-1911. 1908-1910 (13 cases). 1910-1911 (17 cases). 1908-1911 (24 cases).1 No. of experi- ments. No. of periods. No. of experi- ments. No. of periods. No. of experi- ments. No. of periods. Subjects sitting in chair calorimeter: Without food 30 14 11 26 106 45 37 102 3 18 0 23 21 9 53 19 65 78 33 14 29 6 49 21 115 45 90 19 187 78 With food Subjects lying in bed calorimeter: Without food With food Respiration apparatus (lying): Without food With food Experiments with six of these cases are reported both in this publication and in Publication No. 136. CASE A. DESCRIPTION OF THE CASE. Male; born May 2, 1860; single; traveling salesman; developed diabetes in 1900; came under our observation in October 1908; died August 24, 1910. Full details regarding the history of this case and its treatment previous to 1910 may be found in an earlier publication.1 Later history of the case. — During the winter of 1909-10 the patient was in a comfortable condition, and on March 1, 1910 felt quite well. He reported at this time that he had been able to work and that his friends considered that he looked better than he had for two years. The quantity of urine varied from 2.5 to 3 liters. His diet contained approximately 60 grams of carbohydrate, with 8 grams of sodium bicarbonate. In June 1910 abscesses developed in the right ear, and later a furuncle in the occipital region. In the latter part of July there was considerable edema of the right ankle, but this decreased when the sodium bicarbonate was discontinued in the early part of August. In this month the diet was relaxed considerably, the patient eating cantaloupe and watermelon at noon and peaches at night. Constipation was a troublesome symptom, but the strength was fairly good. A physical examination made August 5 showed a weight of 48.6 kilos, without clothes; temperature, 99.1° F.; blood-pressure, 150; pulse-rate, 108; heart of normal size and free from mur- murs; liver not enlarged; pupils equal and reacting to light; knee-jerks normal; moderate edema of the ankles. In the upper right chest a few rales could be heard extending down to about the fourth interspace. There was also a slight cough. Later, August 8, 1910, the findings in the chest were confirmed. The patient was last seen on August 22, 1910, soon after his return from a visit in the country, during which he had suffered from gastric indigestion. As a result of this he had ceased eating, omitted the sodium bicarbonate, and symp- toms of coma appeared, as was evident from his report of difficult breathing upon August 20. He was slightly more comfortable on August 22, but air- hunger was manifest. At this time the pulse-rate was 100, the temperature normal; the acetone odor was absent from the breath. The patient died on August 24, 1910. Urine data. — Only a few observations were made of the urine, and unfor- tunately these are not of great significance, as the patient's diet was not under Benedict and Joslin, Metabolism in diabetes mellitus, Carnegie Institution of Wash- ington Publication No. 136, 1910, p. 30. 18 METABOLISM IN SEVERE DIABETES. control. August 4-5, 1910, the specific gravity was 1.024, with diacetic acid present, 0.11 per cent of ammonia, 0.36 per cent of nitrogen, and 2.8 per cent of sugar by copper reduction and 2 per cent by rotation. August 9-10, 1910, the total amount of urine was 1625 c.c. with 5.64 grams of nitrogen and 64.3 grams of sugar. August 10-11, 1910, the total amount of urine was 1380 c.c, with a slight trace of albumen, and 3 per cent (41 grams) of sugar. Diacetic acid was also present. The reaction was acid in all instances. The acidosis at this time was far less than during most of the year 1909, and much of October and November 1908. The decrease in sugar and in ammonia may bear a relation to the development of active tuberculosis in the lungs. Case R is, however, a more striking example of this feature. EXPERIMENTS WITH CASE A. In the previous publication, 16 calorimeter experiments were reported with this subject. In all but one of these the chair calorimeter was used. The only experiment with the subject reported here is a respiration experiment. The vital statistics are as follows: Date of birth, May 2, 1860; height, 171 cm.; body-weight without cloth- ing during experiment, 46.1 kilos. Respiration Experiment No. Al. Date, August 10, 1910. Body-weight without clothing, 46.1 kilos. The subject came to the laboratory the morning of the experiment, fasting, and lay down upon the couch at 8h 05m a. m. The experiment began at 8h 26ra a. m., continuing for three periods, 11 to 15 minutes in length, with intermis- sions of 15 and 20 minutes. The experiment was without incident. The results are given in table 5. Table 5. — Results of respiration experiment No. Al. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse- rate. Average respiration rate. Aug. 10, 1910: 8h 2Gm a.m 8 52 a.m 9 26 a.m Average min. sec. 10 47 13 49 lj 7 c.c. 136 133 131 c.c. 'm 187 6!7i .70 71 68 68 13 13 13 1133 U88 .71 69 13 1 Carbon dioxide eliminated per kilogram per minute, 2.89 c.c.; oyxgen absorbed per kilogram per minute, 4.08 c.c. CASE B. DESCRIPTION OF THE CASE. Female; born September 9, 1869; married; doing her own housework; first recognized symptoms of diabetes mellitus at the age of 39, December 25, 1908; came under our observation September 1909; died in coma April 13, 1910. The earlier history of this case, with the results of experiments made with her, has previously been published.1 No further metabolism experiments have been made with this subject. The patient gradually failed during the spring of 1910. Her weight on leaving the hospital March 3, 1910, was 40.7 1 Benedict and Joslin, loc. cit., p. 61. STATISTICS OF EXPERIMENTS. 19 kilos., without clothes. During the latter part of March she was troubled with indigestion for which her physician gave calomel, and a sore mouth resulted. She continued to lose flesh, had considerable distress from food, with anorexia and sleepiness. April 1, 1910, moderate jaundice developed, and she died in coma upon April 13, 1910. Death was preceded by a convulsion, which was followed by hemiplegia. The urine was not examined after March 1, 1910. CASE G. DESCRIPTION OF THE CASE. Male; born December 1874; married; broker; sugar in urine, January 3, 1901; came under our observation February 13, 1909, but the case had pre- viously been closely studied for many years; died in coma May 4, 1910. Full details regarding the history of the case and the results of the three calorimeter experiments made with him have been given in the earlier publica- tion.1 No new experiments were made with this subject. During the succes- sive 15 months he gradually failed, despite an increase of carbohydrates in his diet up to 100 grams and large doses of sodium bicarbonate. The urine remained acid in reaction until death. Albumen was present on May 2, 1910. The urinary record is given in table 6. Table 6 — Clinical chart — Case G. Date. Volume of urine. Specific gravity. Nitrogen. Aran Total. lonia. NHj-N Total N Sugar by copper reduction. Carbo- hydrates in diet. Carbo- hydrate balance. Sodium bicar- bonate. Body weight without clothing. 1909. Oct. 23 1910. May 2 ex. 5900 5190 6260 1027 1027 1019 gms. 18.1 20.0 23.8 gms. 2.6 3.4 5.2 p. ct. 11.8 14.0 18.0 qms. 183 151 157 gms. 103 10± gms. -80 gms. 45 45 75 kilos. 59.5 58.0 (') 'Weight without clothing, Apr. 20, 1910, 53.1 kilos. CASE H. DESCRIPTION OF THE CASE. Female; born May 19, 1872; single; nurse; developed diabetes at 17 years of age; sugar found in urine at 20 years of age; came under our observation January 17, 1910; died in coma May 3, 1910. The details of the history of this case may be found in the earlier publication previously referred to.2 Later history of the case. — During the spring of 1910 the patient continued her occupation as superintendent of nurses of a large out-patient department for tuberculosis. Fair health and strength were maintained. On March 25 the patient had a body-weight of 54.5 kilos., and was reported as being better than she had been for years. On April 11 an examination showed that the lungs were normal, but the patient was suffering from pains in the legs. The urine was pale in color, acid in reaction, and with a very slight trace of albumen. The urinary record is given in table 7. The patient suddenly decided to go to Europe and would not be dis- suaded. On the first day out, as rough weather was encountered, she became seasick, and for the next three days was unable to take food; thereupon coma developed and death ensued May 3, 1910. Attention is called to the similar period of starvation preceding coma which took place in Case A. It would Benedict and Joslin, loc. cit. p. 111. ! Benedict and Joslin, loc. cit., p. 118. 20 METABOLISM IN SEVERE DIABETES. appear that whenever the store of available carbohydrates in the body is exhausted, coma develops. For this reason carefully instructed diabetic pa- tients are cautioned to guard against sudden inroads upon their scanty store of glycogen by increasing the quantity of carbohydrates in their diet whenever signs of indisposition appear. These patients, Case A and especially Case H, knew this rule, but they were unable to retain any food. Table 7. — Clinical chart — Case H. Date. Volume of urine. Specific gravity. Diacetic acid. Nitrogen. Sugar. Carbo- hydrate in diet. By copper reduction. By rota- tion. 1910. Mar. 22-23 c.c. 3600 3900 3420 2970 860 i023 1024 + + + gms. i5'2 10.7 12 6 2.7 gms. HO 135 104 26 gms. 130 140 123 gms. 'ioo± 24-25' Apr. 10-11 21-22.. 222 NH3-N 'Ammonia, 3.1 gms.; = r— r; =16.8 per cent.; NaHC03 taken, 4 to 8 gms. iotal N 2 From 7 a.m. to 1 p.m. EXPERIMENTS WITH CASE H. Five calorimeter experiments and one respiration experiment with this subject were reported in the previous publication. One experiment with the bed calorimeter is reported here. The vital statistics were as follows: Date of birth, May 19, 1872; height, 159 cm.; body-weight without clothing during experiment, 54.1 kilos. Table 8. — Measurements of metabolism. — Calorimeter experiment No. HI. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Apr. 22, 1910: 1 9h 23m a.m. to 10h 23m a.m ... . 10 23 a.m. 11 23 a.m 11 23 a.m. 12 29 p.m Total, 3 hr3. 6 mins.2 gms. 18 6 20.0 20.8 c.c. 158 170 161 gms. 17.2 19.6 20.3 c.c. 201 223 215 0.79 .74 .75 87 85 86 23 23 23 59.4 163 57.1 215 0.76 86 23 1 Subject drank a cup of black coffee at 7 a.m. 2Carbon dioxide eliminated per kilogram per minute, 3.01 c.c; oxygen absorbed per kilogram per minute, 3.97 c.c. The urine collected between 7 a. m. and 1 p. m. amounted to 860 c.c. and contained 2.73 grams of nitrogen and 25.6 grams of sugar. Sublingual body-temperature at beginning, 98.4° F.; at end 98.2° F. Calorimeter Experiment No. HI. Date, April 22, 1910. Body-weight without clothing, 54.1 kilos. On the day of the experiment the subject ate no breakfast before coming to the laboratory, taking only a cupful of black coffee at 7 a. m. Her evening meal the day before, which was taken at 7 o'clock, consisted of shad with roe, one French roll, and Romaine salad with French dressing. At 10 p. m. the same day she took one-half pint of heavy cream and 4 ounces of wine. She reached the laboratory at 8h 03m a. m., and entered the bed calorimeter at 8h 26m a. m. The experiment began at 9h 23m a. m., continuing for three 1-hour periods, the last period being extended 6 minutes in order to secure favor- able temperature conditions. The experiment ended at 12h 29m p. m. After STATISTICS OF EXPERIMENTS. 21 the experiment the subject said that throughout the whole experimental period there was a great pressure on the bladder. This doubtless was the cause of the uneasiness shown by the subject as indicated by the calorimeter temperature fluctuations. The measurements of the metabolism and data regarding the pulse and respiration rates and urine are given in table 8. CASE I. DESCRIPTION OF THE CASE. Male; born February 2, 1886; married; chauffeur; date of onset not known, but probably some time in 1900; sugar found in urine May 1902, with indica- tions that it had been present for some time; came under our observation October 25, 1909; died May 1912. The earlier details of the case have pre- viously been published in full.1 An attack of influenza in the spring of 1910 reduced the strength of the patient materially, yet he recovered sufficiently to go into the poultry business Table 9. — Clinical chart — Case I. Ammonia. Body- Date. Volume of Specific gravity. Diacetic acid. 0-oxy- butyric Nitro- Sugar by ro- Carbo- hydrates Carbo- hydrate NaHC03 weight with- urine. acid. gen. Total. NH3-N tation. in diet. balance. out Total N (6) clothes. kilos. 1911. c.c. gms. gms. gms. p. ct. gms. gms. gms. gms. Feb. 17-18.. 870 ± 1035 0 '6.4 18-19.. 900 ± 1038 + '6.4 215± 0 19-20. . 2220 1036 0 =147 210 4+ 60 0 20-21.. 1950 1035 0 2133 230 4+ 95 0 21-22. . 2160 1035 S1.+ i'.h ib'.b 1. 6 u'.i 143 185 + 40 0 22-23.. 2070 1035 SI. + 5.9 11 4 128 ISO + 50 0 23-24. 2555 103R 4.8 13.6 11 13 3 164 175 + 10 0 40 0 24-25. . 1630 1037 "" 0 3.8 8.3 117 155 + 40 0 Oct. 2- 3.. 6000 1038 0 25.8 2^2 'i'.b 3420 1912. Feb. 9-10.. =2040 1036 0 139 175* + 35 12 39.4 10-11.. 2745 1032 ++++ l.i 154 200 ± + 45 12 39.3 11-12.. 3150 1030 +++++ ii's 158 200 ± + 40 12 12-13.. 2910 102SQ 1026 -1 — I-+ + + 13.4 116 200 ± + 85 12 13-14.. 2010+ -j — 1 — 1 — 1 — j- 9.6 L8+ ii!i 76 200 ± +125 12 14-15.. 1320 .... 200 ± 4 'Per cent. - Sugar by fermentation, Feb. 19-20, 151 gms.; Feb. 20-21, 135 gms. s By Fehling's method, 480 gms. 4 Calculated from fermentation record. 5 Sediment showed fine and coarse granular casts. Quantities of urine inaccurate, as patient had so many involuntary stools. 6Thedataregarding the urine for this subject can not be considered reliable, as it was impossible to make a careful collection, owing to diarrhea If such collection had been made, it is probable that this subject would have shown a minus carbohydrate balance, as he did in the period covered by data published in the first report (Publication No. 136, p. 127). and care for some 70 hens. His diet was not limited and included, among other articles, 2 quarts of milk, 6 oranges, and 10 eggs daily. In February 1911, he returned to the hospital on account of diarrhea which had existed for some time. Under hospital care the number of stools decreased from 12 to 5 daily and his condition improved. The physical examination remained the same. The patient's condition did not change during 1911. In the early winter he went to Tampa, Florida, and found the climate agreeable, but in February 1912, as the diarrhea had returned, he again went to the hospital for a few days. Except for emaciation and weakness and the presence of numerous furuncles, his condition had changed but little since his previous visit to the hospital. He was much relieved by the rest and soon returned home. In April 1912 he was considerably weakened by a carbuncle. Attention is called to the remark- able duration of this case, as well as of Case H, and to the hereditary history of diabetes of each. Benedict and Joslin, he. cit., p. 126. 22 METABOLISM IN SEVERE DIABETES. The urinary record is given in table 9. The records for October 1911 show probably a far nearer approach to the patient's average urinary excretion than the quantities recorded in the hospital. During his stay in the hospital the amount of urine excreted was low, owing to the diarrhea, and possibly because of restrictions in diet, while in October 1911 he was absolutely his own master. The low acidosis is notable and can in a measure be explained by the liberal allowance of carbohydrates in the diet. The reaction of the urine was acid throughout the whole period of observation, and there was but a slight trace of albumen. EXPERIMENTS WITH CASE I. Two experiments were reported with this subject in the previous publica- tion; one additional experiment is reported here, for which the bed calorimeter was used. The vital statistics for this subject are as follows: Date of birth, February 2, 1886; height, 176 cm.; body-weight without clothing during experiment, 40.0 kilos. Table 10. — Measurements of metabolism — Calorimeter experiment No. I\. Date and period. Carbon dioxide eliminated. Oxygen . absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Feb. 23. 1911: 1 9h 32m a.m. to 10h 17m a.m 10 17 a.m. 11 02 a.m Total 1 hr. 30 mins.2 gms. 15.7 14.8 c.c. 177 168 gms. 15.6 15.4 c.c. 242 240 0.73 .70 120 120 19 19 30.5 173 31.0 241 .72 120 19 1 Subject drank a cup of clear coffee without sugar at 7" 50ra a.m. - Carbon dioxide eliminated per kilogram per minute, 4.33 c.c; oxygen absorbed per kilogram per minute, 6.03 c.c. Calorimeter Experiment No. II. Date, February 23, 1911. Body- weight without clothing, 40.0 kilos. Previous to this experiment the subject had taken no food since the even- ing meal of the day before, with the exception of a cupful of clear coffee, with- out sugar, at 7h 50m a. m. He arrived at the laboratory at 8h 05m a. m., and entered the bed calorimeter in readiness for the experiment at 8h 53m a. m. The experiment began at 9h32m a. m., continuing for two 45-minute periods, Table 11. — Statistics of urine — Calorimeter experiment No. I\. Date and period. Volume. Specific gravity. Total nitrogen. Sugar. Feb. 23, 1911: i7h00ma.m. to 8h 15m a.m c.c. 133 112 1.036 1.037 gms. 0.82 .80 gms. 7.8 6.6 •Subject drank a cup of clear coffee at 7h 50m a.m., without sugar. ending at llh 02m a. m. The subject telephoned twice during the experiment, once at the beginning of the first period and again in the second period, at 10h 40m a. m., when he asked how much longer he would have to stay in the calorimeter. Aside from this he lay very quietly. As the chair calorimeter had been used in the previous experiments with this subject, this was his first experience with the bed calorimeter. He said that he did not find the experi- ment especially irksome, except that lying still in one position so long made his STATISTICS OF EXPERIMENTS. 23 back tired. The subject urinated at 7 a. m. before coming to the laboratory, and again at 8h 15m a. m. He defecated at 8h 45m a. m., the feces being copious, watery, and light-colored. Immediately after the experiment was over he defecated again at llh 15m a. m. No water was taken during the experiment The measurements of the metabolism and urine are given in tables 10 and 11. CASE J. DESCRIPTION OF THE CASE. Male; born March 26, 1889; single; no occupation; onset of diabetes, February 1908; sugar in urine 10 days later; came under our observation Sep- tember 24, 1909; died, September 17, 1912. The earlier history of this case has already been published.1 Later history of the case. — No experiments have been made with this sub- ject other than those previously published. From February 23, 1910, until August 25, 1910, inclusive, the patient remained comfortable. Upon two occasions the effect of oatmeal was tried. In the first trial, July 20-23, 1910, inclusive, the initial day was a vegetable day; upon the two subsequent days 180 grams of carbohydrates were given each day in the form of oatmeal. A positive carbohydrate balance of 55 and 40 grams respectively was obtained in contrast with a positive carbohydrate balance of 5 grams upon the vegetable Table 12. — Clinical chart — Case J. 6 >> Amnion ia. Sugar. Diet. i "3 -a 43 a 43 ^ m u T3 43 43 a> 3 a m c X-q Date. "o s> 6 3 "o o "53 c3 o 43 o 5 c M o 43 "r3 O 1 otalN y coppe eduction o '■£ a) 43 C o flj .5 c a O O u -*3 c3 o -q o S "3 >■ c o £> H a >• 3 •o o o > 02 (3 2 H 'A H PQ M pa o Ph 2 fe < O O a 1910. c.c. gms. gms. V- ct. gms. gms. gms. gms. gms. g7ns. gms. gms. kilos. Mar. 17-18.. 2820 1025 + 19.1 42 56 16 -25 27-28.. 3240 10.1 33 28-29.. 3240 1016 ++ 3.6 + 19 18 Apr. 15-16... 2160 1022 0 ... + 43 21 54.5 May 29-30. . 1800 1031 S1.+ + 40 30 54.5 July 1-2.... 1800 1033 + 50 20 54.0 20-211 2. 2370 1020 ++ 3.5 + 14 18 12 2 12 + 5 54.0 21-22' 3. 2640 1023 0 5.3 125 106 180 43 5 144 12 2272 +55 54.5 22-23 ' °. 2910 1034 S1.+ 7.3 142 122 180 43 5 144 12 2272 +40 54.5 Aug. 22-231 4. 1980 1023 ++ 9.6 3.2 27 .4 32 20 35 12 2 160 ± 12 1712 + 5 23-241 5. 2490 1027 ++ 6.2 1.7 22 .6 111 95 180 43 7 170 =>= 12 2506 +70 54.0 24-251 8. 1590 1027 +++ 8.8 1.1 10 .3 28 16 40 90 15 170 ± 6 2092 + 10 54.5 1 8 grams of sodium bicarbonate given. 2 Vegetable day. 3 Oatmeal day, 270 gms. oatmeal, 180 gms. butter, beef tea, 120 gms. wine. 4 750 gms. 5 per cent. +6 per cent vegetables, 375 c.c. cream, 105 gms. butter, oil, beef extract, 120 gms. wine. '270 gms. oatmeal, 180 gms. butter, 125 c.c. cream, beef extract, 120 gms. wine Feeling quite well. 62eggs, bacon, 630 gms. vegetables 5, 6, 10 per cent, 60 gms. pineapple, 300 gms. meat, 30 gms. oil, 375 c.c. cream, 90 gms. butter, 60 gms. wine. day. The second experiment was made August 22-25, 1910, inclusive. The first day was a vegetable day with 375 c.c. of cream; the second day an oatmeal day in which 180 grams of carbohydrate were taken in the form of oatmeal; on the third day approximately 40 grams of carbohydrate, 90 grams of pro- tein, 6 grams of alcohol, and 170 grams of fat were eaten. The oatmeal pro- duced a positive carbohydrate balance of 70 grams. Upon the vegetable day preceding the oatmeal day the carbohydrate balance was 10 grams. The urinary record for this case is given in table 12. The reaction for the urine was acid throughout. On April 16 and in the July observations the slightest pos- sible trace of albumen was found. In the August observations, however, this had disappeared. Benedict and Joslin, loc. tit., p. 131. 24 METABOLISM IN SEVERE DIABETES. CASE K. DESCRIPTION OF THE CASE. Male; born June 1863; widower; undertaker; onset of diabetes, November 1907; came under our observation August 19, 1908; died in coma November 4, 1910. The early history of the case has previously been published.1 On February 24, 1910, the patient reported himself as feeling very well. The quantity of urine was said to be 2000 c.c. On March 26, 1910, he said that his face felt alternately flushed or numb, and he suffered from both polyphagia and polydipsia. Although on the day previous he had had diarrhea, he was constipated on this day. He was just recovering from an attack of the grippe, from which he had been suffering six weeks. A physical examination on this date gave the following results : Lungs normal; heart, both first and second sounds at the left border of the sternum prolonged; blood-pressure, 115; pulse-rate, 84. In July 1910, he again entered the hospital. There appeared to be no particular change in his condition, except a loss in weight. His diet had been lax, and he said that he felt better than when on a strict diet. On November 4, 1910, the patient died, having been in coma for about 28 hours. Except for complaints of headache during the previous week, no especial change had been noted in his condition. The data regarding the urine from March 22 to August 24, 1910, inclusive, are given in table 13. At the times of these observations the urine gave an acid reaction. Very slight traces of albumen were found from July 24 to 28, but none later. Table 13. — Clinical chart — Case K. >> 43 ■6 '3 Ammonia. Sug ar. S3 +3 00 X) 1 > '5 © TJ 43 .£ 43 43 O) Date. 6 & "o o d "S3 o c3 >i 43 >> X o c a O 43 "3 43 o Q..2 .- — O £> O 3 c 0 '-3 oS 43 O u o 03 C "3 o o o 3 e-i O O a c8 bf 43 "S.S is ° ~s o o > W 5 Subject ate breakfast at 7h 45™ a.m. ! Carbon dioxide eliminated per kilogram per minute, 3 79 c.c: oxygen absorbed per kilogram per minute, 5.02 c.c. The urine collected between 7h 30m a.m. and 10h 10m a.m. amounted to 434 c.c, specific gravity 1.016, and contained 2.72 grams of nitrogen and 3.7 grams of sugar. CASE M. DESCRIPTION OF THE CASE. Male; born January 23, 1853; married; dentist; sugar found in urine in 1900; came under our observation January 6, 1908; condition November 11, 1912, active work. The earlier details of this case have been published in a previous publication.1 Later history of the case. — During the winter of 1909 and 1910 the patient insists that he did more work than he ever did in his life before, working even Sundays and until 11 o'clock at night. He used oil freely, often putting it on Benedict find Joslin, loc. cit., p. 152. 28 METABOLISM IN SEVERE DIABETES. strawberries, oranges, and grapefruit, and even used it on bananas, apples, and cantaloupe. A physical examination July 5, 1910, showed the blood-pressure to be 120; pulse-rate, 96; heart 5 cm. to the right of the median line, the left border lying within the mammillary line, with systolic murmur at the left border of the sternum and at the base. The liver was 2 to 3 fingers' breadth below the costal margin. The spleen was not palpated. On November 28, 1910, the weight was 82.6 kilos., the pulse-rate 84, and the condition good, except for pain in the vicinity of the sixth rib near the mammillary line. This pain resulted from a fall and a possible fracture of the rib. On December 16, 1910, he was considerably shaken up in a railroad accident, besides being- exposed to a nervous strain in escaping from an overturned car. It will be seen from table 18, which gives the urinary record, that the quantity of sugar in the urine increased at this time. In May 1911 he took a 5 weeks' vacation trip to Europe. A physical examination gave the same results as previously. On October 3, 1911, the patient had symptoms suggesting an attack of biliary colic. These subsided gradually, however, and after a week's rest recovery was complete. On December 28, 1911, his condition was excellent. An examination showed that no murmur could be heard in the heart. The blood- pressure was 125 and the pulse-rate 88. There was a slight resistance, but no tenderness in the region of the gall-bladder. In the observations made of the urine an acid reaction was shown throughout ; there was a slight trace of albu- men on January 1, 1911, and a very slight trace on May 15, October 2, and December 23. Table 18. — Clinical chart — Case M. Date. Volume of urine. Specific gravity. Diacetic acid. Nitrogen. Sugar. Body- weight without clothing. By copper reduction. By rota- tion. 1910. June30-Julv 1 July 14-15 . . . c.c. 1340 940 890 1450 975 750 1200 950 1028 1029 1027 1030 1028 1024 1024 1025 1027 0 + + + SI. + 0 0 0 0 gms. ie]6 grns. 14 gms. 19 6 0 26 8 5 = 0.2 3 kilos. 8L7 80'6 Oct. 1-2 15.5 33 13.4 4- 1911. Dec. 31-Jan. I1 Mav 15-16 Aug. 27-28 10.4 0 + 4- Oct. 1-2 Oct. 3-4 Dec. 22-23.. NH3— N '/3-oxybutyricacid, 1.9 gms.; ammonia, 1.3 gms.; . =6.9 per cent.; sugar by fermentation, 36 gms. 'Per cent. EXPERIMENTS WITH CASE M. Three calorimeter experiments with this subject were reported in the pre- vious publication. In two of the experiments the bed calorimeter was used: the chair calorimeter was used in the third. Two additional experiments are reported here, one with the bed calorimeter and one with the respiration appa- ratus. The vital statistics are as follows: -'- W Date of birth, January 23, 1853; height, 172 cm.; range in body-weight without clothing during experiments, 81.7 to 82.9 kilos. Respiration Experiment No. Ml. Date, August 17, 1910. Body-weight without clothing, 81.7 kilos. This experiment, which was made with the respiration apparatus and with the subject fasting, included four separate periods of 10 to 11 minutes each, STATISTICS OF EXPERIMENTS. 29 with intermissions ranging from 11 to 19 minutes. The experiment began at 8h 13m a. m., and ended at 9h 39m a. m. The subject was instructed not to go to sleep and apparently did not; in the second period he was uneasy, moving his legs and changing his position somewhat several times. In the third period the observer thought the subject opened his mouth and moistened his lips, but he himself thought he did not. The results of the experiment are given in table 19. Table 19. — Results of respiration experiment No. Ml. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. Aug. 17, 1910: 8h 13m a.m 8 43 a.m 9 08 a.m 9 29 a.m Average min. sec. 10 50 11 10 10 9 10 25 c.c. 197 200 187 203 c.c. 271 256 260 6!74 .73 .78 76 76 74 174 9 9 10 9 i =197 = 262 .75 75 9 1 One record of pulse. 2 Carbon dioxide eliminated per kgm. perminute, 2.41 c.c; oxygen absorbed per kgm. per minute, 3.21 c.c. The 100c. c. of urine collected between 6" 45ma.m. and 9h45ma.m. contained 1.56 gm. nitrogen and 1 gm. sugar. Calorimeter Experiment M2. Date, June 15, 1911. Body-weight without clothing, 82.9 kilos. The subject came to the laboratory without breakfast at 7h25ra a. m., entered the bed calorimeter at 7h56m a.m., and the experiment began at 8h52m a. m. Three periods, one of 53 minutes and two of 45 minutes, were included in this experiment. Except in the second period, when he rolled over on his side and used his arms considerably in handling the newspaper he was reading, the subject was very quiet all through the experiment. Afterwards he said he was very comfortable while in the apparatus and suffered no discomfort. The metabolism measurements are given in table 20. Table 20. — Measurements of metabolism — Calorimeter experiment No. M2 Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respira- ; Average Average respira- tion rate. Total. Per minute. Total. Per minute. tory quotient. rate. June 15, 1911: 8h 52m a.m. to 9h 45m a.m 9 45 a.m. 10 30 a.m 10 30 a.m. 11 15 a.m g?ns. 19.7 16.6 17.0 c.c. 190 189 192 gms. 18.0 15.7 15.9 c.c. 239 244 248 0.79 .77 .78 70 68 67 11 Total 2 hrs. 23 min.1 53.3 190 49.6 243 .78 68 !Carbon dioxide eliminated per kilogram per minute, 2.29 c.c: oxygen absorbed per kilogram per minute, 2.93 c.c The urine collected between about 10h 30m p.m. June 14 and 12h 15m p.m. June 15, specific gravity 1.025, amounted to 335 c.c. and contained 4.12 gms. of nitrogen and 3.6 gms. of sugar. CASE N. DESCRIPTION OF THE CASE. Male; born August 1, 1896; developed diabetes just before 13 years of age in July 1909, and came under our observation August 1909; died in coma Feb- ruary 16, 1911. Family history. — Grandmother died of diabetes at the age of 78. The patient was an only child, and his father and mother are well. Past history. — Measles. 30 METABOLISM IN SEVERE DIABETES. Present illness. — Early in June 1909 the boy began losing weight while riding a new bicycle. During the first part of August, frequent micturition developed and in the course of a few days he began to droop. Physical examination.— Height, 146 cm.; greatest weight, 34.5 kilos.; weight August 28, 1909, 29.6 kilos. Fairly well developed. Pupils equal and reacted to light. Tongue and teeth normal. Lungs normal. Heart extended 2 cm. to right of median line and 9 cm. to left of median line (just external to mammillary line). Sj^stolic murmur at apex. The liver extended 2 fingers' breadth below the costal margin. Knee-j erks normal. No edema. Urine data. — The greatest quantity of urine observed was at the onset, when it reached 3500 c.c. The patient's urine contained 6.6 per cent of sugar on August 28 and, on the following day, 162 grams were excreted. By the restriction of the diet to 20 grams carbohydrate, the urine became sugar-free on September 13 and this condition was maintained almost constantly until November 22, 1909; he then evidently broke diet and the sugar in the urine went up to 7 per cent (88 grams) . The sugar did not again disappear from the urine until December 15, when the patient was at the hospital. It remained absent for the 4 days he was there, returning promptly when he left the institution, and never disap- peared save upon two days in January and one in February of the following year. Albumen was either absent or present only in extremely small quantities; during the last few months of life but a trace was present. The urine was invariably acid, save upon one day, December 18, 1909. During the first period of observation, from August 1909 until April 1910, the signs of acidosis were slight and represented at the most by only a moderate reaction for diacetic acid. From that time on they increased, and the acidosis was extreme in November 1910, when the patient was again in the hospital. At this time the urinary record (table 21) shows 35 grams of /3-oxybutyric acid in one day, and on the same day 4.2 grams of ammonia. Death finally occurred on February 16, 1911, after 3 days of coma. The case therefore affords a most excellent example for a study of diabetes with and without acidosis. During its duration of 19 months, the disease ran a course free from complication, with the exception of the persistent ulceration of one incisor tooth. EXPERIMENTS WITH CASE N. With this subject, eight calorimeter experiments were made, in all of which the bed calorimeter was used. In seven experiments the subject entered the apparatus without breakfast, after a 12 hours' fast. One experiment was made following a breakfast of cooked oatmeal. In addition, one respiration experiment was carried out with this subject. The data for the calorimeter experiments are compared in table 33. The vital statistics were as follows: Date of birth, August 1, 1896; height, 146 cm. ; range in body-weight with- out clothing during experiments, 30.5 to 32.5 kilos. Respiration Experiment No. Nl. Date, August 18, 1910. Body-weight without clothing, 32.5 kilos. In this experiment the respiratory exchange was determined by means of the respiration apparatus, the subject lying on a couch. It is probable that he took food previous to the experiment. The experiment began at 8h 1 2ra a.m., covering one 10-minute period and ending at 8h 22m a. m. The subject was Table 21. — Clinical chart — Case N. o > T3 o Ammonia. Sugar. o 03 03 XI o Date. E-S — 3 o ta ■ U3-- '3 O 03 O *-3 a> o « >* -+J - ft o a o O t- o 1 _ u . a a 0.0 X"3 1 a t< o .a -a u 03 J3 a B 03 O o W 03 Body - weij without c thing. > W 5 tQ. £ H K:H ma ffl O a y, 1909. c.c. gms. gms . gms. p. ct. gms. gms. gms. gms. gms. kilos. Aug. 27-28 1032 0 '6.6 29.6 Aug. 29-30 2530 1034 0 13., 162 55 ± -105 0 29.9 Aug. 30-31 3000 0 156 0 29.9 Sept. 1-2 2625 1029 0 110 0 30.1 Sept. 2-3 2250 1030 S1.+ 95 Sept. 3- 4 2750 1031 0 138 30.2 Sept. 7-8 2125 1028 0 85 0 Sept. 8-9 1750 1025 S1.+ 28 0 30. i Sept. 9-10 1500 1021 S1.+ 6 0 30.2 Sept. 10-11 1625 1017 S1.+ 3 0 30.4 Sept. 12-13 750 1021 S1.+ 0 20 0 30.4 Sept. 16-17 1000+ 1019 0 6 20 + 20 0 30.5 Sept. 22-23 2000 1015 0 6 0 31.6 Sept. 21-25 2250 1017 0 9 0 31.2 Sept. 26-27 1500 1015 0 6 0 Oct. 10-11 1250 0 0 20 + 20 0 33.4 Oct. 17-18 0 0 0 33.0 Oct. 24-25 1000+ 1019 0 12 0 32.8 Oct. 31-Nov. 1. 1250 0 6 0 33.1 Nov. 9-10 750 1018 0 0 30 + 30 0 33.0 Nov. 21-22 1250+ 1037 0 + 88 0 33.4 Nov. 23-24 750 1029 0 + 18 0 Nov. 28-29 1500+ 1027 0 + 54 0 Dec. 1-2 1000 1024 0 + 8 0 33.2 Dec. 8-9 1000 1026 0 + 20 0 Dec. 12-13 1250 1035 0 + 53 0 33.4 Dec. 15-16 900 1023 0 0 0 20 + 20 0 32.1 Dec. 19-20 1750 1020 0 + 14 0 33.7 1910. Jan. 2-3 1250 1020 0 + 5 Jan. 6-7 1500 1025 S1.+ 18 6 33.7 Jan. 9-10 750 1026 S1.+ +' 5 Jan. 17-18 1014 0 0 Feb. 3-4 1000 1021 + 10 6 Feb. 10-11 750 1024 0 0 0 34.6 Mar. 4-5 875 1022 + 4 0 33.3 Mar. 29-30 1250 1036 S1.+ + 85 0 Apr. 10-11 1625 1035 S1.+ 111 0 33.8 Apr. 17-18 1375 1027 ++ + 30 0 33.0 Mav 1-2 1700 1033 + + 95 0 33.2 May 15-16 2000 1034 0 + 104 0 Mav 23-24 1375 1034 + 7.< I 1.7 17.7 66 4 32.7 2170 1025 S1.+ 9.' ... 65 61 4 32.3 Julv 1-2 1530 1034 ++ + 89 4 32.0 Julv 14-15 1375 1032 ++ 2.0 = 51 50 4 Julv 31-Aug. 1.. 1560 1030 +++ 103 4 Aug. 8-9 1750 1031 ++++ 12. 1 2.5 17.0 72 60 4 30.8 Aug. 23-24 2125 1035 ++ 13.. 103 119 8 31.3 Aug. 30-31 2160 1030 ++ 11. i I ... 84 78 30.8 Sept. 2-3 1250 1036 ++++ 45 Sept. 14-15 1875 1033 +++ 83 31.9 Nov. 15-16 3 1750 ++++ + 46 Nov. 2 1-22 l.... 1033 ++ 112 2750 1028 ++++ 94 80 - is 20 Nov. 23-24 2740 1027 ++++ 93 80 - 15 20 32.3 Nov. 24-25 2880 1029 ++++ 92 80 - 10 20 32.4 Nov. 25-26 2620 1026 ++++ 2.1 79 80 20 32.3 Nov. 26-27 2900 1024 ++++ 28.9 64 15 - 50 20 32.4 Nov. 27-2S 2960 1028 ++++ 89 55 - 35 20 32.7 Nov. 28-29 2780 1024 ++++ 10. < 2.8 22.1 67 55 - 10 20 32.0 Nov. 29-30 3120 1021 +++ 2.4 69 62 55 - 15 20 31.8 Nov. 30-Dec. 1.. = 2940 1021 ++++ 35.0 8.: ! 4.2 42.1 41 35 15 - 25 20 Dec. 1- 2 6 3000 1020 +++ 6 : > 3.0 39.8 69 60 135 + 65 16 30. i Dec. 2-3 2212 1023 ++++ 6 : » 2.7 35 8 58 49 45 - 15 20 30.8 Dec. 3-4 1810 1020 +++ 5.1 1.6 25 8 38 33 30 - 10 31.4 Dec. 4- 5 2840 1021 +++++ 10.' r 2.3 17.7 77 68 35 - 40 32.3 Dec. 5-6 2950 1022 ++ 30 6 9 ■ r 2.3 19 5 41 41 35 - 5 32.1 Dec. 6-7 2840 1023 +++ 26.5 10. 2.3 18.7 61 51 35 - 25 32.1 Dec. 7-8 2005 1025 ++++ 22 3 7: r 1.8 19 2 53 40 45 - 10 20 32.4 Dec. 8-9 2600 1027 ++++ 15.1 6.i i 1.6 19.4 117 104 45 - 70 20 32.5 Dec. 9-10 2500 1029 +++ 20.7 5.: : 1.6 24.8 138 125 45 - 95 16 31.8 Dec. 10-11 3135 1030 ++ 21 8 8 ) 2.8 28.8 180 163 45 -135 16 31.4 Dec. 11-12 2760 1032 + 16.9 8. 2.3 23.4 163 155 45 -120 16 31.8 Dec. 12-13 2510 1026 +++ 21 2 8. 1 2.4 24 7 98 95 145 + 45 16 31.5 Dec. 13-14 2650 1022 +++ 18.3 10. 2.3 18.7 56 53 45 - 10 16 31.4 Dec. 14-15 2450 9 , 70 45 - 25 16 Dec. 16-17 3000 1024 +++ 2.2 + 78 45 - 35 30.3 Dec. 23-24 2170 1031 ++ + 78 55 - 25 30.2 Dec. 27-28 1875 1029 ++++ 1.2 + 45 .... 1911. Jan. 6- 7 3 2375 1032 +++ + 105 Jan. 19-20 2250 1026 +++ 63 30.6 Feb. 5-6 2375 1026 ++++ 62 Feb. 15-16 7 330 1019 0 + 4 1 Per cent. * By fermentation. 3 Many fine and coarse granular casts in urinary sediment. 4 Less than 24 hrs. 6 Period of 23 hrs. 45 ruin. Vegetable day, including 240 c.c. cream. 6 Period of 24 hrs. 15 min., 192 gms. oatmeal, 240 c.c. cream. 7 3 hrs. Many casts, chiefly coarse granular, in urinary sediment. 31 32 METABOLISM IN SEVERE DIABETES. reported as being restless, opening his mouth once and raising his hand to his face. Before coming to the laboratory the subject urinated at 5 a. m., and after the experiment was over he urinated at 8h 50m a. m. The carbon dioxide eliminated per minute was 181 c.c, and per kilogram per minute 5.57 c.c. The oxygen absorbed per minute was 237 c.c. per minute, and per kilogram per minute, 7.29 c.c. The respiratory quotient was 0.76. During the experi- mental period the pulse-rate averaged 73 and the respiration-rate, 17. The urine collected between 5 a. m. and 8h 50m a. m. amounted to 145 c.c. and con- tained 0.67 gram of nitrogen and 7.1 grams of sugar. Calorimeter Experiment No. N2. Date, December 1, 1910. Body-weight without clothing, 31.2 kilos. For this experiment, the subject came to the laboratory without break- fast at 7h 05m a. m., and entered the bed calorimeter at 7h 17m a. m. The experiment began at 8h 04m a. m., and continued for three 45-minute periods, ending at 10h 19m a. m. The pulse and respiration rates were obtained by the usual methods, but no records of the body-temperature were made. The sub- ject was very quiet, lying on his back and reading throughout the whole experi- ment. Two samples of the alveolar air were taken both before and after the experiment. Before coming to the laboratory, the subject urinated at 6h 45m a.m., and again after the experiment at 10h 28m a.m. The records of the experiment are given in tables 22 and 25. Table 22. — Measurements of metabolism — Calorimeter experiment No. N 2. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Dec. 1, 1910: Sh 4m a.m. to 8h 49m a.m 8 49 a.m. 9 34 a.m 9 34 a.m. 10 19 a.m Total 2 hrs. 15 min.5 gms. 12.6 11.8 11.0 c.c. 143 133 126 qms. '10.8 12.8 11.0 c.c. 168 199 171 0 85 .67 .73 76 78 172 17 18 19 35.4 133 34.6 179 1 One record at 101' 03m a.m. 2 Carbon dioxide eliminated per kilogram per minute, 4.26 c.c; oxygen absorbed per kilogram per minute, 5.74 c.c. Calorimeter Experiment No. N3. Date, December 2, 1910. Body-weight without clothing, 30.9 kilos. On the morning of the experiment the subject ate a breakfast consisting of 300 grams of cooked oatmeal and came to the laboratory at 7h 55m a. m. At 8h 10m a. m. he entered the respiration chamber of the bed calorimeter; the experiment began at 8h 48m a. m. and continued for two 45-minute periods and one 53-minute period, ending at llh llm a. m. In the first period he lay very quietly on his back, reading, but did not read in the second period and moved slightly two or three times; he seemed to be asleep near the end of the period. At the beginning of the third period he was asleep, but soon awoke and read for a short time, then lay quietly without reading. According to the observer's record, the subject moved considerably more in this period than in the two pre- ceding, and it was necessary to extend the period 8 minutes in order to obtain satisfactory temperature equilibrium at the end. Samples of alveolar air were taken before and after the experiment. The subject urinated at 7 a. m. before coming to the laboratory and again at llh 26m a. m. after the experiment was over. The records for the experiment are given in tables 23 and 25. STATISTICS OF EXPERIMENTS. 33 Table 23. — Measurements of metabolism — Calorimeter experiment No. N 3. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse rate. Average respira- tion rate. Total. Per minute. Total. ?Z minute. Dec. 2. 1910: 1 8h 48m a.m. to 9h 33m a.m 9 33 a.m. 10 18 a.m 10 18 a.m. 11 11 a.m Total 2 hrs. 23 min.2 QIIIS. 12.4 11.9 14.4 c.c. 140 134 139 gms. 11.7 11.4 13.8 c.c. 182 178 182 0.77 .76 .76 79 81 84 17 14 16 38.7 138 36.9 181 1 Subject ate 303 gms. of cooked oatmeal about 1 hr. 30 min. before the experiment began. 2 Carbon dioxide eliminated per kilogram per minute, 4.47 c.c; oxygen absorbed per kilogram per minute, 5.86 c.c. Calorimeter Experiment No. N4. Date, December 3, 1910. Body-weight without clothing, 30.5 kilos. When the subject came to the laboratory at 7h 02m a. m. on the experi- mental clay, aside from a small cupful of black coffee he had had no food since the evening meal of the day before. After two samples of alveolar air had been taken, he entered the bed calorimeter at 7h 23m a. m. The experiment began at 8h 08m a. m., continued for three 45-minute periods, and ended at 10h 23m a. m. The subject was very quiet throughout the experiment, reading most of the time except near the end of each period; he did not sleep at all. After the experiment was over, he urinated at 10h 35m a. m.; two additional samples Table 24. — Measurement of metabolism- -Calorimeter experiment No. N4- Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Dec. 3, 1910: i 8h 08m a.m. to 8h 53m a m 8 53 a.m. 9 38 a.m 9 38 a.m. 10 23 a.m Total 2 hrs. 15 mins.2 gms. 11.0 10.2 11.0 c.c. 124 116 124 gms. 10.8 9.8 10.3 c.c. 168 152 161 0.74 .76 .77 56 58 58 14 14 13 32.2 121 30.9 160 1 Subject drank a small cup of black coffee about 1 hr. 15 mins. before the experiment began 2 Carbon dioxide eliminated per kilogram per minute, 3.97 c.c. ; oxygen absorbed per kilogram per minute, 5.25 c.c. of alveolar air were also taken. The subject said that he did not feel quite so tired and hungry as he had at the close of preceding experiments. On the morning of December 5 his mother said that during the afternoon of the exper- imental day and all the next day the subject was much brighter and better than he had been for some time. He was quite lively and in good spirits, Table 25. — Statistics of urine — Calorimeter experiments Nos. N2-N4- Date and period. Dec. 1, 1910: 6b 45™ a.m. to 10h 3Sm a.m. Dec. 1-2, 1910: 10h 38m a.m. to7ha.m... Dec. 2, 1910: 7 a.m.1 to llh 26m a.m Dec. 2-3, 1910: llh 26m a.m. to 7 a.m. . . Dec. 3, 1910: 7 a.m.2 to 10h 35m a.m Dec. 3-4, 1910: 10h 35™ a.m. to 7 a.m. . . . Volume. c.c. 473 2520 512 1700 250 1560 Specific gravity. 1.019 1.020 1.022 1.030 Total nitrogen. Sugar. gms. 1.26 4.86 .98 5.09 .95 4.11 gms. 5.7 64.8 17.9 40,6 8.1 29.4 1 Subject ate 300 gms. of cooked oatmeal just before coming to the laboratory at 7h 55m a.m. 2 Subject drank a small cup of black coffee just before coming to the laboratory at 7n 02m a.m. 34 METABOLISM IN SEVERE DIABETES. although previously he had been very melancholy and his physical condition had preyed upon his mind so that he had not been at all happy. The meas- urements of metabolism and the average pulse and respiration rates are given in table 24, and the statistics of urine in table 25. Calorimeter Experiment No. N5. Date, December 5, 1910. Body-weight without clothing, 31.7 kilos. For this experiment the subject came to the laboratory at 7h 05m a. m., without breakfast, and entered the bed calorimeter at 7h 29m a. m. ; the experi- ment began at 8h 22ra a. m., ending at 10h 38m a. m., after three 45-minute periods. Throughout the whole period the subject was quiet, reading much of the time. Samples of the alveolar air were taken both before and after the experiment. The subject urinated at 7 a. m., before coming to the laboratory, and at 10h 56m a. m. after the experiment was over. He said at the conclusion of the experiment that, while he was tired and sleepy and somewhat hungry, he felt quite well. The records of the experiment are given in table 26. Table 26. — Measurements of metabolism — Calorimeter experiment No. N5. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Deo. 5, 1910- 8h 22m a.m. to 9h 07ra a.m 9 07 a.m. 9 52 a.m 9 52 a.m. 10 38 a.m Total 2 hrs. 16 min.1 gms. 11.2 10.5 11.9 c.c. 127 119 132 gms. 11.1 11.1 111 c.c. 172 172 168 0.74 .69 .78 54 55 58 16 16 16 33.6 126 33.3 171 'Carbon dioxide eliminated per kilogram per minute, 3.97 c.c.; oxygen absorbed per kilogram per minute, 5.39 c.c. The urine collected between 7 a.m. and 10h 56m a.m. amounted to 590 c.c. and contained 1.96 gms. of nitrogen and 8.8 gms. of sugar. Calorimeter Experiment No. N6. Date, December 7, 1910. Body-weight without clothing, 32 kilos. The subject arrived at the laboratory without breakfast at 7h 05ma. m. The experiment began at 8h 20m a. m. and continued for three 45-minute periods, ending at 10h 35m a. m. Throughout the experiment the subject lay on his back, quietly reading. He did not sleep at all. As usual samples of alveolar air were taken before and after the experiment. Before coming to the laboratory the subject urinated at 6h 30m a. m. and at 10h 50m a. m., after the experiment was over. On coming out of the bed calorimeter the subject com- plained of no discomfort, saying only that he was quite hungry. The records of the experiment are given in table 27. Table 27. — Measurements of metabolism — Calorimeter experiment No. N 6. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Dec. 7, 1910: 8h 20m a.m. to 9" 05m a.m 9 05 a.m. 9 50 a. in 9 50 a.m. 10 35 a.m Total 2 hrs. 15 min.1 nms. 11.4 12.2 10.9 c.c. 129 139 122 gms. 11.2 11.7 11.1 c.c. 174 181 172 0.74 .77 .71 56 57 57 17 17 16 34.5 i::n 34.0 176 'Carbon dioxide eliminated per kilogram per minute, 4.06 c.c; oxygen absorbed per kilogram per minute, 5.50 c.c. The urine collected between 61' 30m a.m. and 10h 50m a.m. amounted to 545 c.c, specific gravity 1.019, and contained 1.90 gms. of nitrogen and 7.9 gms. of sugar. STATISTICS OF EXPERIMENTS. 35 Calorimeter Experiment No. N7. Date, December 10, 1910. Body-weight without clothing, 31.8 kilos. The subject arrived at the laboratory at 7h 10ra a. m., without breakfast. Before he entered the bed calorimeter at 7h 33m a. m., samples of alveolar air were taken and a record made of the ventilation of the lungs. The experiment began at 8h22ma. m., ending at 10h 40m a. m., after three 45-minute periods. At 9h 56m a. m. the subject drank 76 c.c. of water. During the first period he Table 28. — Measurements of metabolism — Calorimeter experiment No. N 7. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Dec. 10, 1910: 8h 22m a.m. to 9h 07m a.m 9 07 a.m. 9 54 a.m 9 54 a.m. 10 40 a.m Total 2 hrs. 18 min.1 0H1S. C.C. 12.9 146 12.6 137 13.0 143 gms. 11.9 12.4 12.6 c.c. 184 184 192 0.79 .75 .75 75 77 81 19 18 18 38.5 142 36.9 187 1 Carbon dioxide eliminated per kilogram per minute, 4.47 c.c; oxygen absorbed per kilogram per minute, 5.88 c.c was very quiet, reading. He did not read during the second period, but lay very quietly, and slept about 20 minutes. In the third period, however, he moved considerably and gave evidence of being very restless. Samples of the alveolar air were also taken after the experiment. The subject urinated before the experiment at 6h 45In a. m. and after the experiment at llh 05m a. m. The data regarding the metabolism measurements and the average pulse and respi- ation rates are given in table 28 and the statistics of urine in table 29. Table 29. — Statistics of urine — Calorimeter experiment No. N7. Date and period. Volume. Specific gravity. Total nitrogen. Sugar. Dec 10,1910- 6h45ma.m. to llh 0om a.m.. . c.c. 475 2660 1.027 1.031 gms. 1.47 6.66 gms. 15.2 164.0 Dec 10-11, 1910- llh 05m a.m. to 6h 45m a.m Calorimeter Experiment No. N8. Date, December 12, 1910. Body-weight without clothing, 31.7 kilos. The subject reached the laboratory at 7 a. m., without breakfast, and entered the bed calorimeter at 7h 38m a. m., after two samples of the alveolar air had been taken and records made of the ventilation of the lungs. A blood- pressure of 90 mm. was also recorded at 7h 30m a. m. The experiment began at 9 a. m., continuing for two 30-minute and one 40-minute periods, ending at 10h 40m a. m. The pulse and respiration rates were obtained as usual by the stethoscope and pneumograph. The telephone was used once during the experiment, at the beginning of the first period, but otherwise the subject was very quiet, reading nearly all of the time except near the end of each period. Samples of the alveolar air were taken at the end of the experiment, as usual. Before coming to the laboratory, the subject urinated at 6h 45m a.m., and again at llh 08m a. m., after the experiment was over. No water was taken during the experiment. The data regarding the metabolism measurements and the average pulse and respiration rates are given in table 30 and the statistics of urine in table 31. 36 METABOLISM IN SEVERE DIABETES. Calorimeter Experiment No. N9. Date, December 14, 1910. Body-weight without clothing, 31.4 kilos. The subject arrived at the laboratory without breakfast at 7h 10m a. m., and entered the bed calorimeter at 7h 32m a. m. The experiment began at 8h 21m a. m., continuing for two 45-minute periods and one 40-minute period, Table 30. — Measurements of metabolism — Calorimeter experiment No. N 8. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. l ?ert i minute. Total. Per minute. Dec. 12, 1910: 9h00ma.m. to 9h 30m a.m 9 30 a.m. 10 00 a.m 10 00 a.m. 10 40 a.m gryis. c.c. 8.0 135 7.5 127 10.0 128 gms. 8.2 7.5 10.1 c.c. 192 173 176 0.70 .73 .72 59 61 61 15 15 15 Total 1 hr. 40 min.1 25.5 130 25.8 181 1 Carbon dioxide eliminated per kilogram per minute, 4.10 c.c.; oxygen absorbed per kilogram per minute, 5.71 c.c. ending at 10h 31m a. m. As usual with this subject, he lay quietly reading dur- ing practically the whole experiment, save at the beginning of the third period, when he moved quite a little. Samples of alveolar air were taken and records made of the ventilation of the lungs both before and after the experiment; a Table 31. — Statistics of urine — Calorimeter experiment No. NS. Date and period. Volume. Specific gravity. Total nitrogen. Sugar. Dec. 12, 1910: 6h 45m a.m. to llh 08m a.m Dec. 12-13, 1910: llh08ma.m. to6h45ma.m c.c. 350 2160 1.032 1.026 gms. 1.84 5.99 gms. 16.7 80.0 record of 90 mm. for the blood-pressure was obtained at 7h 10m a. m. The sub- ject urinated at 7 a. m., before coming to the laboratory, and at 10h 55m a.m., after the experiment was over. No water was taken. The results of the experiment are given in table 32. Table 32. — Measurements of metabolism — Calorimeter experiment No. N9. Date and period. Carbon dioxide , /-»-,.„. „i,„„,k„,i eliminated. °xygen absorbed. Respi- ratory quotient. Average pulse - rate. Average respira- tion rate. Total. : ?ert minute. Total. Per minute. Dec. 14, 1910: 8h 21m a.m. to 9h 06m a.m 9 06 a.m. 9 51 a.m 9 51 a.m. 10 31 a.m Total 2 hrs. 10 min.' gms. 11.0 10.8 9.6 c.c. 126 121 121 gms. 10.9 12.0 9.4 f.C 169 187 164 0.74 .65 .74 61 58 58 14 15 14 31.4 123 32.3 174 'Carbon dioxide eliminated per kilogram per minute, 3.92 c.c: oxygen absorbed per kilogram per minute, 5.54 c.c. The urine collected between 7 a.m. and 10h 55m a.m. amounted to 390 c.c, specific gravity 1.025, and contained 1.49 gms. of nitrogen and 10.6 gms. of sugar. CASE 0. DESCRIPTION OF THE CASE. Female; born August 16, 1894; single; no occupation; onset of diabetes at age of 13, February 1908; sugar in urine, March 1908; came under our obser- vation April 18, 1908; died in coma December 10, 1910. STATISTICS OF EXPERIMENTS. 37 Family history. — No history of diabetes in the family. Father died of pneumonia; mother and brother well. Past history. — Scarlet fever, dysentery at 3 years of age, measles, mumps, whooping-cough, chicken-pox, enuresis nocturna which ceased at the age of 4. Had always a voracious appetite, sometimes eating six potatoes at a meal; ate much candy. General history of the case. — During the year preceding the onset of the dis- ease the patient developed rapidly both in height and weight. In February 1908, she showed weariness. Early in March, polydipsia, polyuria, and poly- phagia were present, and sugar was demonstrated in the urine. One year pre- vious the urine had been examined and was said to be normal. During the whole period of illness the patient remained in good condition and attended school with comfort. The diet was rigidly adhered to and not relaxed except when the diagnosis was at one time doubted by the local physi- cian. Catamenia was established for the first time in March 1909. No essential change in the physical examination took place. The patient died in coma on December 10, 1910. Table 33. — Comparison of metabolism experiments in bed calorimeter with Case N. EXPERIMENTS WITHOUT FOOD. Experi- ment No. Date. Weight of subject. Length of experi- ment. Per minute. Respi- ratory quotient. Average pulse per minute. Average respira- tion per minute. Carbon dioxide eliminated. Oxygen absorbed. N2 N4 N5 N6 N7 N8 N9 1910. Dec. 1 Dec. 31 Dec. 5 Dec. 7 Dec. 10 Dec. 12 Dec. 14 kilos. 31.2 30.5 31.7 32.0 31.8 31.7 31.4 hr. min. 2 15 2 15 2 16 2 15 2 18 1 40 2 10 c.c. 133 121 126 130 142 130 123 c.c. 179 160 171 176 187 181 174 0.74 .76 .73 .74 .76 .72 .71 75 57 56 57 78 60 59 18.0 13.5 16.0 16.5 18.5 15.0 14.5 EXPERIMENT WITH FOOD. N3 1910. Dec. 2 2 kilos. 30.9 hr. min. 2 23 c.c. 138 ex. 181 0.76 81 15.5 1 About 1 hr. 15 min. before experiment began, subject drank a small cup of black coffee. 2About 1 hr. 30 min. before the experiment began, subject ate 300 gms. of cooked oatmeal. Physical examination. — A healthy appearing girl. Greatest weight, Janu- ary 1908, 60.8 kilos, without clothing; weight, April 20, 1908,49.2 kilos, without clothing. Height, 173 cm. No acetone odor. Pupils equal and reacted to light; tongue and teeth normal. Few cervical and axillary glands. Apex of heart within nipple line; no murmurs. Nothing abnormal felt in abdomen. Knee-jerks normal. The greatest quantity of urine was approximately 5,000 c.c, just previous to April 18, 1908. Urine data. — The course of the disease is given in table 34. Although the urine showed 4.8 per cent of sugar on April 18, 1908, it will be seen that under the restriction of the carbohydrates to approximately 10 grams the urine became sugar-free. The tolerance for carbohydrates gradually increased, and reached approximately 90 grams of carbohydrates in February 1909, where it remained until after October 28, 1909. The weight rose from 49.2 kilos., April 20, 1908, to 55.8 kilos., July 28, 1909. The health was so good that the local physician would not believe that the patient had diabetes, and allowed a free diet on Thanksgiving Day, 1909. Sugar returned early in December 1909, but disappeared at once when the diet was again restricted. A tolerance of 55 38 METABOLISM IN SEVERE DIABETES. grams of carbohydrate was reached February 18, 1910, but after April 21 of that jrear sugar was seldom absent until the patient's death. The reaction of the urine was acid throughout, except upon April 30, 1908. Diacetic acid was present when the patient was first seen, but disappeared when the urine became sugar-free, not returning until September 1910. The /3-oxybutyric acid reached 14.3 grams upon September 23-24, 1910, but the ammonia was low, which was due in part to the sodium bicarbonate admin- istered. Table 34. — Clinical chart — Case O. Date. 6 .S 3 "3 O S _3 > >> a u & CIS "3 o Oc 02 T3 '3 03 c '-3 o o cj 3 •6 '3 £3 o '£ >> -*> 3 .O >, X o a CD w o Ammonia. Sugar. a CO CD -^> cj . >v3 A o J3 u a O O O w 03 i "3 .a it s • o Xi 3 O J2 J3X! .»■§ CB — * ° O P3 "3 o H 1 X y. o 3 o 9- ° 0 a n a o eg -^> O >. ffl 1908. Apr. 18-19 c.c. 1800 2610 1710 1890 1600 ± 1650 1650 1590 2970 1650 1830 i 1140 1830 2200 2640 2340 1470 2760 2760 2940 1440 2820 3420 3420 2880 3280 2577 2410 3270 2460 I860 2210 2300 1750 2000 102- 101' 103C io2; 102c 102c 101S 1024 101c 102$ 1022 1026 1025 1025 1021 1023 102£ 1022 1024 102!) 102S 102S 1034 1031 + r ++ ++ + + + + + 0 0 ' 0 1 + ++ + » + + ++ ++ +++ +++ +++ 0 +++ +++ +++ +++ ++ ++ +++ +++ +++ ++++ +++ gms. 12.6 13 0 14.3 14.1 gms. 20 A iz'.b 20!7 20.1 U.2 15.6 18.3 8.7 13.6 12.9 15.2 14.1 11.2 8.0 10 0 11.1 12.6 14.9 15.9 gms. 1.9 'i'.h "i.i 'i'.i 'o.'s 0.4 0.5 0 6 0.5 oil) 1.0 2.0 2.4 p. ct. 'Y.k 5.7 3.6 3.8 3.0 '4.4 5 1 6.7 6.5 ii'.b 12.4 gms. 0 0 0 gms. 50 78 44 60 42 20 17 16 12 2 44 47 53 33 12 11 22 29 29 11 27 14 40 24 43 39 44 60 49 64 49 64 gms. 90 90 64 60 60 40 20 15 10 12 16 "16 10 10 10 10 10 10 10 145 15 15 15 15 15 165 15 15 15 20 gms. 8 8 8 8 8 8 8 8 8 8 0 0 0 0 8 20 20 20 20 20 20 20 20 20 20 gms. + 40 + 10 + 20 + '20 + 20 + 5 +'io + 15 -'35 - 35 - 45 - 25 -'26 - 35 + 120 -'36 - 25 - 40 kilos. 49 .'2 49.2 49.2 49.4 49.5 49.6 50.2 50.4 50.0 50.2 50.9 50.9 51.4 51.3 52.2 52.3 52.4 52.4 51.6 52.0 53.0 52.3 52.7 52.8 52.9 52.3 52.6 52.3 52;5 54.2 53.6 52^6 Apr. 19-20 Apr. 20-21.... Apr. 21-22 Apr. 22-23 Apr. 23-24 Apr. 24-25 Apr. 25-26 Apr. 26-27 Apr. 27-28 May 1-2 1910. Sept. 8- 9 Sept. 9-10 Sept. 10-1 1 Sept. 11-122 Sept. 12-13 Sept. 13-14 Sept. 14-15 Sept. 15-16 32 47 27 17 43 38 54 42 50 19 54 55 62 80 + Sept. 16-17 Sept. 17-18 3 Sept. 18-194 Sept. 19-20 *.... Sept. 20-21 .... Sept. 21-22 Sept. 22-235 20 - 25 Sept. 23-24 6 20 20 20 16 12 12 +115 - 5 - 40 - 40 - 40 Sept. 24-25 5 Sept. 25-26 Sept. 26-27... Oct. 3- 4 Oct. 13-14 Oct. 25-26 Nov. 16-17 Nov. 29-30 1 12 hours. 2 Vegetable day. 3 Oatmeal day with 120 c.c. cream and 215 gms. butter. * Vegetable day, with 240 c.c. cream. 'Vegetable day, 240 c.c. cream, 4 eggs. 6 Oatmeal day, 240 gms. oatmeal, 240 gms. butter, 120 c.c. cream. EXPERIMENTS WITH CASE O. Four respiration experiments were carried out with this subject, of vary- ing character. The vital statistics are as follows: Date of birth, August 16, 1894; height, 173 cm.; range in body-weight without clothing during experiments, 52.3 to 52.8 kilos. Respiration Experiment No. 01. Date, September 22, 1910. Body-weight without clothing, 52.8 kilos. On the day of the experiment the subject reached the laboratory, fasting, at 8h 05m a. m., and lay down on the couch immediately after the pneumograph had been adjusted. The stethoscope was not used in this experiment, the pulse- STATISTICS OF EXPERIMENTS. 39 rate being counted at the wrist. The experiment began at 8h 23m a. m., con- tinuing for three periods of 11 to 13 minutes, with intermissions of 10 to 17 minutes, ending at 9h 26m a. m. The subject remained quiet throughout all three periods, except for raising her hand to her head once in the first period. The surgeon's plaster was not used to close the mouth, nor did it appear to be necessary. The subject urinated at 7 a. m., and again after the experiment at 9h 30m a. m. The results are given in tables 35 and 39. Table 35. — Results of respiration experiment No. 01. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respi- ratory quotient. Average pulse- rate. Average respira- rate. Sept. 22, 1910: 8h 23m a.m 8 53 a.m 9 15 a.m Average min. sec. 12 51 12 29 10 36 c.c. 167 165 167 c.c. 231 219 228 0.73 .75 .73 62 63 68 17 18 18 '166 1226 0.74 64 18 i Carbon dioxide eliminated per kilogram per minute, 3.14 c.c; oxygen absorbed per kilogram per minute, 4.28 c.c. Respiration Experiment No. 02. Date, September 22, 1910. Body-weight without clothing, 52.8 kilos. This experiment was carried out in the afternoon of the day on which experiment No. 01 was made, after food had been taken. The diet for this day was that of a regular vegetable day, with the addition of 4 eggs and one-half pint of cream. The subject arrived at the laboratory at about 3 p. m., and immediately lay down upon the couch. The experiment began at 3h 12m p.m., continued for three periods 11 to 12 minutes in length, with the usual inter- missions, and ended at 4h 16m p. m. During the second period, some difficulty was experienced in obtaining a record of the pulse-rate. The subject was extremely quiet throughout the whole experiment. The records are given in tables 36 and 39. Table 36. — Results of respiration experiment No. 02. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Sept. 22, 1910: i.3h 12mp.m 3 39 p.m 4 06 p.m.... Average min. sec. 12 2 12 3 10 5 c.c. 208 213 197 c.c. 284 299 267 0.73 .71 74 64 2 72 69 21 17 19 3 206 3283 0.73 19 ■ The subject had probably taken food before this experiment. 2One record at 3a 47m p.m. 3 Carbon dioxide eliminated per kilogram per minute, 3.90 c.c; oxygen absorbed per kilogram per minute, 5.36 c.c. Respiration Experiment No. 03. Date, September 23, 1910. Body-weight without clothing, 52.3 kilos. The experiment was made on an oatmeal day, the first being a fasting period, and the second period following an oatmeal breakfast. The subject then returned to the hospital, but after a dinner containing oatmeal, came back to the laboratory and two additional periods followed. The experiment was concluded by two periods after the subject had been again to the hospital and eaten a lunch containing oatmeal. In the morning she reached the laboratory at 7h 55m a. m., without break- fast, and lay on the couch about 10 minutes before the experiment began at 40 METABOLISM IN SEVERE DIABETES. 8h 15m a. m. There was but one 15-minute period at this time, the subject lying very quietty throughout. Immediately after the fasting period was over, she was given oatmeal, which was eaten between 8h 45m a. m. and 8h 53m a. m. She again lay down upon the couch at 9h 46m a. m.; the next period began at 10h 01m a. m., con- tinuing for 15 minutes. The subject was very quiet throughout the period. At 2 p. m. the subject returned from the hospital, and immediately on her arrival at the laboratory lay down upon the couch. The measurements were begun at 2h 15m p. m., continuing for two periods, 10 and 12 minutes long, respectively, with an intermission of 15 minutes. No blanket was used to cover the subject, as she seemed comfortable without it. For the later periods, the subject came to the laboratory at 5h 30m p. m., and the measurements began at 5h 38m p. m., continuing for two periods of 12 and 13 minutes each, with an intermission of 10 minutes. As in the previous periods, the subject lay very quietly. The results of the measurements are given in tables 37 and 39. Table 37 — Result s of respiration experiment No. 03. Carbon dioxide Oxygen Respi- Average Average Date and time. Duration. absorbed ratory pulse- respira- per minute. per minute. quotient. rate. tion rate. Sept. 23, 1910: min. sec. c.c. c.c. Without food- s'* 15ma.m 14 45 1165 i 232 0.71 60 18 After oatmeal — - 10h01ma.m. ... 15 1 175 235 .74 66 18 2 15 p.m.... 11 55 175 257 .68 64 17 2 42 p.m 10 9 180 254 .71 68 17 5 38 p.m.... 12 9 183 262 .70 72 16 6 00 p.m.... 12 45 194 276 .70 70 16 = 181 3 257 .71 68 17 ■Carbon dioxide eliminated per kilogram per minute, without food, 3.15 c.c; oxygen absorbed per kilogram per minute, without food, 4.44 c.c. 2 Subject ate oatmeal between 8" 45m a.m. and 8 53m a.m. and throughout the day. (See notes.) 3 Carbon dioxide eliminated per kilogram per minute, with food, 3.46 c.c; oxygen absorbed per kilogram per minute, with food, 4.91 c.c. Respiration Experiment No. 04. Date, September 24, 1910. Body-weight without clothing, 52.6 kilos. The subject arrived at the laboratory, without breakfast, at 8h 03m a. m., and immediately lay down upon the couch. The experiment began at 8h 17m a. m., continuing for two periods of 12 and 13 minutes, with an intermission of 13 minutes. In both periods she was very quiet, only one slight movement of the hands in the second period being noted. As the subject seemed tired at the end of the second period, the experiment was discontinued. The results are given in tables 38 and 39. Table 3S. — Results of respiration experiment No. 04- Date and time. Duration. Carbon ,~. n - , dioxide Oxygen Respi- , Average rlii inn+orl absorbed ratory pulse- per minute. Per minute- c>uotient- ! rate" Average respira- tion rate. Sept.,24, 1910: 8h 17ma.m 8 42 a.m Average min. sec. 12 6 12 42 CO. 155 149 c.c. 213 0.73 209 .71 58 60 16 16 U52 1211 .72 59 16 i Carbon dioxide eliminated per kilogram per minute, 2.89 c.c; oxygen absorbed per kilogram per minute, 4.01 c.o. STATISTICS OF EXPERIMENTS. 41 Table 39. — Statistics of urine- -Respiration experiments Nos. 01-04- Date and period. Volume. Specific gravity. Total nitrogen. Sugar. Sept. 22, 1910: c.c. gms. gms. 7h 00m a.m. to 9h 30m a.m 520 1.010 0.91 4.2 9 30 a.m. 10 00 a.m 165 1.024 .02 2.5 10 00 a.m. 12 noon 600 1.019 1.64 7.8 12 00 noon 3 00 p.m.1.... 240 1.025 .74 4.1 3 00 p.m. 6 00 p.m 300 1.029 1.33 3.4 6 00 p.m. 8 15 p.m 315 1.029 1.27 3.4 8 15 p.m. 11 45 p.m 390 1.031 1.87 5.7 Sept. 22-23. 1910: llh45mp.m. to 7h00ma.m 750 1.024 3.00 11.0 Sept. 23, 1910: 7h00ma.m. to 9h 10m a.m.2.. . . 432 1.016 1.08 5.9 9 10 a.m. 11 30 a.m 480 1.022 1.39 9.3 11 30 a.m. 4 00 p.m 420 1.018 1.21 6.3 4 00 p.m. 7 15 p.m 330 1.027 1.04 6.4 7 15 p.m. 9 20 p.m 285 1.026 .79 5.6 Sept. 23-24. 1910: 9h 20m p.m. to 2h 15m a.m 420 1.034 1.49 8.3 Sept. 24, 1910: 2h15ma.m. to 7h 00m a.m 210 1.035 1.05 4.1 7 00 a.m. to 7 00 p.m 1250 1.025 5.08 5.9 Sept. 24-25, 1910: 7h 00™ p.m. to 7h 00™ a.m 1162 1.023 4.89 313.1 'Food was probably eaten at about noon. 2 Oatmeal was eaten between 8h 45m a.m. and 8h 53m a.m. and throughout the day. 3 Sugar by fermentation. CASE P. DESCRIPTION OF THE CASE. Male; born May 10, 1894; single; no occupation; lost strength in Decem- ber 1910; came under our observation September 1911; diagnosis of diabetes, which was confirmed by his physician, in January 1911 ; died in coma November 5, 1911. Family history. — Father and one sister well; mother in poor health; one sister died at 2 months, cause unknown. No history of diabetes in the family. Past history. — Measles. Always good health. As the family moved fre- quently from place to place he was much retarded in his studies at school ; this caused him much anxiety, and he consequently worked very hard. General history of the case.— -In December 1910, at the age of 17, his health failed, and the disease was diagnosed as diabetes in January 1911. He suffered from numerous furuncles which did not yield to local treatment, or treatment with vaccines. Worn out by these, the patient gradually failed, and suc- cumbed to coma on November 5, 1911. Physical examination. — Greatest weight, 49.9 kilos.; usual weight, 48.6 kilos.; January 1911, 45.8 kilos.; September 16, 1911, 42.1 kilos.; all weights without clothing. Height, 173 cm. Acetone odor to breath. Examination negative except for numerous furuncles, especially about the neck. Urine data. — The quantity of urine in January 1911 was approximately 5,000 c.c. The sugar disappeared after treatment for a month, but then per- manently returned. The reaction of the urine was acid throughout the period of observation. The ammonia amounted to 3.3 grams shortly after the patient came under observation in September 1911, rising to 6.5 grams October 14-15. The acidosis was so considerable that no great restriction of diet was attempted. The albumen never exceeded a very slight trace. The urinary record is given in table 40. 42 METABOLISM IN SEVERE DIABETES. EXPERIMENTS WITH CASE P. With this subject, three bed-calorimeter experiments were made and eight respiration experiments; the larger part of these formed a part of two series. Series I, which was made on September 29, 1911, consisted of three experi- ments, i.e., a respiration experiment (P2), followed by an experiment with the bed calorimeter (P3), and concluded by a second respiration experiment (P4). Series II, which was carried out October 9-10, 1911, included five experiments, beginning with a respiration experiment (P5) with the subject fasting, which was followed by two oatmeal experiments, the first with the bed calorimeter Table 40. — Clinical chart — Case P. Date. © a 'C 3 *o >> '> s V '5 o a ■d '3 d '■£ CD O s c o to o u -*> 2 Ammonia. Su< ;ar. c m 0 -w c5 . u -^> "73 tu 0 .a u c3 O Xl 0 C3 . t- CD ^5 JZ a 0 X! u 03 O 6 0 ■z J) h '3.2 i- = ^° pq kilos. 42.1 42.1 41.5 40.9 40.9 40.2 40.8 41.1 40.9 41 3 40.9 39.9 39.7 39.1 38.6 39.5 40.5 40.5 40.8 40.7 41 4 41.1 40.0 39 5 39.5 39 .6 39.9 39.1 39.1 38.4 38.9 39.4 39.5 39.4 39.3 38.9 3S.9 39 1 39 1 38.4 o H 1 C £ ° 0 e £.2 = 0 ° 3 >•£ « p c 0 *■£ 05 ■+^ 0 >> « 1911. Sept. 16-17 c.c. 1033 1030 102S 1027 1026 1027 1027 1025 1021 1027 1025 1024 1022 1034 1023 1025 1026 1025 1027 1026 1021 1026 1034 1024 1023 1026 1024 1024 1026 1027 1032 1029 1027 1026 1022 1025 1024 1022 1025 i027 + + + S1.+ + ++ ++ ++++ ++++ +++ ++ ++++ 0 +++ ++++ ++++ ++++ ++++ ++ +++ +++ ++ ++ S1.+ ++++ ++++ +++ +++ ++++ ++++ +++ ++++ ++ +++ ++++ + +++++ gms. 13 A 14.5 U.4 10.9 5 3 10.6 14.4 18.4 16.9 14.9 i3"2 17.8 11.1 8.2 16 0 14.2 14.9 14.0 22.4 17.7 16.1 13.6 19.5 15.8 15.4 22.0 14.2 is'2 17 9 14.5 giyis. S.3 4.5 4 6 4.4 i.9 4^2 4.5 4^4 2 1 5.0 4.1 4^9 4.2 4.7 4.5 6.5 5.5 5.0 4.5 4.7 5.3 4.0 4^i 4.1 3^7 p. ct. 28.3 26.1 37l6 32!6 25.7 i3*i 23.1 30.4 25 2 24.3 25.9 26.4 23.9 25.6 25 5 27.2 19.8 27.6 21.4 23!7 21.6 gms. "15 144 '86 108 '75 96 105 81 59 65 117 78 117 120 13.8 163 48 99 79 95 115 114 114 112 116 84 127 141 91 127 149 116 77 119 97 106 gms. 14.8 14.0 14.O 130 94 75 90 61 54 78 74 63 39 55 88 101 106 112 13.O 139 44 63 36 62 74 83 88 84 86 104 69 105 113 68 107 127 96 58 '84 gms. '85 85 100 so 75 75 55 45 gms. -'45 - 15 - 10 - 35 - 5 - 30 gms. 0 0 0 8 12 12 12 12 12 12 12 12 20 20 24 24 24 24 24 20 20 20 16 20 20 20 24 20 20 20 16 24 20 20 20 20 20 20 16 12 16 Sept. 17-18 3360+ 1920+ 3430 3360 2200 3000 2780 2980 2980 3090 2880 32S0 1840 3650 36; m 4080 4000 3320+ 4080 4360 4500 3020 2335 3330 3200 36SI) 3800 4320 4000 2885 3100 3520 3380 4100 4520 3420 3220 3720 3340 2800 Sept. 18-19 Sept. 19-20 Sept. 20-21 Sept. 21-22 Sept. 22-23 Sept. 23-24 Sept. 24-25 Sept. 25-26 40 - 55 40 - 65 Sept. 26-27 Sept. 27-28 411 15 165 80 80 80 SO 60 60 50 50 15 25 45 40 50 44 55 - 40 - 45 + 100 - 35 -'35 - 40 -105 + 2 - 50 - 40 -'70 - 70 - 75 - 65 - 70 - 60 Sept. 28-29 2 Sept. 29-30' Sept. 30 to Oct. 1 Oct. 1- 2 Oct. 2- 3 Oct. 3-4 Oct. 4-5 Oct. 5-6 Oct. 6- 7 Oct. 7- 8 Oct. 8- 9 Oct. 9-10 Oct. 10-11 Oct. 11-12 Oct. 12-13 Oct. 13-14 Oct. 14-15.. Oct. 15-16 Oct. 16-17 50 - 35 Oct. 17-18 80 80 75 80 75 75 75 - 45 - 60 - 15 - 45 - 75 - 40 Oct. 18-19.. Oct. 19-20 Oct. 20-21 Oct. 21-22 Oct. 22-23 Oct. 23-24 Oct 24 25 Oct. 25-26. Oct. 26-27 ++ 'Per cent. 2 Vegetable day, vegetables, bacon, broths, 240 c.c. cream. 3 Oatmeal day, 240 gms. oatmeal, 180 gms. butter, 240 c.c. cream. (P 6) and the other with the respiration apparatus (P 7) . In the fourth experi- ment (P8), the subject spent the night in the bed calorimeter, and the series was concluded by a respiration experiment (P 9) following a beefsteak break- fast. A comparison of the data for the calorimeter experiments is given in table 57. The vital statistics for this subject were as follows: Date of birth, May 10, 1894; height, 173 cm.; range in body-weight with- out clothing during experiments, 38.7 to 40.9 kilos. STATISTICS OF EXPERIMENTS. 43 Respiration Experiment No. PI. Date, September 25, 1911. Body-weight without clothing, 40.9 kilos. On the morning of the experiment the subject came to the laboratory, fasting, having had only a cupful of moderately strong coffee at 7 a. m. He lay down upon the couch at 7h 32m a. m.; mosquito netting was thrown over his face, shoulders, and arms; his feet were crossed and his arms folded upon his chest. The experiment began at 8h 54m a. m., continuing for three 15-minute Table 41. — Results of respiration experiment No. PI. Date and time. Duration. Carbon r\ Respiratory! Average ^3® quotient, i pulse-rate. ! ^te Sept. 25. 1911: »8h54ma.m 9 24 a.m 9 55 a.m min. sec. 15 8 14 59 14 56 c.c. 164 144 145 C.C. 215 0.76 214 .67 215 .68 72 18 72 19 69 19 = 151 2 215 .70 71 19 1 Subject drank a cup of coffee (quite strong) at 7 a.m. 2Carbon dioxide eliminated per kgm. per minute, 3.69 c.c; oxygen absorbed per kgm. per minute, 5.26 c.c. periods, with intermissions of 14 to 17 minutes. In the first period he un- crossed his feet at 9h 04m a. m. In the third period he moved his arm to his side, as it felt cramped. Aside from these movements, the subject was quiet and awake throughout the experiment. Previous to the experiment, he uri- nated at 7 a. m., and at 8h 30m a.m. he urinated and defecated. The results of the^experiment are given in tables 41 and 42. Table 42. — Statistics of urine — Respiration experiment No. PI. Date and period. Volume. Specific gravity. Total nitrogen. Sugar. Sept. 25, 1911: i7h00ma.m. to 8h 30™ a.m 8 30 a.m. 10 14 a.m Sept. 25-26, 1911: 10h 14ra a.m. to 7" 00m a.m c.c. 197 174 2610 1.025 1.023 1.029 gms. 0.93 .77 12.91 gms. 5.0 3.7 82.9 1 Subject drank a cup of strong coffee at 7 a.m. Respiration Experiment No. P2. Date, September 29, 1911. Body-weight without clothing, 39.7 kilos. This was the initial experiment of Series I, and was divided into two parts, the first part following a fast, and the second following the ingestion of food. The subject arrived at the laboratory, without breakfast, at 7h 40m a. m., and lay down upon the couch at 7h 52m a. m. At 8h 01m a. m. he drank a glass of water. The fasting portion of the experiment began at 8h 20m a. m., con- tinued for three periods of 14 to 15 minutes, and ended at 9h 28m a. m. The subject then ate 375 grams of cooked oatmeal and 45.5 grams of cream, taking at the same time 4 grams of sodium bicarbonate in 100 c.c. of water, and drinking 200 c.c. of cold water. The food was taken between 9h 42ra a. m. and 10h 34m a. m., although not all at one time. He urinated at 9h 30m a. m., and lay down on the couch again at 10h 35m a. m. for the final periods of the experiment ; four 15-minute periods followed, beginning at 10h 51m a. m. and ending at lh 04m p. m. He urinated at llh 41m a. m. and again at lh 26m p. m., after the experi- ment was over. The mouthpiece was used in all of the periods, the pulse and respiration rates being taken in the usual manner. After the third fasting 44 METABOLISM IN SEVERE DIABETES. period the subject complained that his legs felt stiff from keeping still so long. He was awake and very quiet during practically all of the experiment, save for a few slight movements of the hands and feet which seemed to be due to nervousness. The results of the experiment are given in tables 43 and 46. Table 43. — Results of respiration experiment No. P2. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. Sept. 29, 1911: Without food— 8h20ma.m. 8 46 a.m. 9 13 a.m. min. sec. 15 0 14 3 14 59 c.c. 147 145 147 c.c. 205 206 214 0.72 .70 .69 69 71 75 17 17 19 U46 177 162 162 157 '208 249 228 232 227 .70 .71 .71 .70 .69 72 82 80 80 77 18 19 19 19 18 With food— 210h51ma.m. 11 16 a.m. 12 22 p.m. 12 50 p.m. 14 55 15 4 14 57 14 45 Average 3 165 3 234 .70 80 19 'Carbon dioxide eliminated per kilogram per minute, without food, 3. 63 c.c.; oxygen absorbed per kilogram per minute, without food, 5.24 c.c. - Subject ate 375 gms. cooked oatmeal and 45.5 gms. cream between 9™ 42m and 9 55m a.m. and between 10h 30m and 10h 34m a.m. 3 Carbon dioxide eliminated per kilogram per minute, with food, 4.16 c.c; oxygen absorbed per kilogram per minute, with food, 5.89 c.c. Calorimeter Experiment No. P3. Date, September 29, 1911. Body-weight without clothing, 39.7 kilos. In this experiment, which was the second in Series I, the bed calorimeter was used for the first time with this subject. Food had been taken during one of the intermissions in the respiration experiment which preceded the calori- meter experiment. At lh 12m p. m., a meal consisting of 241 grams oatmeal and 37 grams of cream was eaten, together with 4 grams of sodium bicarbonate taken in 100 c.c. of water. The subject entered the bed calorimeter at lh 37m p. m. and the experiment began at 2h 20m p. m. After two 45-minute periods, the experiment ended at 3h 50m p. m. Both pneumographs, also the stetho- scope, were used for the regular records, but during the last 20 minutes of the second period the pulse-rate could not be obtained, as the subject had turned over on his side. He had boils on the back of his neck, but said after the exper- iment that he was very comfortable in the calorimeter, and, in fact, slept the greater part of the time. He urinated at lh 26m p. m. and 3h 55m p. m. No water was taken during the experiment. The records of the experiment may be found in tables 44 and 46. Table 44. — Measurements of metabolism — Calorimeter experiment No. PS. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total- nfito. Total. Per minute. Sept. 29, 1911: i 2h 20m p.m. to 3h 05m p.m 3 05 p.m. 3 50 p.m Total 1 hr. 30 min gms. 14.0 c.c. 2 158 gms. 14 6 15.0 c.c. 227 233 0.70 73 70 18 17 29.6 3230 1 Subject ate 241 gms. of cooked oatmeal and 37 gms. of cream between lh 12m p.m. and lh 24m p.m. 'Carbon dioxide eliminated per kilogram per minute, 2° 20m to 3b0am p.m., 3.98 c.c, •Oxygen absorbed per kilogram per minute, 2h 20™ to 3h 50™ p.m., 5.79 c.c. STATISTICS OF EXPERIMENTS. 45 Respiration Experiment No. P4. Date, September 29, 1911. Body-weight without clothing, 39.7 kilos. This experiment was the third in Series I, respiration experiment P2 and calorimeter experiment P3 preceding it. Immediately after the subject had left the bed calorimeter, he ate 114 grams of oatmeal and 10.5 grams of cream between 4h 02m and 4h 09m p. m. At 4h 10ra p. m. he lay down upon the couch. Table 45. — Results of respiration experiment No. P/+. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. Sept. 29, 1911: »4h 36m p.m... . 5 03 p.m min. sec. 14 59 9 27 c.c. 179 169 c.c. 241 0.74 78 82 19 19 = 174 2241 .74 80 19 'Subject ate 114 gms. oatmeal and 10.5 gms. cream between 4 02m and 4h 09m p.m. 2 Carbon dioxide eliminated per kilogram per minute, 4.38 c.c; oxygen absorbed per kilogram per minute, 6.07 c.c. At 4h 26m p. m. he took 4 grams of sodium bicarbonate in 100 c.c. of water. The experiment began at 4h 36m p. m., continuing for two periods of 15 and 9 minutes respectively, ending at 5h 12m p. m. He urinated at 3h 55m p. m. and 5h 35m p. m. The mouthpiece was used in this experiment, also, in preference to the nosepiece. The subject was reported as comfortable, very quiet, and awake. The results of the experiment are given in tables 45 and 46. Table 46. — Statistics of urine — Respiration experiments Nos. P2 and P 4, and calorimeter experiment No. P 3. Date and period. Volume. Specific gravity. Total nitrogen. Sugar. Sept. 29, 1911: 1 7h 00™ a.m. to 9b 30ra a.m 9 30 a.m. 11 41 a.m 2 11 41 a.m. 1 26 p.m 1 26 p.m. 3 55 p.m 3 3 55 p.m. *5 35 p.m c.c. 257 255 308 365 265 1 023 1.024 1.026 1.026 1.046 gins. 0.91 .78 .80 .98 .67 gms. 6.0 8.4 11 6 15 8 11.0 1 Subject ate 375 gms. of cooked oatmeal and 45.5 gms. of cream and drank 300 c.c. of water between 9h 42m and 10h 34m a.m. 2 Subject ate 241 gms. of cooked oatmeal and 37 gms. of cream and drank 100 c.c. of water between lh 12m and lh 24m p.m. 'Subject ate 114 gms. of cooked oatmeal and 10.5 gms. of cream and drank 100 c.c. of water between 4h 02m and 4h 09m p.m. 1 Subject ate 107 gms. of cooked oatmeal and 18.5 gms. of cream between 5h 30™ and 5h 34m p.m. Respiration Experiment No. P5. Date, October 9, 1911. Body-weight without clothing, 40 kilos. This was the initial experiment in Series II. The subject fasted during the experiment, having taken no food for at least 12 hours preceding it. He came to the laboratory at 7h 45m a. m., lay down upon the couch at 7h 50m a. m., and the experiment began at 8h llm a. m., continuing for two 15-minute periods. The mouthpiece and noseclip were used instead of the nosepieces. The room was very warm before the experiment began, but by opening the windows a little the temperature was gradually lowered. Throughout the two periods the subject was very quiet. After it was over he complained that his mouth was dry and that he felt weak. He also said that his stomach was out of order and he was troubled by gas, but felt hungry. The records of the experiment are given in tables 47 and 52. 46 METABOLISM IN SEVERE DIABETES. Table 47. — Results of respiration experiment No. Po. Date and time. Duration. Oct. 9, 1911: 8h llma.m. 8 37 a.m. Average . . mm. 15 15 sec. 4 Carbon dioxide eliminated per minute. c.c. 148 145 absorbed Respiratory Average permLute. ^otient' P«lse"rate- Average respiration rate. c.c. 219 212 0.68 .68 71 77 17 18 '147 '216 .68 74 18 .40 c.c. 1 ( arbon dioxide eliminated per kilogram per minute, 3.67 c.c; oxygen absorbed per kilogram per minute, 5. Calorimeter Experiment No. P6. Date, October 9, 1911. Body-weight without clothing, 40 kilos. This experiment was the second in Series II, following the fasting experi- ment P5 with the respiration apparatus. Between 9h 15m a. m. and 9h 35m a. m. the subject ate 355.7 grams of oatmeal, 52.1 grams of butter, and 49.3 grams of cream. He defecated at 9h 18m a. m. Before entering the bed calori- meter the subject also took 4 grams of sodium bicarbonate in about 150 c.c. of water. The stethoscope and pneumographs were used, but considerable diffi- culty was found in adjusting the stethoscope properly. He entered the appa- ratus at 9h 50m a. m., and the experiment began at 10h 59m a. m., continuing for two 45-minute periods, one 59-minute period, and one 36-minute period. During the third period he urinated at lh15m p.m. After the experiment the subject said he had been very comfortable throughout the whole time and had slept the greater part of the experiment. His statement was borne out by the records of the changes in the temperature of the calorimeter, for he was very quiet nearly all of the time. The measurements taken during the experiment are given in tables 48 and 52. Table 48. — Measurements of metabolism — Calorimeter experiment No. P6. Date and period. Carbon dioxide eliminated. Total. '' fc\ j minute. Oxygen a Total. bsorbed. Per minute. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Oct. 9, 1911: i 10h59ma.m. to 11" 44m a.m 11 44 a.m. 12 29 p.m 12 29 p.m. 1 28 p.m 1 2S p.m. 2 04 p.m Total 3 his. 5 min.2 gms. c.c. gms. 15.5 174 16.1 13.7 156 12.7 18.4 158 20.3 11.5 163 9.4 c.c. 250 198 242 183 0.70 .79 .66 .89 77 79 81 7S 18 18 17 19 59 1 163 58.5 221 1 Subject ate 355.7 gms. of cooked oatmeal, 52.1 gms. of butter, and 49.3 gms. of cream between 9h 15m and 9h 35m a.m. = Carbon dioxide eliminated per kilogram per minute, 4.08 c.c; oxygen absorbed per kilogram per minute, 5.53 c.c. Respiration Experiment No. P7. Date, October 9, 1911. Body-weight without clothing, 40 kilos. This experiment, which was the third in Series II, was divided into two parts, the subject taking food previous to the first and the fifth periods. After experiment P 6 was over, and the subject had left the bed calorimeter, he ate between 2h 10m p. m. and 2h 23m p. m., 297 grams of oatmeal, 40 grams of cream, and 44 grams of butter. He also took 4 grams of sodium bicarbonate in about 100 c.c. of water, and drank 200 c.c. of water in addition. At 2h 28m p. m. he lay down upon the couch, and the mouthpiece and noseclips were adjusted. The first part of the experiment began at 2h 36m p. m., continued for four STATISTICS OF EXPERIMENTS. 47 periods, each from 10 to 15 minutes in length, and ended at 5h 05m p. m. In the first and second periods the subject thought there was a slight leak about the noseclip, especially during one of three long breaths taken in the second period. He was very quiet in these two periods, except for adjusting the noseclip in the first minute of the first period. Between the second and third periods he sat up between 3h 09m and 3h 37m p. m., and drank 200 c.c. of water at 3h 10m p. m. He also drank 100 c.c. of water between the third and fourth periods, at4h 47m p. m. In this intermission he slept most of the time. At the close of the fourth period he had a slight headache. Before the second part of the experiment, the subject ate at 5h 40m p. m. 141.1 grams of oatmeal, 10.9 grams of butter, and 23.4 grams of cream. He also drank 100 c.c. of water. At 6 p. m. he defecated, and at 6h 10m p. m. he took 4 grams of sodium bicarbonate in 100 c.c. of water. At 6h 15m p. m. he drank 200 c.c. of water. He lay down upon the couch again at 6h 26m p. m., and four additional 15-minute periods followed, the first beginning at 6h 44m p. m., and the fourth ending at 9b 40m p. m. Between the fifth and sixth periods he sat up, but lay down again at 7h 31m p. m. In the intermission between the sixth and seventh periods, he urinated at 8h 03m p. m., and also drank 100 c.c. of water. During this period he expressed himself as being quite tired, and lay down at 8h 30m p. m. In the seventh period he was very quiet and awake, taking several long breaths near the end. He was reported as tired in the last period, also, and very quiet and awake. After the experi- ment was over he urinated and defecated at 9h 50m p. m. The records of the experiment are given in tables 49 and 52. Table 49. — Results of respiration experiment No. P7. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. Oct. 9,1911: '2h36mp.m 2 53 p.m 2 3 56 p.m.. 4 50 p.m.... Average min. sec. 10 13 15 8 14 55 14 48 c.c. 181 165 162 169 c.c. 243 243 245 232 0.74 .68 .66 .73 83 88 84 86 19 20 20 20 H69 3 241 .70 85 20 •>6h44mp.m. . . . 7 46 p.m 8 47 p.m 9 25 p.m 14 49 14 59 15 3 14 59 172 161 154 153 247 262 230 230 .70 .62 .67 .67 74 19 73 20 73 20 80 21 U60 5 242 .67 75 20 1 Oatmeal, 297 gins., butter, 43.6 gms., and cream, 45.7 gms., were eaten between 2h 10m and 2h 23m p.m. 2 Subject slept most of the time between this and the following period. 3 Carbon dioxide eliminated per kilogram per minute, 4.23 c.c; oxygen absorbed per kilogram per minute, 6.03 c.c. 4 Oatmeal, 141.1 gms., butter, 10.9 gms., and cream, 23.4 gms., were eaten between 5h 40'" and 6h 15m p.m. 6 Carbon dioxide eliminated per kilogram per minute, 4 c.c; oxygen absorbed per kilogram per minute, 6.05 c.c. Calorimeter Experiment No. P8. Date, October 9-10, 1911 . Body-weight without clothing, 40 kilos. In this experiment, which was the fourth of Series II, the subject spent the night in the bed calorimeter. When the subject entered the apparatus at 10h 15m p. m., he was dressed in pajamas and socks, and two pillows and two blankets were given him. The stethoscope and the pneumograph about the chest were not used, but only the pneumograph about the thighs to obtain, a record of the muscular movements. The measurements of the metabolism began at llh49m p. m., October 9, and continued for six periods of varying length, ending at 7h 41m a. m., October 10. The subject was reported as having moved in the fourth period; in the fifth period he moved about, telephoned, 48 METABOLISM IN SEVERE DIABETES. urinated at 5h 48m a. m., and drank 84 c.c. of water at about 5h 30m a. m. When telephoning he reported himself as feeling well. After the experiment was over he urinated again at 7h 52m a. m. The measurements made are given in tables 50 and 52. Table 50. — -Measurements of metabolism — Calorimeter experiment No. P 8. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Total. Per minute. Total Per minute. Oct. 9 and 10, 1911: > lib 49m p m t0 12h 49m a m 12 49 a.m. 1 49 a.m 1 49 a.m. 2 49 a.m 2 49 a.m. 4 27 a.m 4 27 a.m. 6 40 a.m Total 7 hrs. 52 min.2 oms. 15.9 16.5 16.3 27.7 38. 7 18.2 c.c. 135 140 138 144 148 152 gms. 17.0 18.5 17.3 28.1 41.0 18.4 c.c. 198 216 202 201 216 211 0.68 .65 .68 .72 .69 .72 133.3 144 140.3 208 1 Subject ate oatmeal, butter, and cream between 5h 40™ and 6h 15m p.m. 2 Carbon dioxide eliminated per kilogram per minute, 3.60 c.c. ; oxygen absorbed per kilogram per minute, 5.20 c.c. Respiration Experiment No. P9. Date, October 10, 1911. Body-weight without clothing, 38.7 kilos. Previous to this experiment, which concluded Series II, the subject ate a breakfast between 8 h 15In a. m. and 8h 30m a. m., consisting of 1G8.9 grams of beefsteak, 16 grams of butter, and 2 small onions, sliced and fried crisp. He also took 4 grams of sodium bicarbonate in 100 c.c. of water, and drank in addi- tion 250 c.c. of water. At 8h 35m a. m. he lay down upon the couch ; the experi- ment began at 9h 05m a. m., and continued for four 15-minute periods, ending at 12h 10m p. m. In all of the periods the subject was very quiet, except for slight movements of the hands and feet. Between the first and second periods the subject lay upon the couch and read a newspaper; between the second and third periods he sat up, but lay down again about 15 minutes before the next period began; during the intermission between the third and fourth periods the subject slept. He urinated at 10h30m a. m. and again at 12h 12m p. m. During the experiment he drank water only once, 120 c.c. at 10h 30m a. m. The records of the experiment are given in tables 51 and 52. Table 51. — Results of respiration experiment No. P9. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. Oct. 10, 1911: 19h05ma.m 9 57 a.m 10 59 a.m 11 55 a.m min. sec. 14 54 14 52 14 42 14 59 c.c. 158 166 169 172 c.c. 243 244 248 241 0.65 .68 .68 .71 77 79 81 85 19 20 19 19 2 106 2 244 .68 81 19 1 Subject ate 168.9 gms. beefsteak, 16 gms. butter, and 2 small onions between 8h 15m and 8h 30m a.m. 2 Carbon dioxide eliminated per kilogram per minute, 4.29 c.c. ; oxygen absorbed per kilogram per minute, 6.30 c.c. Respiration Experiment No. P 10. Date, October 16, 1911. Body-weight without clothing, 39.1 kilos. This experiment was divided into two sections. The first three periods were fasting, no food having been taken since the evening meal of the day STATISTICS OF EXPERIMENTS. 49 before, with the exception of 60 c.c. of black coffee at 8 a. m. The last five periods followed the ingestion of food. The subject had a slight cold on the day of the experiment. Table 52. — Statistics of urine — Respiration experiments Nos. P5 to P9 and calorimeter experiments Nos. P 6 and P S. Date and period. Volume. Specific gravity. Total nitrogen. Sugar. Oct. 9, 1911: c.c. gms. gms. » 7h 00m a.m. to 9^ 13m a.m 280 1.020 0.92 5.2 9 13 a.m. 1 15 p.m 480 1.023 1.41 14.6 21 15 p.m. 2 12 p.m 144 1.023 .42 4.5 2 12 p.m. 5 06 p.m 460 1.025 1.18 14.4 5 06 p.m. 8 03 p.m 373 1.023 .84 12.2 8 03 p.m. 9 50 p.m 256 1.025 .64 6.9 Oct. 9-10, 1911: 3 9*> 50m p.m. to 5h 48m a.m 610 1.024 2.13 12.8 Oct. 10, 1911: 5M8ma.m. to 7h 52m a.m 232 1.027 .84 6.1 4 7 52 a.m. 10 30 a.m 350 1.019 1.00 8.6 10 30 a.m. 12 12 p.m 270 1.022 1.01 7.6 Oct. 10-11, 1911: 12b I2m p.m. to 7h00ma.m 2760 14.11 79.8 1 Subject ate 355.7 gms. cooked oatmeal, 49.3 gms. cream, and 52.1 gms. butter between 9*» 15m and 9h 35m a.m., and drank 150 c.c. water at 10 a.m. 2 Subject ate 297 gms. cooked oatmeal, 45.7 gms. cream, and 43.6 gms. butter, and drank 300 c.c. of water between 2h 10™ and 2h 23m p.m. 3 Subject ate 141.1 gms. cooked oatmeal, 23.4 gms. cream, and 10.9 gms. of butter, and drank 400 c.c. of water between 5h 40m and 6h 15m p.m. 4 Subject ate 168.9 gms. beefsteak, 16 gms. butter, and 2 small onions, and drank 350 c.c. water between 8h 15m and 8h 30™ a.m. As usual with this subject, the mouthpiece and noseclip were substituted for the nosepieces. Both pneumographs were used, also the stethoscope. The subject lay down upon the couch at 8h 17m a. m. The experiment began at 8h 48m a. m., continued for three periods 12 to 15 minutes in length which ended at 9h 48m a. m. The subject then ate 301.5 grams of beefsteak and 20.8 grams of butter, finishing at 10h 10m a. m. He drank with the food 600 c.c. of water Table 53. — Results of respiration experiment No. P 10. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. Oct. 16, 1911: Without food. i8M8ma.m.... 9 11 a.m.... 9 36 a.m.... Average min. sec. 14 55 15 3 11 35 c.c. 159 154 152 c.c. 221 217 219 0.72 .71 .69 75 77 77 17 19 19 2 155 164 166 178 169 181 2219 241 247 260 257 256 .71 .68 .67 .68 .66 .71 76 79 82 83 81 88 18 19 19 19 17 20 With food. 3 10h3Sraa.m.... 11 28 a.m.... 12 22 p.m.... 1 00 p.m.... 1 31 p.m.... Average 15 0 15 7 14 44 14 43 15 3 4 172 4 252 .68 83 19 'Subject drank 60 c.c. of black coffee at 8 a.m. 2Carbon dioxide eliminated per kilogram per minute, without food, 3.96 c.c; oxygen absorbed per kilogram per minute, without food, 5.60 c.c. 3 Subject ate 301 5 gms beefsteak and 20.8 gms. butter between 9h 53ra and 101* 10™ a.m. 4 Carbon dioxide eliminated per kilogram per minute, with food, 4.40 c.c; oxygen absorbed per kilo- gram per minute, with food, 6.45 c.c. and took 4 grams of sodium bicarbonate in about 100 c.c. of water. The next period began at 10h 38m a. m., the five 15-minute periods ending at lh 46m p. m. The subject was very quiet throughout the experiment, only slight movements being reported. During the last three periods he said he felt rather tired; in 50 METABOLISM IN SEVERE DIABETES. the seventh period he was sleepy, and the observer thought the lips dropped away from the mouthpiece and that the subject fell asleep once. He was awake in the last period, however. In the intermission between the fourth and fifth periods he lay upon the couch reading a newspaper. Between the sixth and seventh periods he left the room to telephone, and lay on the couch only about 5 minutes before the next period began. Between the seventh and eighth periods he stood up and took some water. In addition to the water taken with the food he drank one glassful at 8.25 a. m., 100 c.c. at 12h 44ni p. m., and 100 c.c. at lh 25m p.m. He urinated at 7 a.m., 9h 50m a.m., 12h llm p. m., and lh 48m p. m. The records of the experiment are given in tables 53 and 54. Table 54. — Statistics of urine — Respiration experiment No. P 10. Date and period. Volume. Specitfio gravity. Total nitrogen. Sugar. Oct. 16, 1911: '7h 00m a.m. to 9h 50m c c 352 1.024 282 1.025 210 1 025 2040 gms. 1.S2 1.54 1.28 11.49 gms. 8.9 G.2 4.9 59.3 29 50 a.m. 12 11 p.m 12 11 p.m. 1 4S p.m Oct. 16-17, 1911: lh 48m p.m. to 7h 00"1 a.m 1 Subject drank 60 c.c. of black coffee at 8 a.m. and 200 c.c. of water at 8h 25m a.m. 2 Subject ate 301.5 gms. of beefsteak and 20.8 gms. of butter and drank 700 c.c. of water between 9h 53m a.m. and 10" 25m a.m. » Respiration Experiment No. Pll. Date, October 25, 1911. Body-weight without clothing, 39.1 kilos. This experiment was similar to the preceding experiment in that it was divided into two parts, the subject fasting in the first three periods, and the last periods following the taking of food. The mouthpiece and noseclips were used instead of the nosepieces. On the morning of the experiment, the subject came to the laboratory without breakfast, and lay down upon the couch at 7h 35m a. m. The first three 15-minute periods began at 7h 59m a. m., Table 55. — Results of respiration experiment No. Pll. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average Average p££& ^ration Oct. 25, 1911: Without food — 7h59ma.m.... 8 26 a.m 8 49 a.m.... min. sec. 15 0 15 5 14 59 c.c. 145 146 147 c.c. 201 202 210 0.72 .72 .70 66 17 69 18 71 19 Average U46 149 160 194 172 ■204 244 243 265 244 .71 69 18 .61 74 16 .66 74 19 .73 76 19 .70 74 18 With food— lOMo^.m2.... 11 16 a.m.... 12 32 p.m.... 1 31 p.m.... 14 56 14 56 15 15 15 2 Average 3 169 3 249 .68 75 18 1 1 Carbon dioxide eliminated per kgm. per minute, without food, 3.73 c.c; oxygen absorbed per kgm. per minute, without food, 5.22 c.c. 2 Subject ate 284.5 gms. beefsteak, 23.3 gms. butter, and 2 small onions between 9h 24m and 9h 41m a.m. 3 Carbon dioxide eliminated per kilogram per minute, with food, 4.32 c.c; oxygen absorbed per kilogram per minute, with food, 6.37 c.c and ended at 9h 04m a. m. The subject then ate, between 9.24 and 9.41 a. m., 284.5 grams of beefsteak, 23.3 grams of butter, and two small onions, fried. He also took 4 grams of sodium bicarbonate in 100 c.c. of water. After eating, he lay down upon the couch at 9h 43m a. m., and the four succeeding periods began at 10h 10m a. m., ending at lh 46m p. m. He was very quiet and awake STATISTICS OF EXPERIMENTS. 51 throughout all of the periods. Several slight motions were reported by the observer. The third period seemed very long to the subject. He was sleepy in the period directly following the taking of food, but did not go to sleep. In the intermission between the sixth and seventh periods he sat up for a time and Table 56. — Statistics of urine — Respiration experiment No. PH. Date and period. Volume. Specific gravity. Total nitrogen. Sugar. Oct. 25, 1911: 7h 00m a.m. to 10h 50m a.m.i. . . . 10 50 a.m. 1 00 p.m 1 00 p.m. 2 45 p.m Oct, 25-26, 1911: 2h 45™ p.m. to 7h00ma.m c.c. 476 390 276 2200 1.022 1.023 1.024 1.024 gms. 1.96 1.75 1.56 12.54 gms. 11.6 10.4 6.9 67.8 1 Subject ate 284.5 gms. beefsteak, 23.3 gms. butter, and 2 small onions, and drank 500 c.c. water between 9h 24™ and 9h 55m a.m. said he felt quite tired. In this intermission, also, he drank a glass of water containing 4 grams of sodium bicarbonate. The subject urinated at 7 a. m., 10h 50m a. m., 1 p. m., and 2h 45m p. m. The records of the experiment are given in tables 55 and 56. Table 57. — Comparison of metabolism experiments in bed calorimeter with Case P. EXPERIMENT WITHOUT FOOD. Experi- ment No. P8 Date. 1911. Oct. 9-10 1. Weight of subject. kilos. 40.0 Length of ex- periment hrs. min. 7 52 Per minute. Carbon dioxide elimi- nated. c.c. 144 Oxygen absorbed c.c. 208 Respi- ratory quotient. 0.69 Average pulse per minute. Average respira- tion per minute. EXPERIMENTS WITH FOOD. 1911. kilos. hrs. ?}iin. c.c. c.c. P3 Sept. 29 2. . 39.7 1 30 3 158 230 30.70 72 P6 Oct. 9 *. . 40.0 3 05 163 221 .73 79 17.5 18.0 1 About 6 hours before the beginning of the experiment the subject ate 141.1 gms. cooked oatmeal, 23.4 gms. cream, and 10.9 gms. butter. 2 About 1 hour before beginning of experiment the subject ate 241 gms. cooked oatmeal and 37 gms. cream. 'The carbon dioxide eliminated and the respiratory quotient for this experiment are for the period 2h 20™ to 3h 05™ p.m. 4 About 1 hour 30 minutes before the experiment began the subject ate 355.7 gms. cooked oatmeal, 52.1 gms. butter, and 49.3 gms. cream. CASE Q. DESCRIPTION OF THE CASE. Male; born March 1, 1896; single; no occupation; developed symptoms of diabetes at the age of 13, September 1909; came under our observation Novem- ber 1910; diagnosed as diabetes January 1910; died in coma March 14, 1911. Family history. — No history of diabetes in the family. Father, mother, and one brother well. Past history. — Greatest weight, 54.0 kilos, without clothes ; weight Novem- ber 13, 1910, 51.6 kilos, without clothes. Measles, mumps, whooping-cough, severe tonsilitis in 1907. General history of the case. — Symptoms of diabetes were first observed in September 1909. A single specimen of urine voided on rising in August 1909 was free from sugar. In November 1909 a sticky deposit was observed about the urinal, but diabetes was not proved present until January 1910. The con- 52 METABOLISM IN SEVERE DIABETES. dition of the patient while at the hospital in November 1910 was critical. From December 28, 1910, to March 1, 1911, he was under the care of Dr. A. J. Hodgson, at Waukesha, Wisconsin, where he gained in weight up to 54.9 kilos, without clothing. The treatment was said to have consisted of a large quan- tity of vegetables, nuts, and water. Unfortunately no analysis of a specimen of the 24-hour quantity of urine was made during this period. Death occurred in coma March 14, 1911. An examination of the organs of the patient was made by Prof. F. B. Mallory, of the Harvard Medical School, who writes that it showed absolutely nothing abnormal; the pancreas was in all respects normal. Physical examination. — A well-developed and nourished boy with good color. Height 168 cm. Pupils equal and reacted to light. Knee-jerks nor- mal. No edema. High-arched palate. Pulse-rate 96. Physical examina- tion was otherwise negative in September 1910. Urine data.- — The urinary record is given in table 58. Previous to Novem- ber 1910, when the patient first came under observation, the greatest quantity of urine was 3000 c.c. It subsequently rose to 3500 c.c. on December 15, 1910, but after that date there is no accurate record. The reaction of the urine was acid during this period. The ammonia reached 6.4 grams on December 15, 1910, and on November 18-19, 1910, the quantity of /3-oxybutyric acid was 30 grams. The albumen never exceeded a very slight trace. During the summer of 1910, the patient was sugar-free for several months. Throughout the period of observation, 20 grams of sodium bicarbonate were given the patient each day. Table 58. — Clinical chart — Case Q. Date. ffl* c 'C 3 «** O o s > >> ■6 '3 03 Nitrogen. Ammonia. Sugar. Carbohvdratea in diet.6 03 £) a> +a c3 . i <^ >>£ 0 oi O J; ? ti -^ S "SO ps 0 i? = ^° m > o! O '3 a a m "2 '3 d o '■3 o o 03 3 o >> +3 3 O "3 -^ o H I 5 "3 +» o H o • a c a. o 0+3 3 "3 £8 c" o OS -^ O L. >> ffl 1910. Nov. 12-13 Nov. 13-14 Nov. 14-15 Nov. 15-16 Nov. 16-17 Nov. 17-18 Nov. 18-19 Nov. 19-20 Nov. 20-212.... Nov. 21-22 3.... Nov. 22-23 4.... Nov. 23-24 5.... Nov. 24-25 Nov. 25-26 Dec. 14-15 c c 13030 3090 3260 3200 2200 2620 2X20 2570 2520 1430 1565 2250 3500 3500 1036 1032 1029 1032 1034 1034 1033 1027 1029 1037 1038 1033 1030 1035 +++ ++++ ++ ++++ ++++ ++++ +++ +++ +++ +++++ ++++ '"+ +++ ++ 1 1 1 ms. too >7 5 '6.7 9.7 9.6 gms. 2IK2 18.7 17.0 16.6 18.1 15.6 14 0 11.2 7.0 7.0 12^3 13.7 gms. 3.9 4.S 5.2 4 6 4.0 3 0 2.2 6'4 p.ct. i7'2 23.8 27A 27.0 29.4 35 3 25 9 gms. 105 ioi 83 iii 67 73 69 92 '90 117 gms. 121 93 75 90 70 94 96 51 60 63 81 'si 105 140 gms. "55 55 55 55 55 55 55 55 165 165 '26 gms. -50 -20 -50 - 3 -40 -55 -10 -20 +95 +75 -70 kilos. 51.6 52.5 52.1 51.5 51.3 51.1 51.6 51 4 51 4 51.5 1 For 20 hours. 2 Vegetable day; vegetables, 6 eggs, 240 c.c. cream, bacon, coffee, broths. 'For 24? hrs.; oatmeal day. 'Oatmeal day. 6For record of urine for Nov. 23-24, see table 63. 8 NaHC03 given each day, 20 gins. EXPERIMENTS WITH CASE Q. Four calorimeter experiments were made with this subject, all with the bed calorimeter. In the first and fourth experiments, the metabolism after a 12-hour fast was studied, and in the second and third experiments, after the ingestion of oatmeal. A comparison of the results of these experiments is made in table 64. There were no respiration experiments with this subject. The vital statistics were as follows: Date of birth, March 1, 1896; height, 168 cm.; range in body-weight with- out clothing during experiments, 51.4 to 52.0 kilos. STATISTICS OF EXPERIMENTS. 53 Calorimeter Experiment No. Ql. Date, November 19, 1910; body-weight without clothing, 51.4 kilos. The subject came to the laboratory early in the morning without break- fast and entered the bed calorimeter at 7h10m a. m. The experiment began at 8h 09m a. m., and continued for three 45-minute periods, ending at 10h 24m a. m. The pulse and respiration rates were obtained in the usual way. Throughout the whole experiment the subject lay on his back, reading, and was very quiet. After the experiment was over he said that although he felt rather warm he was very comfortable and found his stay in the chamber pleasant. The records of the experiment may be found in table 59. Table 59. — Measurements of metabolism — Calorimeter experiment No. Q 1. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Nov. 19, 1910: 8h 09m a.m. to 8h 54m a.m 8 54 a.m. 9 39 a.m 9 39 a.m. 10 24 a.m gms. 16.4 15.4 14.9 c.c. 184 174 169 gms. 15.5 15.5 13.8 c.c. 241 241 216 0.77 .72 .78 79 79 79 23 20 19 46.7 176 44.8 232 1 Carbon dioxide eliminated per kilogram per minute, 3.42 c.c.; oxygen absorbed per kilogram per minute, 4.51 c.c. The urine collected between 6h 4 5m and 10h 4'Jm a.m. amounted to 270 c.c; specific gravity 1.029, and contained 1.75 gms. nitrogen and S gms. sugar. Calorimeter Experiment No. Q2. Date, November 21, 1910. Body-weight without clothing, 51.5 kilos. Previous to coming to the laboratory at 7 a. m. the subject ate a break- fast consisting of approximately 60 gms. oatmeal (weight uncooked) and 90 gms. cream. He entered the bed calorimeter at 7h20m a.m.; the experiment began at 8h 18m a. m., and continued for three 45-minute periods, ending at 10h 33m a. m. The subject was dressed in his ordinary clothing, and lay on Table 60. — Measurements of metabolism— Calorimeter experiment No. Q 2. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Nov. 21, 1910: 1 8h 18m a.m. to 9h 03m a.m 9 03 a.m. 9 4S a.m 9 48 a.m. 10 33 a.m Total 2 hrs. 15 min.2 gms. 17.6 17.0 16.4 c.c. 199 192 186 gms. 14 .8 15.9 15.9 c.c. 230 248 247 0.86 .78 .75 81 82 83 18 26 30 51.0 192 46.6 242 ■Subject ate for breakfast at about 6h 33ra (?) a.m. approximately 60 gms. oatmeal (weight uncooked) and 90 gms. cream. 2 Carbon dioxide eliminated per kilogram per minute, 3.73 c.c ; oxygen absorbed per kilogram per minute, 4.70 c.c. a pneumatic mattress, with his head resting upon two pillows and lifted to an angle of 35° by means of a wooden head-rest. Throughout the experiment he lay very quiet on his back, without reading. Just before entering the calorim- eter the subject drank water, but no water was taken during the experiment. He urinated at 6h 50m a. m., before coming to the laboratory, and again at 10h 51m a. m., after the experiment was over. The records are given in tables 60 and 63. 54 METABOLISM IN SEVERE DIABETES. Calorimeter Experiment No. Q3. Date, November 22, 1910. Body-weight without clothing, 51.8 kilos. This experiment also followed the ingestion of oatmeal, the subject eating a breakfast consisting of approximately 70 gms. of oatmeal (weight uncooked) , 15 gms. butter, and 60 gms. cream. The subject reached the laboratory at 7h 35m a. m., entered the bed calorimeter at 7h 46m a. m., and the experiment began at 8h 26m a. m., continuing for three 45-minute periods and ending at 10h 45m a. m. The subject was very quiet during the first two periods, and was probably asleep during the second period. At the beginning of the third period he began reading and continued to read until shortly before the close of the experiment. The subject urinated both before and after the experi- ment, at 7h 20m a. m. and llh 05m a. m. respectively. The records are given in tables 61 and 63. Table 61. — Measurements of metabolism — Calorimeter experiment No. Q 3. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Nov. 22, 1910: i8h26ma.m. to 9h 12™ a.m 9 12 a.m. 9 57 a.m 9 57 a.m. 10 45 a.m Total 2 hrs. 19 min.2 gms. 16.3 15.9 16.7 c.c. 179 180 178 gms. 15.5 14.3 15.9 c.c. 235 222 232 0.76 .81 .77 70 68 66 23 22 26 48.9 179 45.7 230 •• 'Subject ate for breakfast at about 7 (?) a.m. approximately 70 gms. oatmeal (weight uncooked), 15 gms. butter, and 60 gms. cream. 2Carbon dioxide eliminated per kilogram per minute, 3.46 c.c: oxygen absorbed per kilogram per minute, 4.44 c.c. Calorimeter Experiment No. Q4. Date, November 23, 1910. Body-weight without clothing, 52.0 kilos. On the morning of the experiment the subject came to the laboratory with- out breakfast at 7h 35m a. m., and entered the bed calorimeter at 7h 42m a. m. The experiment began at 8h 35m a. m., and continued for three 45-minute periods, ending at 10 h 50m a. m. Throughout the experiment the subject was very quiet, not even reading. He urinated both before and after the experi- ment, at 7h 25m a. m. and 1 1 h 03m a. m., respectively. The records of the experi- ment are given in tables 62 and 63. Table 62. — Measurements of metabolism — Calorimeter experiment No. Q 4. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Nov. 23, 1910: 8h 35™ a.m. to 9h 20™ a.m 9 20 a.m. 10 05 a.m 10 05 a.m. 10 50 a.m Total 2 hrs. 15 ruin.2 0 m .<; . 15.3 15.7 14.3 c.c. 173 178 162 gms. 13 7 15.3 13.5 c.c. 213 238 210 0.81 .75 .77 163 66 65 30 28 31 45.3 171 42.5 220 1 One record at 9h 18™ a.m. 2 Carbon dioxide eliminated per kilogram per minute, 3.29 c.c; oxygen absorbed per kilogram per minute, 4.23 c.c. STATISTICS OF EXPERIMENTS. 55 Table 63. — Statistics of urine — Calorimeter experiments Nos. Q 2-Q 4- Date and period. Volume ! £*£ c c Nov. 21, 1910: 6h 50™ a.m.' to 10h 51m a.m 410 Nov. 21-22, 1910: 10h 51m a.m. t-> 7h 20™ a.m 1020 Nov. 22, 1910: 7h 20ma.m.» to llh05ma.m 327 Nov. 22-23, 1910: ll1' 05m a.m. to 7h 25m a.m. . . . 1240 Nov. 23, 1910: 7h 25™ a.m. to llh 03m a.m 116 Nov. 23-24, 1910 * 1.035 1.038 1.043 1.038 1.041 1.032 Total nitrogen. Sugar. (jms. 1.93 L56 5.44 .70 6.35 gms. 27.0 !40.4 26.4 69.3 7.0 21.1 ' Subject ate oatmeal at about 6h 30m (?) a.m. 2 Sugar by fermentation. 3Subject ate oatmeal at about 7 (?) a.m. ( Volume of urine analyzed was 900 c.c. It could not be learned whether this was the total for the remainder of the 24 hours. The nitrogen and sugar for the total 24 hours are, therefore, not known. Table 64.— Comparison of metabolism experiments in the bed calorimeter with Case Q. EXPERIMENTS WITHOUT FOOD. Experi- ment No. Date. Weight of subject. Length of ex- periment. Per minute. Respi- ratory quotient. Average pulse per minute. Average respira- tion per minute. Carbon dioxide elimi- nated. Oxygen absorbed. Ql Q4 1910. Nov. 19... Nov. 23... kilos. 51 4 52.0 hrs. min. 2 15 2 15 c.c. 176 171 c.c 232 220 0.76 .78 79 65 20.5 29.5 EXPERIMENTS WITH FOOD. Q2 Q3 1910 Nov. 21i.. Nov. 222.. kilos. 51.5 51.8 hrs. min. 2 15 2 19 c.c. 192 179 c.c. 242 230 0.80 .78 82 68 24.5 23.5 1 Subject ate oatmeal for breakfast about 1 hour 45 (?) minutes before experiment began. 2 Subject ate oatmeai for breakfast about 1 hour 30 minutes (?) before experiment began. CASE R. DESCRIPTION OF THE CASE. Male; born March 16, 1863; married; financier; developed symptoms of diabetes in November 1903, but the diagnosis was not made until March 21, 1904; came under our observation June 27, 1910; died of pulmonary tuber- culosis March 14, 1912. Family history. — No history of diabetes in the family. Father well at 82; mother died of arterio-sclerosis at 69. Three sisters and four children well. Seven uncles died of pulmonary tuberculosis. Past history. — Wiry but not strong. Measles, mumps, whooping-cough, typhoid, scarlet fever, jaundice at approximately 15 years of age, malaria twice. General history of the case. — The record of the case is given in full, because no patient has come under our observation who more carefully carried out modern dietetic treatment and also because of the extreme acidosis which dis- appeared with the onset of tuberculosis. In November 1903 the patient was "run down." In January 1904 he had polydipsia and was a trifle irritable. The urine of March 21, 1904, had a specific gravity 1.041, with a sugar content of 7.8 per cent. Under dietetic treatment sugar disappeared from the urine on April 15, 1904, and did not return until March 13, 1905, when the diet was somewhat relaxed. Later it again disappeared, not recurring until October 24, 1905. It was absent throughout 1906, and present at only two of 15 analyses 56 METABOLISM IN SEVERE DIABETES. during 1907. On January 24, 1908, 0.3 per cent of sugar was present; in April of the same year Prof, von Noorden found difficulty in making the urine sugar-free despite vegetable days and oatmeal days, and following the patient's visit to Vienna the sugar was invariably present. Along with the gradual increase in acidosis which was first noted in 1908, the diet was gradually relaxed, and apparently each time with benefit. During the latter part of December 1911 tuberculosis appeared and the weight fell rapidly. With the appearance of the tuberculosis there was a gradual increase in the tolerance for carbohydrates and a decrease in the acidosis, a condition similar to that which occurred in Case A. Similar occurrences have been recorded by various writ- ers. All data relating to the case from the beginning of observation, June 27, 1910, until death on March 14, 1912, can be considered absolutely reliable. Physical examination. — Greatest weight, 66.7 kilos, without clothing; June 27, 1910, 60.5 kilos, without clothing. Height, 181 cm. Pupils equal and reacted to light. Teeth in excellent condition, undoubtedly due in part to cleansing by dentist every 6 weeks. Lungs normal. Heart, apex in mammil- lary line, systolic at base and apex. Blood-pressure, 126. Pulse-rate, 96. Right kidney large and palpable throughout. Liver, spleen, and left kidney not palpable. No note of abnormality of knee-jerks. Urine data. — The reaction of the urine was acid throughout the period of our observation, but according to von Noorden's records, it had previously been alkaline several times. The acidosis was extreme from June 1910 until the last few months of life. In no other case coming under our observation has the quantity of /3-oxybutyric acid been greater than with this patient, increas- ing to over 50 grams in March, April, August, September, November, and December 1911, the amount on Christmas Day being 54.8 grams. Although the amount of nitrogen in the diet was kept at a moderate level, the ammonia was high from the first, reaching 8 grams in February 1911, notwithstanding 20 grams of sodium bicarbonate were being taken daily. The quantity of sugar steadily rose from approximately 50 grams in June 1910 up to 200 grams in March 1911, but subsequently somewhat decreased, falling far below this in the spring of 1912, coincident with the presence of tuberculosis. A minus car- bohydrate balance was present from June 1910 until the last two months of life. The body-weight slowly fell from 60.5 kilos, on June 29, 1910, to 34.5 kilos, on March 23, 1912. The urinary record is given in table 65. EXPERIMENTS WITH CASE R. With this subject one calorimeter experiment was made, in which the sub- ject fasted and the bed calorimeter was used; three respiration experiments were also made, each of which was preceded by the ingestion of food. The vital statistics were as follows: Date of birth, March 16, 1863; height, 181 cm.; range in body-weight without clothing during experiments, 55.3 to 58.2 kilos. Respiration Experiment No. Rl. Date, August 1, 1910. Body-weight without clothing, 56.4 kilos. This was intended to be only a trial experiment, since it was the first respiration experiment with this subject. After a breakfast consisting of 36 gms. of Quaker oats (weight uncooked), 125 c.c. of cream, 2 eggs, one-half biscuit, and 2 cupfuls of coffee containing 100 c.c. of sugarless diluted milk, also 4 grams of sodium bicarbonate in water, the subject came to the labora- tory and lay down upon the couch at 9h 50m a. m. The experiment included but one period of 12 minutes, beginning at 9h 55m a. m. and ending at 10h 07m a. m. The pulse-rate ranged from 95 to 100, and the respiration-rate from 15 to 17. The results of the experiment are given in table 66. STATISTICS OF EXPERIMENTS. 57 cent ruit. cent, oat- ul. cent, oat- ful. cent, oat- ful. c.c, half cent, »ms., 6-10 pel f grape -10 per pefruit, espoonf l).«0 CD--' 0 JJ? D. 3 O Q. 3 O OJ 5-6-10 grapefr tablesp 5-6-10 grapefr tablesp , cream s. 0-375 c 3 5-6-10 oatmea M 0> « / m o £==:_ <"-3 ^^ 2 ~ »0 CD - c3 E § +3 o O 43 Rarely a hyaline cas Vegetables and eggs. Strict diet; vegetable groups, cream 250 c Strict diet, vegetabl cream 250 c.c, ha meal 36 gms., peas 03 O CS CD M>o ths. am etab jonfu M day. ay. day. ; mea da j'. 03 £c? to «? ' M » To H cjcdco o y fflir o > fi > C^f o "^ Tn ^ »T^ - o3 .-K- oO -rt^ CsJD .„ ri 2 ss^a -oo ^--s^o Strict diet Vegetable Do. Oatmeal d Do. Do. Vegetable Do. Strict diet Vegetable Do. 43 4J CO CD co> Strict diel cream 3 meal 36 Strict diel cream 3 meal 36 Vegetable 14 eggs, Vegetable As August Do. Strict die grapefru peas 1 ta potato 9 Body- weight without cloth- ing. ©£ -OS -OO -CO -COO) ■ •*** ■ IO "0 CM OS O -CD CM os -r^ oo ^« -^ OS t-^ oot^t^co •OOOM OO ^ -co -co -co -coco ■ co ■ CD «0 »o O • • O • lO »o »Q*OiOiO '£OOH«N =0 ■ ,-. ^ CM CM • • CM CM (M ^■^ ^t* ^7* ^* 03 CM CM CM bo- rate nee. • o •O O io lO • * iC) • »o "0 O iJO lOO <^o o iC>-OiOO iO cjjs g o -3 •-'-HIM IO »o »io cs C3 o S P. O too • • ■OO Is- CO CO oo • r-- co CM COuOOO >;Z a eo ^ •* • ■ •CO CO I>- OO aS c* o a +3 O 3 CO By cop- per re- duction. ^ OO Ol l>- l-» 00--" Ol'J'iOO - CO •CM -*PiO •<* CM -HO OO CM ■ M* CO OCO co »o COCO CM Tt< fc -h -o -oooo -o o o • h ttl o . Sg ^ O ■ ■ CD "*« OS OS CO i— < CO 00 • * "?■ CO o CO OC o CM O CO uO t~ IO OO OO CO OHCOCO lOONO CM • •CM OS (M OS 00 £M C- CM ■ ■ f-H *H il *"" ' ■ (M T-l (M 1— ^ ^H fl-oxy- butyric acid. •t-~ r-t Ci t>- Tt< • Oi «— ♦ CO CO CO OS OO ■•-< CO ~h CC i-< CM CO o«^"* r~ co oc ^h t^ CM CO Cft Cft 1^ O 3 Vc^^y^r-t^ciCAr-i-r*^ (M *— r-. • CM ^H CM CO CM CM CN o > o ,r- oo uo co -^ lO CO Oi 00 . . ccc/ ooiinh ~* oc t~- OO CN lilt _i r i r i i -— ^ 0) -cot-, cm r- en oo -^ co co r^ -r 1 — 1 — " t— ■** CM CO ■^••o oor^ +3 03 •HrtHiHWNWNNNCO e» * d_OCl « Hf Q ) ^- C C — . — . — i — — v 3 3 3 3 3 3 c. -. X M tC tCbH bC bfl he bb "S J 3 1>-J 3 3 3 3 3 333o 58 METABOLISM IN SEVERE DIABETES. T3 3 .2 a o O T. -1 U a g S 250 c.c cream, 6 eggs, vegetables 450 gms., bacon 150 gms., claret 75 gms. Oatmeal 180 gms., cream 300 gms., eggs 3, brandy 60 gms., claret 90 gms., butter 262 gms. f> *• »«» * Cream 125 c.c, vegetables 500 gms., eggs 6, bacon, bouillon, much butter. Strict diet; oatmeal 36 gms., cream 375 c.c, half grapefruit, vegetables 200 gms. As August 8. Strict diet; vegetables 5-6-10 per cent groups, 1 tablespoonful 15 per cent, oatmeal 36 gms., cream 250 c.c, half grapefruit, potato, 90 gms. Vegetables, eggs 7^, bacon, cream 300 c.c. Butter, 7 eggs, vegetables, bacon, cream, alcohol. Do. Do. Strict diet; vegetables, 5-6-10 per cent groups, 1 tablespoonful 15 per cent, oatmeal 36 gms., cream 300 c.c, half grapefruit, potato 90gms.,bread30gms. Strict diet; vegetables 5-6-10 per cent, oatmeal 18 gms., potato 90 gms., bread 60 gms., cream 500 gms., grape- fruit, half orange, bananas 45 gms., macaroni 60 gms. Essentially the same. Do. Do. Do. Do. Do. Do. Do. Do. 4 eggs, cream 375 c.c, bacon, vegetables 5-6-10 per cent. Body- weight without cloth- ing. kilos. 57.2 56.8 57.1 56.1 OOOO -CN •O if? • t— 56.1 58.0 co ■ co -ot~- -comm -r- f- ■ CO ■ to »i0 -CO-^CO -to O i-O ■ IO »C ■ *0 IO »C3 ■ *co 'cOOH«N ~ o o o •* £ cm cnj cq t-i o o ■ o cm cm • c-i •OO o • OJ CM CM oo o ooooo ■ O O O CO CM CM CM CMCMCMCMCM-CMCMCMCM Carbo- hydrate balance. o^io co o m |l + 1 1 o o -o CO CO -CD ll : 1 ■ou; tn ■com •* : 1 1 1 lO »0 O IOU3IOIOO -OOO • iO »C CO t-»f3~*ocO ■ ^ *"* ' II 1 I 1 t I I : I + : 43 o s Alco- hol. Vi ~- X O O CO 2: rr co cm CO O • O CM CO -CO ■ COCO CO OO O OOOOO- OOOO coco co coeocoeoco • coeococo o oi O -a »o Ifl o »c .-, cm cn e» ^ CSi <* >oo ■ o •CN CM •OO O • I— CI CM OO 'O ifJiOiOCwj •wjiCifiO CM OS O) CI CI CM CO CM CM CJ CM C) 1* bi 3 03 By ro- tation. J. *-* • CO 'rf ~ -J* T CO C3V o o ■ o ccc. • I— • oco o - *-< *-Oz »c OO "*f CO ■*TjJ'CO~HCMCO-CMCOt--«0 o ci 10 r— io *-< co co - «o cm ~h ■ By cop- per re- duction. ~ CO Ci OS CM ^ CO ,— CO Ci COCO ^Cl — C» ~* 00 eo cm r- -»f ■^ CO t- CO •^tO OOOi. c. g 1029 1027 1028 1029 1029 1029 1028 1031 1030 1025 1027 t^O • CiI--00000-COt-COco CM CM • CM CM CO CM CM ■ CM CM CM CI OO * OOOOO -OOOO Volume of urine. c.c. 2560 3250 2900 3200 3340 3570 3230 3175 us o o o CM 00 O O CO CO 'O OO CO CO CO CM OO o oo»oooooooo* COCO O fMOONOOVWiCO • ** Tjri -^ »0 tJ< CO ""J< CO o *-*• CO CO • Date. 1910. Sept. 14-15.. Sept. 15-16 Sept. 16-17.. Sept. 17-18.. CM CO p- CM C" 1 1 J CM C* v. _ C - CO 1 "j c 2 Nov. 27-28 Dec 7- 8 Dec. 26-27 1911. Jan. 11-12 Jan. 25-26 Feb. 19-20 Mar. 5- 6 Mar. 16-17 Apr. 2- 3 Apr. 26-27 May 10-11 May 12-13 May 28-29 July 5- 6 July 30-31 Aug. 9-10 STATISTICS OF EXPERIMENTS. 59 01 Cj- g bD cB.t: 3 ^ O > 0 & °£ 6 6 0 CM En , except p c.c. cream johydrate 1 150 gms., = 180 gms +3 03 U ja 0 XI CO M 03 C >. h 03 £ 1 0 onl 300 ate. . ca tme real 0 CM 43 co q. So 2d -s^-Sd^ 0- a §« 30 1 B Cv CO M-c 0. August Feb. 19- 0. ible pro eggs a 1 carboh Feb. 19- Sept. 17 0. Feb. 19 plus 10 0. 0. -60 gms h, 600 c 1 >n Is •*j 03 a CD CO 00 O O d to § s bU 00 S,B§oo 0 g ££ co to cj--* 3 co co en ci 3 a s a 0 a 0 S 03 ... cj« m m c3 O <<< > <)<<•< oa m < < CO 3-a ^'•SO^ K'r &JOO CO CM CO tF O f» CO CM t*- CO CO CO *-< CM t>. ■* 07.3 0 c O • O 'O 10 >C iO ICOO "** *^ CO ~f ^ •* CO 0 •CO -cooi T* ■ • • co as «&-g«" .J* -O kO "0 »0 iO «0 »0»C<0 lO "COOiO >o to >o UCM .la co i>- co co co co co co co co co co co CO CO CO noooioiomwjioicOioicio rt go l(J^il"l\. HOKMiMN C)(MCQ CM N(NINN CM CM CM C)COCOCOCMC\|CN)CNl»-ii-i^H CO 1 GO +J o°g OiOOiOO 0i0"0 lO irjWiOiO >o iO lO O O iO O OiOOiOO»OiO»00 03'CN CM CM •— < ■*}*»— (CMkOUO'*1^ CM •O OW'-"M •iCCO'^CNt-*-'— ii- 1 tJ* CO •03 03 if —3 C 1 1 II 1 1 1 1 1 1 1 1 1 1 1 1 1 + 1 III ++++++ 0 « -CJ2 3r • ^25 J3 0 »0 S CO OOOOO O O O O OOOO 10 "5 LO 10 »o O O lO ■ if> iC 0 >C m lO ic 10 §£3 coeocococo co co co co co co 00 co •* -I- •* •^xfCOCO^f •^t'T^'»T+i'»rt,^^**^!*<^ 4i ■<•* o> *" *-*■*-»■■- »" 5 T3 03 O K 0 u a. 3 2io ioo^»oo t*. 0 O CO lO »0 »C O 0 i« >o OOOiOOO-^OOOOOOO •710 J^ei 'He- << CM a £ Cs as CM CM CM CO 1— t CO CO CM CO CO CO -—t cc re CO •CONO'OOOiOiO'OiO'C'OO ■4-3 a o U 0 -S cd to to e 0 5 i- 0 cocoor-co r— coco •C0COcO^t*0-)0CiO>OI>- GC C-l 1— " CO O O-l — < ^h »0 »0^»OCM ™ oxri'.oo -CO-=Ji|>-COQO— -»— OGO >i+3 lO 03 bt 3 m$ CD> CD C.A <= 03 0 £ 0 oi'M NtDCO^H OOCOiO «M OCCOH ■* 00 on W c U+* 2cM O -t CUC r)< nO^iO CO OiQOOi^J* -f CO 00 OiCO>OCM ■0500C35C4COCOCOOOS »H a >> a 2 a >> B "3 H ^^ 03 a . ■85 2 rt co 1 - ~J eo ■* O « lO ^ ic>j -^cocnj CO CO CO • cococo -CMCOCO • •!-* ■ • O a < ^ gg a cSo bd Oo ■* "3 +3 I— CO CO-hiO CO tcM C^ W3 fcO *— < »C ^cH -# CM 05 IO--HQ0U0 -(NCMCNI -as -co • • ^ ^ -3* ^* ^c« »C O 1ON1O1O >o O CO CO »o ^ ^f • »o CO CO *o • i-H ■ • H Ol 0 g « 03 e» -g 0 . is c Sos t- CO CO CM CO • ■ o • ooasoo • co 0 co co i— • »— 1 as -co O 03 *~ CO -* •moo • t>- co «*< as as cm as -y-> £bB Oi • *— * H 'iHHH i-H - i-H .42 a OS^ Q, oi« . CO o3 S -H ..2 . co 00 t-» uO C3i CO O OOCD cO-HCncOCM -^ W ^t< CM CO 00 up to Jun uent to th rmentatic Togen, 10 < >3 C i => 03 t»co ^ iO CO CO «o CO O CO •V 10 si + + +++ +++ + ++++ + + + ++++ -J [__^_o OOOOO + + +++ +++ + +++ + + + ++ 'oSTd't" .2 2V e ■a n >i.. S-a Si +++ +++ + + + + • + + + " ^- «5 J? t^ -^OCTSOiOi tNHCO »-• ONNQO 00 CO r~ O3J0 4| o-2 CM i-H oo>oo» O Carbo cor Per c Protei 3'C 0 O "3 => «53 COCOCOCOCO CO CM CO CO CO "^ "<=*« CO CO ■«< •<»« ^JlTtlCO^»OTt<^t*»0'^CMC4CMCM>— » >o r^ ffi ■«■ 1— 1 CM CO t— t— 00 CO OS O • Oi CO CO iO <-■' CO o*ocoooiot-~cocouooocor--oooo o3 i 1 1 1 1 1 III — *— . 1 "1 1 1 1 0 - CN ^ 1 h in »_. ~- 1 t-. ,_, 1— t C>1 •-' ■— 1 CM OJ 1 1 1 1 1 1 ! 1 1 1 1 1 1 1 as'^uot-^Tt'cDtrjiO'^t^-cMcocMt-* ,_; ■""• ■ ' eg • ^h ^h i-H ,— 1 CM H f— • CM CM Q S£? 0 saaS-S1 ©cBcacD«««H0^ 5 llll2 § 1 s 1 ^-So-2 s s s 03 s, ei 60 METABOLISM IN SEVERE DIABETES. Respiration Experiment No. R2. Date, August 15, 1910. Body-weight without clothing, 58.2 kilos. This experiment was preceded by the ingestion of food, and consisted of but one 14-minute period, beginning at 10h 15m a. m. The results of the experi- ment are given in table 66. Table 66. — Results of respiration experiments Nos. Rl to RS.1 Experi- ment No. Date and time. Rl R2 R3 Carbon Duration. I ,!lioxid+e , eliminated per minute. absSd rass* per minute.' ^^nt. 1910 Aug. 1. 9h55ma.m. Aug. 15. 10b15ma.m 14_ Average pulse-rate. mitt. sec. 12 6 c.c. 2 227 c.c. 2310 0.73 98 24 3 224 Sept. 15. lh07mp.m 11 52 1 25 p.m j 11 58 207 208 3 334 0.67 81 Average respiration rate. 16 15 310 310 .67 .67 82 83 16 18 Average . '208 "310 .67 I 83 17 1 Food was taken by the subject before each of these experiments. !Carbon dioxide eliminated per kilogram per minute, 4.02 c.c.; oxygen absorbed per kilogram per minute, 5.50 c.c. The urine collected between 7'1 55m and 10 25m a.m. amounted to 340 c.c. and contained 2.47 gms. nitrogen and 16.5 gms. sugar. 3 Carbon dioxide eliminated per kilogram per minute, 3. 85 c.c; oxygen absorbed per kilogram per minute, 5.74 c.c. 1 Carbon dioxide eliminated per kilogram per minute, 3.64 c.c; oxygen absorbed per kilogram per minute, 5.42 c.c Respiration Experiment No. R3. Date, September 15, 1910. Body-weight without clothing, 57.2 kilos. This experiment was also made after the ingestion of food and included two periods, each of 12 minutes. The subject arrived at the laboratory at 12h 45m p. m., and lay on the couch for about 10 minutes before the experiment began at 1^ 07m p. m. The stethoscope was not used, the pulse-rate being counted at the wrist. The subject lay perfectly quiet throughout the whole experiment. The results are given in tables 66 and 67. Table 67. — Statistics of urine — Respiration experiment No. R3. Date and period. Volume. c.c. 250 433 145 1115 1310 •T0tal Sugar, nitrogen. = Sept. 15, 1910:i 7!l 30m a.m. to 101' 00m a.m 10 00 a.m. 1 00 p.m 1 00 p.m. 1 55 p.m 1 55 p.m. 9 30 p.m Sept. 15-16, 1910: 9h3Gmp.m. to 7!'30ma,m gms. 1.65 1.99 .65 4.01 4.68 gms. 9.9 19.2 6.6 43.6 44 4 1 Subject probably ate food as usual. Calorimeter Experiment No. R4. Date, May 12, 1911. Body-weight without clothing, 55.3 kilos. The subject fasted in this experiment, coming to the laboratory at 7h 20m a. m., without breakfast. This was the first time the bed calorimeter had been used with this subject and, after he entered the apparatus at 7h 51m a. m., he seemed somewhat nervous and apprehensive, asked a great many questions, and moved around considerably. The experiment began at 81' 54m a. m., and continued for two periods, one of 45 minutes and the other of 47 minutes, end- ing at 10h 26m a. m. Especially during the first period he was more active than the average subject, telephoning, urinating, and drinking water. The pulse-rate was obtained as usual with the stethoscope, and the two pneumographs were STATISTICS OF EXPERIMENTS. 61 used to obtain records of the respiration rate and the major movements. At 9h 20m a. m. the subject drank 60 cc. of water. After coming to the laboratory in the morning he urinated at 7h 28m a. m., also during the experiment, at 9h 15m a. m., and after the experiment was over, at 10h 40m a. m. The records are given in tables 68 and 69. Table 68. — Measurements of metabolism — Calorimeter experiment No. R4- Date and period. C^Z£fe ' Cygen absorbed. Respi- Average ratory i pulse- quotient. ! rate. Average respira- tion rate. Total. ?e' ' Total, minute. Per minute. May 12, 1911: b1' :Am a.m. to 9!l 39™ a.m 9 39 a.m. 10 26 a.m Total 1 hr. 32 min.1 gms. 17.1 17.9 c.c. 193 194 gins. IS. 2 17.4 283 0.68 i 70 200 .75 70 17 16 35.0 194 35.6 271 .72 70 17 1 Carbon dioxide eliminated per kilogram per minute, 3.51 c.c : oxygen absorbed per kilogram per minute, 4.90 c.c. Table 69. — Statistics of urine — Calorimeter experiment No. R4- Date and period. May 12, 1911: 7h 2Sma.m 7 28 a.m. to 9h 15ra a.m 9 15 a.m. 10 40 a.m Volume. Specific gravity. c.c. 115 251 182 1.026 1.025 1.024 Total nitrogen. Sugar. gms. 0.55 1.19 .87 gms. '2.8 5.9 3.9 CASE S. DESCRIPTION OF THE CASE. Male; born 1853; married; merchant; onset of diabetes in 1899; came under our observation May 12, 1910; died in coma October 19, 1910. Family history. — No history of diabetes mellitus. Father died at 87; mother of cancer; one brother of liver trouble; one brother and one sister in infancy; one son 33 years old, well. Past history. — Health neither very poor nor very good. Measles, mumps, herpes, hemorrhoids. General history of case. — The diabetes was first apparent in 1899 with malaise. The greatest quantity of sugar noted was 3.5 per cent, while the greatest volume of urine was 2400 c.c. The general condition of the patient was excellent. The patient was under observation for only a short period of time. Death occurred some 5 months afterwards while the patient was travel- ing, and was considered due to coma. Physical examination. — Greatest weight, April 1901, was 71.1 kilos, with- out clothes; May 13, 1910, 57.6 kilos, undressed. Height, 177 cm.; tour de taille 76 cm.; pupils equal, reacted; knee-jerk normal; blood-pressure 120; pulse 72. Nothing abnormal noted about the heart and lungs. Liver extended 2 fingers' breadth below costal margin. Spleen extended to the costal margin and was hard. Urine data. — The urinary records of the case are given in table 70. Throughout the observation of the urine the reaction in all cases was acid, and the slightest possible trace of albumen was present on every day except May 16-17. On all days of the observation, 8 grams of sodium bicarbonate were given. 62 METABOLISM IN SEVERE DIABETES. EXPERIMENTS WITH CASE S. Two experiments were made with this subject, in both of which the respi- ration apparatus was used. One was a fasting experiment and the other followed the ingestion of oatmeal. The vital statistics were as follows: Date of birth, , 1853; height, 177 cm.; body-weight without clothing during experiments, 58 kilos. Table 70. — Clinical chart — Case S. Date. 6 c .-g Diacetic acid. Nitrogen. Ammonia. Sugar. Carbohydrates in diet.1 1 J3 +3 3 "3 £ "o > > a u bo a « 0 a. m "c3 O 1 F n -s r. ° u CD • &S D. O OS O 0 3 -73 >>g d 0 '-£ C3 ^» O 0 u a O +3 --t >> 3 TS 0 0 G 1910. 13-14 14-15 15-16 16-17 17-18 18-19 19-20 20-21 21-22 22-23 c.c. 1626 2520 2400 1830 1920 I860 1800 2220 1800 1740 1023 1019 1020 1020 1022 1022 1019 1021 1024 1021 1 1023 1 0 S1.+ ++ + S1.+ + ++ _i_ 0 ++ + gms. 13 'i 13.8 11 7 10.6 10.4 7 3 ii*5 8 6 9.5 gms. l'.'o 1.6 1.2 p. ct. i'.'i 12^7 13.5 gms. i6 34 39 38 34 26 58 31 30 (7??:s. 21.4 8 10 19 22 19 15 29 44 13 24 gms. 3 20 20 15 20 20 45 45 45 45 45 gms. + '5 -15 -25 -20 -15 +20 -15 +15 +10 kilos. 57.6 57.8 57.7 57.6 57.7 58 2 57 9 58.1 5.8.3 57 9 57. 5 J8 gms. sodium bicarbonate given each day. Beginning May 13 the diet contained 200+ gms. fat and 12 gms. alcohol. 2 Per cent. 3 12 ± gms. nitrogen. Respiration Experiment No. SI. Date, May 18, 1910. Body-weight without clothing, 58 kilos. As this subject had not previously been experimented upon and was somewhat elderly, only three periods of 10 to 11 minutes were run, so as not to overtire him. The subject came from the hospital at 8h 15m a. m., without breakfast, and lay down upon the couch for some 10 minutes before the experi- ment began at 8h 40m a. m. Surgeon's plaster could not be used on account of his moustache and beard. The stethoscope, also the pneumographs about the chest and thighs, were used. The experiment was without incident, the sub- ject lying quietly throughout. After the experiment was over the subject urinated at 9U 45m a. m. The results are given in table 71. Table 71. — Results of respiration experiment No. SI. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. Mav 18, 1910: 8h40ma.m 9 03 a.m 9 25 a.m Average min. sec. 11 21 10 20 10 9 c.c. 148 154 156 c.c. 2i8 208 6!7i 75 59 53 57 8 9 9 '153 ■ 213 73 58 9 ■Carbon dioxide eliminated per kilogram per minute, 2.64 c.c; oxygen absorbed per kilogram per minute, 3.G7 c.c. The urine collected between 8 and 9h 40™ a.m. amounted to 92 c.c. and contained 0.53 gm. nitrogen and 1.9 gms. sugar. STATISTICS OF EXPERIMENTS. 63 Respiration Experiment No. S2. Date, May 21, 1910. Body-weight without clothing, 58 kilos. The subject came to the laboratory after eating at the hospital a break- fast of approximately 250 gms. of cooked oatmeal between 7h 30m a. m. and 7h 45m a. m. He lay down upon the couch at 8h 10m a. m., and the experiment began at 8h 16m a. m., continuing for four periods, 11 to 12 minutes long, with intermissions of 12 to 15 minutes. Both pneumographs were used. The subject urinated at 7h 45m a. m., before the experiment, and again after the experiment, at 10 a. m. The data are given in table 72. Table 72. — Results of respiration experiment No. S2. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. May 21, 1910: i8h 16ma.m 8 43 a.m 9 10 a.m 9 34 a.m ruin. sec. 11 14 12 5 11 41 12 21 c.c. 162 162 156 162 c.c. 208 223 212 213 0.78 .72 .73 .76 62 58 58 57 8 9 9 10 2161 2214 .75 59 9 1 Subject ate oatmeal for breakfast between 7h 30™ and 7h 45™ a.m. 2 Carbon dioxide eliminated per kilogram per minute, 2.78 c.c; oxygen absorbed per kilogram per minute, 3.69 c.c. The urine collected between 7h 45m and 10 a.m. amounted to 245 c.c. and contained 1.04 gms. nitrogen and 10.2 gms. sugar. In order to compare his metabolism with that of a normal subject after eating oatmeal, an experiment was made with another subject who had eaten 434 gms. of cooked oatmeal. The time intervening between the ingestion of the oatmeal and the beginning of the experiment was the same as in the experi- ment with the diabetic. The respiratory quotients obtained with the normal subject were 0.806, 0.807, 0.854, and 0.780, respectively. CASE T. DESCRIPTION OF THE CASE. Male; born 1867; married; farmer; onset of diabetes in September 1908; diagnosed November 1908; came under our observation December 5, 1910; died in coma March 5, 1911. Family history. — No history of diabetes mellitus. Father died at 77 years of heart disease; mother at 63 years of cancer; wife and six children well; one child died of heart disease. Past history. — Measles, mumps, whooping-cough, scarlet fever. General history of case. — September 1908, there were polydipsia and poly- uria, with loss of weight for a month previous to the diagnosis in November 1908. The chief symptom was weakness. Carbuncles and boils developed in October 1910, and the patient also suffered from constipation. The diet was at no time strict, as the feebleness of the patient, his inability to bear sodium bicarbonate well, and the severity of the acidosis made restrictions of diet appear impracticable. The patient failed to respond to diet, and died in coma March 5, 1911, shortly after returning home. Physical examination. — Greatest weight without clothing, 71.2 kilos.; normal weight without clothing, 67.6 kilos.; weight December 5, 1910, 52.7 kilos, without clothing. Height, 180 cm. Pupils equal and reacted. Knee- jerk normal. No edema. Lungs and heart normal. Pulse-rate, 72. There were numerous boils and ulcers, some of which were partially healed, over the clavicle, neck, arms, and back — a truly pitiable sight. The breath had an acetone odor. 64 METABOLISM IN SEVERE DIABETES. at about the acidosis was Urine data.- — The greatest quantity of urine was 10,000 c.c. time of onset. When the patient came under observation the extreme; this is indicated by the 6 grams of ammonia shown in table 73, which gives the urinary record during observation. The reaction of the urine during this period was acid throughout, with a slight trace of albumen. The carbo- hydrate balance was for the most part minus throughout. Beginning January 31, 1911, 22 grams of alcohol were given daily. Table 73. — Clinical chart — Case T. Date. 6 a '£ 3 "3 S _3 "3 > > v. M a «B 'o CD C, W '5 C3 '■+3 o c 5 'o a o "C >. +} 3 >> 0 <4 B 03 M O Ammonia. Sugar. .5 CO 0 +3 0 O Carbohydrate bal- ance. NaHCOs. Body-weight with- out clothing. i "3 o H 1 to "3 +3 O 0) o &' u S" 3 g-a O ■2Sc C O rt 1910. Dec. 4- S c.c. 5000 3 5000 6000 '3200 4500 ± 3400 4700 44S0 5100 5740 5700 2980 2960 4000 3420 5000 4000 4380 4580 4180 3305 3335 3190 3120 1037 1033 1037 1035 1037 1036 1031 1029 1030 1027 1032 1037 1033 1032 1030 1033 1033 1032 1031 1032 1027 1023 1028 0 S1.+ 81.+ ++ ++ +++ +++ +++ +++ ++ ++ ++ + ++ ++ +++ + ++ ++ + +++ gins. 43 '3 40.6 50.1 39.7 30.2 gms 16> 18. 17. < 13. ( 11.1 11.' 9 : n. i . gms. 6.0 j I ... ) ... 5 5.5 5 5.2 J 5.5 f 4.6 ) p.ct. 33!3 36.9 38.7 40.7 gms. + + + m 230 184 219 198 179 133 73 58 128 gms. 2 7.2 240 408 211 279 204 197 179 204 184 171 131 178 176 150 200 168 210 174 167 119 53 57 125 gms. . . . 195 200 200 200 185 165 155 140 185 150 140 140 140 140 140 140 130 15 166 115 gms. -'85 - 5 + 5 + 20 - 20 - 20 - 15 - 5 + 5 - 25 - 10 - 90 - 45 - 80 - 60 - 40 - 10 - 60 +110 - 15 gms. .. .. 24 31) 30 30 30 20 12 12 12 12 12 12 12 12 12 12 12 12 kilos. 53.9 52.7 52.4 50.9 50.6 51.7 53.2 53.1 51.8 50.6 52.3 52 7 52.8 52.8 52.4 53.2 53.2 52.6 51.5 51.5 50.9 52.2 Dec. 2S-29 1911. Jan. 27-28 Jan. 28-29 Jan. 29-30 Jan. 30-31 Jan. 31-Feb. 1 Feb. 1-2 Feb. 2-3 Feb. 3-4 Feb. 4-5 Feb. 5-6.. Feb. 6- 7. . . Feb. 7-8 Feb. 8-9 Feb. 9-10 Feb. 10-11 Feb. 11-12 Feb. 12-13 Feb. 13-14 Feb. 14-15 Feb. 15-16 5 Feb. 1S-176 Feb. 17-18 1 Whisky, 45 gms. daily throughout stay in hospital. 2Per cent. 'Urinary sediment contained many fine and coarse granular casts. 4 18 hours. Urinary sediment, contained many hyaline, fine, and coarse granular casts. 6 Vegetable day 240 c.c. cream, 4 eggs. 6 Oatmeal day, 240 gms. oatmeal, 240 gms. butter, 240 c.c. cream. EXPERIMENTS WITH CASE T. Two fasting experiments were made with this subject, in both of which the bed calorimeter was used. A comparison of the data obtained is made in table 76. The vital statistics were as follows: Date of birth, 18G7; height, 180 cm.; range in body-weight without cloth- ing during experiments, 51.3 to 51.5 kilos. Calorimeter Experiment No. Tl. Date, February 14, 1911. Body-weight without clothing, 51.5 kilos. Previous to this experiment no food had been taken by the subject since the evening meal of the day before, with the exception of a cupful of coffee at 6h 30m a. m. When the subject arrived at the laboratory at 8 a. m. he appeared to be a very weak, sick man, and somewhat apprehensive in regard to the experiment. He was dressed in unusually warm, heavy clothing, and on enter- ing the bed calorimeter, at 8h 26ra a.m., was also covered with a blanket. The experiment began at 9h 18m a. m. and continued for two 45-minute periods, ending at 10h 48m a. ra. During the whole experiment the subject lay very quietly on his back, without reading, save near the close of the first period, STATISTICS OF EXPERIMENTS. 65 when he moved considerably. After the experiment was over he seemed to be very tired and glad that it was over. Before coming to the laboratory the sub- ject urinated at 7h 30m a. m., and again, after the experiment, at llh 03rn a. m. The records of the experiment are given in table 74. Table 74. — Measurements of metabolism — Calorimeter experiment No. T 1. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- Average Average Total. Per minute. Total. Per minute. quotient. ; rate. tion rate. Feb. 14, 1011: iQh 18™ a.m. to 10u 03™ a.m 10 03 a.m. 10 48 a.m Total 1 hr. 30 min.2 gms. 15.0 15.2 c.c. 170 172 gms. 15.0 15.8 c.c. 233 246 0.73 .70 66 66 15 16 30.2 171 30.8 240 1 Subject drank a cup of coffee at 6h 30m a.m. : Carbon dioxide eliminated per kilogram per minute, 3.32 c.c.; oxygen absorbed per kilogram per minute, 4.66 c.c. The urine collected between 7h 30m a.m. and llh03m a.m. amounted to 345 c.c, specific gravity 1.030, and contained 1.52 gms. nitrogen and 12.4 gms. sugar. Calorimeter Experiment No. T2. Date, February 16, 1911. Body-weight without clothing, 51.3 kilos. This was also a fasting experiment, neither food nor coffee being taken after the evening meal of the day before. The subject came to the laboratory at 7h30ma. m., and the experiment began at 8h 47m a. m. After two 45- minute periods the experiment ended at 10h 17m a. m. Throughout the whole experiment the subject lay quietly on his back. He appeared to be somewhat tired at the end of the experimental period, but had evidently become more Table 75. — Measurements of metabolism — Calorimeter experiment No. T 2. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Feb. 16, 1911: 8h 47™ a.m. to 9h 32m am 9 32 a.m. 10 17 a.m Total 1 hr. 30 min.1 gms. 14.8 14.7 c.c. 168 167 gms. '14.0 14.7 c.c. 217 229 0.77 .73 67 69 15 15 29.5 167 28.7 223 'Carbon dioxide eliminated per kilogram per minute, 3.26 c.c; oxygen absorbed per kilogram per minute, 4.35 c.c The urine collected between 7 and 7h 42ma.m. amounted to 80 c.c, specific gravity, 1.030, and contained 0.34 gms. nitrogen and 2.4 gms. sugar. accustomed to the apparatus and the routine. The pulse and respiration rates were obtained in the usual way with the stethoscope and pneumograph, a second pneumograph being used about the thighs to give a record of any major movements. The subject urinated at 7h 42m a. m., but was unable to urinate again after the experiment was over. The records of the experiment are given in table 75. Table 76. — Comparison of metabolism experiments in the bed calorimeter with Case T in experiments without food. T-> Weight of subject. Length of ex- periment. Per minute. Respi- ratory quotient. Average pulse per minute. Average respira- tion per minute. Experi- ment No. Date. Carbon dioxide eliminated. Oxygen absorbed. 1911. T 1 : Feb. 14i . T2 Feb. 16.... kilos. 51.5 51.3 hrs. min. 1 30 1 30 c.c. 171 167 c.c. 240 223 0.71 .75 66 15.5 68 15.0 1 2 hours and 48 minutes before the experiment began the subject drank a cup of coffee. 66 METABOLISM IN SEVERE DIABETES. CASE U. DESCRIPTION OF THE CASE. Female; born November 16, 1873; single; teacher; onset of diabetes, April 1909; sugar found in the urine August 1, 1909; first came under our observa- tion April 18, 1910; died in coma August 11, 1911. Family history. — No history of diabetes in family. Father, mother, and two brothers well; one brother has arthritis deformans. Past history. — Healthy ; scarlet fever three times, measles, mumps, whoop- ing cough. Pneumonia at 14. Catamenia normal. Overwork and worry, especially because of the brother's illness. General history of case. — In April 1909 there were loss of weight and poly- dipsia. In May 1909, polyuria, furuncles, and weariness appeared. Follow- ing the discovery of sugar in the urine, thirst and nervousness nearly disap- peared and the strength improved; nevertheless the patient had polyphagia. The course of the disease is shown in table 77. Notwithstanding the severity of the disease, the patient taught daily until May 1911. There was a gradual loss in strength, as well as in weight, and she died in coma August 11, 1911. Physical examination. — Greatest weight, summer of 1908, 53.1 kilos.; April 1909, 49.9 kilos. ; May 1909, 45.4 kilos. ; August 1909, 41.7 kilos. ; April 18, 1910, 39.7 kilos. Height, 160 cm. Pupils equal and reacted to light. Knee- jerks normal. Bilateral submaxillary glands. Emaciated. Tongue and teeth normal. Heart just within mammillary line, systolic at the apex. Pulse- rate, 112. Blood-pressure, 100. Lungs normal. Abdomen, right movable kidney but otherwise normal. No edema of lower extremities. Urine data. — The quantity of urine August 1, 1909, was 5,750 c.c; spe- cific gravity 1.040. The reaction of the urine was acid throughout the period of observation. The acidosis was marked from the very first, but decreased sub- sequently with the use of sodium bicarbonate. The greatest quantity of ammonia was 5.2 grams, April 22, 1911. On March 11, 1911, the urinary sedi- ment contained numerous fine and coarse granular casts. The quantity of sugar in the urine when the patient first came under observation amounted to 7.2 per cent in a single specimen, and to 6.2 per cent (132 grams) during the 24 hours of April 19-20, 1911. This steadily decreased, but the patient never became sugar-free. Albumen never exceeded a slight trace. EXPERIMENTS WITH CASE U. With this subject three bed calorimeter experiments were made and nine respiration experiments. A number of these were made in series. Series I included a calorimeter experiment (U5) in which the subject fasted, and a respiration experiment (U6). In this latter experiment the subject fasted the first two periods, then took food. Series II, which included five experiments, began with a respiration experiment (U8), which was followed by an oatmeal breakfast; an experiment was then made with the bed calorimeter (U9), which was in turn succeeded by a second respiration experiment (U10). The sub- ject spent the night in the bed calorimeter, metabolism measurements being made during the latter part of the night (Ull). In the morning of the next day, a third respiration experiment (U12) was made after a beefsteak break- fast, completing the series. A comparison of the data obtained in the calo- rimeter experiments is given in table 92. The vital statistics for this subject are as follows: STATISTICS OF EXPERIMENTS. 67 Date of birth, November 16, 1873; height, 160 cm.; range of body-weight without clothing during experiments, 35.8 to 44.2 kilos. Table 77. — Clinical chart — Case U. Date. 1910. Apr. 17-18. o © s _3 "o > 19-20.. 22-23.. 25-26.. 29-30.. 1- 2.. 4- 5.. 9-10.. 13-14.. 18-19 K 19-20.. May 23-24.. May 25-26.. 26-27 7. 27-28.. 8- 9.. 14-15.. 25-26.. 1- 2.. Apr. Apr. Apr. Apr. May May May May May May May June July July July Aug. Aug. 17-18. Sept. 12-13. Oct. 7- 8. Nov. 4- 5. Nov. 22-23. Dec. 16-17. 1911. Jan. 13-14. Feb. 10-11. Mar. 10-11. Mar. Mar. Apr. Apr. Apr. Apr. Mav 24-25. 311 I/-" 1- 2. 2- 3. 21-22. 19-20. May 311 June l/"" June 1-2 ". June 2-3 12. July 6-7... c.c. 2125 2000 1875 2000 2000 2375 2190 2500 2125 6 325 2250 2000 275 2500 2000 2375 2500 2000 2750 2750 2750 2750 3250 9 3000 3250 2420 102330 3135 ' 3000 3250 1805 3500 03 (- tl! © a. 1039 1042 1032 1030 1031 1030 1033 1023 1026 1027 i034 1C35 1035 1034 1032 1026 1030 1029 1030 1028 1033 1031 1031 1025 1024 1030 1029 1029 1032 1021 1027 03 3 o V.sl.+ V.sl.+ 0 ++ + + + ++ ++ +++ +++ ++++ ++++ +++ ++++ ++++ +++ +++ ++ 3 X> >> X I a © O gms. +++ +++ ++ gms. Ammonia. o 19.7 30.0 22 3 27.3 20.6 25.5 18.0 11.5 9.0 1.2 10.7 9.8 0 6 25.5 13.8 i3!3 10.0 13^3 13.4 12.h 9 5 9.2 9 9 13.6 30.42 6.9 gms. 4.4 4.3 3.5 1.7 2^8 i!i 4.0 4.4 4.7 5.0 3 6 3.7 4 0 5.2 4.7 I - p.ct. 31.5 39.3 26^9 Sugar. © ■ ao © O 3 ■n 23.0 27.0 32^9 31.2 33.1 33 2 31.4 gms. + + 74 15 104 77 3 "135 50 '98 72 ' + 117 90 156 120 75 97 105 127 34.74 36 158 Diet.1 pq gms. 37.2 132 68 79 60 56 67 31 60 51 86 120 64 52 90 52 77 105 88 99 91 66 137 84 98 126 o +i 03 T3 u bf) o gms. 70 80 70 80 65 75 100 70 95 '80 '75 75 75 85 80 76 70 ± 75 75 65 75 65 55 75 gms. 12 o o 15 13 i9 12 16 ii= 12J 15=i i6 i8= gms 12 15 15 15 12 12 12 i2 12 12 12 12 12 12 12 12 12 03 © 03 . Jb & -a * o .a gms. -10 +20 + 15 + 15 +35 + 15 +25 -35 +20 -55 +io +25 -25 +15 + 5 -30 -20 -25 -40 -25 -80 -40 -70 -85 3 O 03 gms ) 8 i6 16 16 lti [2 16 16 16 12 12 12 lti 12 12 12 12 > CO %l o m kilos. 39.5 40.2 40.4 39.5 39.0 38.3 39.3 46!5 42.3 43.3 41.8 43.6 44 0 43.6 41.1 41.1 40.9 40.4 38.2 37.2 39.5 37.7 37.0 36.1 1 Fat in diet, May 9-10, 175 gms.; Dec. 16-17, 150± gms. 'Approximate. 'Per cent. '16 gms. NaHC03 given daily, May 14, 15, and 16. 6 120 gms. oatmeal, 120 gms. butter, 240 c.c. cream, 240 c.c. milk, 4 eggs. 'From 8h 30m to Uh 50111 a.m., May 19. 7 From 7 to 9h 45m a.m., May 26. 8 By fermentation. 9 Urinary sediment contained fine and coarse granular casts. 10 23 hours 40 minutes. " 12 hours. 1=23 hours 25 minutes. Respiration Experiment No. Ul. Date, May 14, 1910. Body-weight without clothing, 39.0 kilos. This experiment was made simply to accustom the subject to the respira- tion apparatus, and consisted of but one 10-minute period, beginning at 9h 55m a.m. The breakfast for that morning was an egg and an orange. The stetho- scope and pneumograph were not used, and no records of pulse and respiration were taken other than two records of the respiration from the tension equalizer, which gave an average of 20 respirations to the minute. The carbon dioxide eliminated per minute was 155 c.c, and per kilogram per minute 3.97 c.c. The oxygen absorbed per minute was 210 c.c, and per kilogram per minute 5.38 c.c The respiratory quotient was 0.74. 68 METABOLISM IN SEVERE DIABETES. Respiration Experiment No. U2. Date, May 19, 1910. Body-weight without clothing, 39.3 kilos. A breakfast consisting of a dish of oatmeal, an egg, a piece of bacon, and a cup of coffee was taken before the experiment. The day preceding was an "oatmeal day," and as the subject usually felt considerably better on these days, it seemed desirable to determine the respiratory quotient under such circumstances. The subject arrived at the laboratory about 10h 15m a.m., lay down on the couch at 10h 30m a. m., and the experiment began at 10h 40m a. m., continu- ing for three periods of 10 to 11 minutes, with intermissions of 9 to 12 minutes. The subject urinated before the experiment at 8h 30m a. m., and afterwards at 1 1 h 50m a. m. The records of the experiment may be found in table 78. Table 78. — Results of respiration experiment No. U 2. Date and time. Carbon T,..„ni: dioxide JJuration. ■< . j eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average /^rage pulse-rate. , Tesp£tfon May 19, 1910: 10h40ma.m.i... 11 01 a.m.... 11 24 a.m.... Average min. sec. i c.c. 10 31 164 10 37 157 10 05 153 c.c. 222 212 217 0.74 .74 .71 90 17 86 17 87 17 2 15S 2217 .73 88 17 'The subject had eaten breakfast as usual. 2Carbon dioxide eliminated per kilogram per minute.4.02 c.c; oxygen absorbed per kilogram per minute, 5.52 c.c. The urine collected between 8° 30m and ll'1 50m a.m. amounted to 323 c.c. and contained 1.20 gms. nitrogen and 15 gms. sugar. Respiration Experiment No. U3. Date, May 26, 1910. Body-weight without clothing, 41 .2 kilos. The subject came to the laboratory without breakfast about 8h 30m a. m., and lay down upon the couch for 10 minutes before the experiment began at 8h 44m a. m. Three periods of about 10 minutes each were included in the experiment, with intermissions of 10 to 12 minutes. The subject urinated at 7 a. m. before coming to the laboratory, and again at 9h 45m a. m. After the experiment was over she was given a breakfast consisting of oatmeal with cream, and boiled eggs. The records of the experiment are given in table 79. Table 79. — Results of respiration experiment No. U3. Date and time. Carbon D"»*»- ! elSSfcd per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. May 26, 1910: 8h 44m a.m 9 04 a.m min. sec. c.c. 10 03 160 9 58 152 9 52 152 c.c. 215 182 (?) 214 0.74 .84 (?) .71 85 89 89 17 16 16 Average ! '155 ':'!«{ .76 88 16 'Carbon dioxide eliminated per kilogram per minute, 3.76 c.c; oxygen absorbed per kilogram per minute, 4.95 c.c. The urine collected between 7 and 9h 45m a. m. amounted to 274 c.c. and contained 0.64 gm. nitrogen and 2.8 gms. sugar. Respiration Experiment No. U4. Date, September 13, 1910. Body-weight without clothing, 44.2 kilos. This experiment followed a breakfast taken at 6h 45m a. m. consisting of oatmeal and cream, small amounts of melon and bacon, and an egg. She reached the laboratory at 10h 45m a. m., and almost immediately lay down STATISTICS OF EXPERIMENTS. 69 upon the couch. The experiment began at 11 a. m., continued for three periods of 12 to 13 minutes each, with intermissions of 12 to 16 minutes. Throughout the whole experiment the subject was very calm and quiet. The results of the experiment are given in table 80. Table 80. — Results of respiration experiment No. U 4- Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. Sept. 13. 1910: llh00ma.m.i... 11 28 a.m.... 11 53 a.m. . . . Average min. sec. 12 14 13 12 12 11 c.c. 158 154 151 c.c. 224 221 212 0.71 .70 .71 90 18 88 18 90 17 = 154 =219 .71 89 18 1 Subject ate breakfast at 6h 45ln a.m. 2 Carbon dioxide eliminated per kilogram per minute, 3.48 c.c.; oxygen absorbed per kilogram per minute, 4.95 c.c. Calorimeter Experiment No. U5. Date, March 31, 1911. Body-weight without clothing, 39.9 kilos. This was the initial experiment of Series I, and the first with this subject in the bed calorimeter. She arrived at the laboratory at 7h 40m a. m., without breakfast, and entered the apparatus at 7h 55m a. m. The experiment began at 8h 50m a. m., continuing for two 45-minute periods, ending at 10h 20m a. m. The subject lay very quietly reading during all of the experiment, except near the end of the periods. Both pneumographs and the stethoscope were used to obtain the respiration-rate, the muscular activity, and the pulse-rate. The results of the experiment are given in tables 81 and 83. Table 81. — Measurements of metabolism — Calorimeter experiment No. U5. Date and period. Carbon dioxide eliminated. Average pulse- rate. Average respira- tion rate. Total- | minute. Mar. 31, 1911: 8h 50m a.m. to 9h 35m a.m 9 35 a.m. 10 20 a.m Total 1 hr. 30 min.1 qms. c.c. 13.6 154 13.8 j 157 84 84 18 19 27.4 155 1 Carbon dioxide eliminated per kilogram per minute, 3.88 c.c Respiration Experiment No. U6. Date, March 31, 1911. Body-weight without clothing, 39.9 kilos. This experiment, which was the second and last of Series I, was divided into two parts, the subject continuing to fast after leaving the bed calorimeter until after the first two periods had been concluded. She then took 100 grams levulose, 100 c.c. weak coffee, and 175 c.c. hot water. Six additional periods followed. The experiment began at 10!l 50m a. m., the two fasting periods ending at llh 38m a.m. The food was taken at 12 o'clock, and the following six periods began at 12h 16m p. m., ending at 3h 08m p.m. Each period was about 15 min- utes long, the intermissions ranging from 8 to 31 minutes. The subject was awake during the first period, and coughed once at 10h 51m a. m., also several times in the second period. There were slight movements reported in the fourth, seventh, and eighth periods. The subject urinated after the experiment at 3h 15m p. m. The results of the experiment may be found in tables 82 and 83. 70 METABOLISM IN SEVERE DIABETES. Table 82. — Results of respiration experiment No. U6. Date and time. Carbon Nation. elSd per minute. absSfed "SB"* per minute., ^tlent- Average pulse-rate. Average respiration rate. Mar. 31. 1911: Without food — 10h50ma.m. ... 11 23 a.m.... min. sec. i c.c. 14 59 151 15 0 145 c.c. 205 211 0.74 .69 86 88 18 17 Average ' U48 1208 .71 87 17 With food— 12h 16mp.m.2... 12 44 p.m 1 30 p.m.... 2 05 p.m 2 28 p.m 2 53 p.m.... 15 10 172 14 58 184 14 47 180 15 7 172 14 27 171 14 36 166 271 .63 261 .70 246 .73 235 .73 250 .68 240 .69 90 90 87 89 89 19 19 19 18 20 19 3 174 3 251 .69 89 19 1 Carbon dioxide eliminated per kilogram per minute, without food, 3.71 c.c; oxygen absorbed per kilo- gram per minute, without food, 5.21 c.c. 2 Subject took 100 gms. levulose in 200 c.c. of very weak coffee (hot) at 12 noon. 3 Carbon dioxide eliminated per kilogram per minute, with food, 4.36 c.c; oxygen absorbed per kilo- gram per minute, with food, 6.29 c.c. Table 83. — Statistics of urine — Calorimeter experiment No. U 5 and respiration experiment No. U 6. Date and period. Volume. ' Specitfic i gravity. Total a„„. nitrogen.; Sugar- Mar. 31, 1911: 7b 00™ a.m. to 10h 30m a.m 10 30 a.m. 3 15 p.m.1.... Mar. 31-Apr. 1,1911: . 3h 15m p.m. to 7h 00™ a.m c.c. 246 555 1620 1.029 1.030 gms. 1.16 1.50 6.76 gms. 7.5 24.5 87.6 i Subject took 100 gms. levulose in 200 c.c. very weak hot coffee at 12 noon. Respiration Experiment No. U7. Date, April 2, 1911. Body-weight without clothing, 39.8 kilos. This experiment was (like U6) divided into two parts, the first three periods being fasting periods, and the last six periods following the ingestion of 518 grams of cooked oatmeal and 38 grams of butter. On coming to the laboratory, the subject lay down on the couch at 7h 47m a. m., and the experiment began at 8h 17m a. m. In all of the three fasting periods, which were each 15 minutes in length with intermissions of 13 to 14 minutes, the subject was reported as awake and very quiet. The oatmeal was taken between 9h 40m and 9h 55m a. m., and the subject lay down on the couch again at 10 a. m. The six periods following the food began at 10h 13m a. m., with intermissions of the usual length, except between the last three periods, these being about an hour each. During the fourth, fifth, sixth, and seventh periods the subject was reported as restless, coughing and moving her hands and feet. Between the seventh and eighth periods the subject sat up in a chair and did not lie down on the couch again until about 15 minutes before the next period began. She was much quieter in the eighth period than previously, although she reached once for her handkerchief. She felt sleepy during this period, and took a 35-minute nap between the eighth and ninth periods. The results for this experiment are given in tables 84 and 85. STATISTICS OF EXPERIMENTS. 71 i ^0" Respiration Experiment No. U8. Date, June 2, 1911. Body-weight without clothing, 37.1 kilos. Before this experiment, which was the first of Series II, the subject took grain strychnine. She arrived at the laboratory at 7h 25m a. m., without breakfast, and lay down upon the couch at 7h 40m a. m. The experiment began at 8h 10m a. m., continuing for two periods of 15 minutes each, with an intermission of 12 minutes. The subject was quiet throughout the experiment, with the exception of a few movements of the hands during the second period. The results of the experiment may be found in tables 86 and 91. Table 84. — Results of respiration experiment No. U7. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory, Average quotient, pulse-rate. Average respiration rate. Apr. 2, 1911: Without food- s'1 17ma.rn.... 8 45 a.m.... 9 14 a.m Average min. sec. 14 58 15 3 14 47 c.c. 148 151 154 c.c. 199 203 213 0.75 86 .74 90 .72 92 IS 18 18 ! '151 '205 .74 89 18 With food— 10h 13ma.m.2... 10 39 a.m.... 11 08 a.m.... 12 12 p.m.... 1 28 p.m.3... 2 37 p.m.... 15 3 14 5S 15 4 14 54 15 6 14 49 163 167 177 170 154 163 234 228 236 230 206 209 .70 .73 .75 .74 .75 .78 100 99 99 86 88 92 18 19 19 19 19 18 M66 4 224 .74 94 19 1 Carbon dioxide eliminated per kilogram per minute, without food, 3.79 c.c; oxygen absorbed per kilo- gram per minute, without food, 5.15 c.e. , - Subject ate 518.4 gms. cooked oatmeal and 38 gms. butter between 9" 40,n and 9n 55m a.m. 3 Subject slept about 35 minutes after this period and was awakened at 2" 31™ p.m. 4 Carbon dioxide eliminated per kilogram per minute, with food, 4.17 c.c; oxygen absorbed per kilo- gram per minute, with food, 5.63 c.c. Table 85. — Statistics of urine — Respiration experiments No. U7. Date and period. Vo^e. ni^n Sugar. Apr. 2,1911: 6h40ma.m.to 7h 35m a.m 7 35 a.m. 9 33 a.m 9 33 a.m. 11 50 a.m.1 11 50 a.m. 2 58 p.m Apr. 2-3, 1911: 2h58mp.m. to 6h30ma.m c.c. 100 216 425 475 1920 gms. 0 42 71 .88 1.09 6.73 gms. 2.2 3.7 10.2 18.1 62.8 1 Subject ate 518.4 gms. of cooked oatmeal and 38 gms. of butter between 9h 40m and 9h 55m a.m. Table 80. — Results of respiration experiment No. U8. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. June 2, 1911: 8h 10m a.m 8 37 a.m Average min. sec. 14 56 14 47 c.c. 145 142 c.c. 203 202 0.71 .70 75 79 18 18 1 144 1203 .71 77 IS !Carbon dioxide eliminated per kilogram per minute, 3.88 c.c; oxygen absorbed per kilogram per minute ,5.47c. 72 METABOLISM IN SEVERE DIABETES. Calorimeter Experiment No. U9. Date, June 2, 1911. Body-weight without clothing, 37.1 kilos. This experiment immediately followed respiration experiment No. U 7, and was preceded by a breakfast of 477 grams of oatmeal and 157 grams of heavy cream. She also drank 200 c.c. of water. Before entering the bed calorimeter the subject urinated at 91' 30m a. m. The experiment began at 10h 46m a. m. and continued for four 45-minute periods, ending at lh 46m p. m. The sub- ject was very quiet, except for several slight movements, reading until 12h 30m p. m., when she was reported asleep by the nurse in attendance. At lh 16m p. m. it was noted that the subject was again reading. The stethoscope and pneumograph were used in this experiment, but, owing to a loose adjustment, the records of the respiration were unsatisfactory. The pulse records were also difficult to obtain. The measurements of the oxygen indicated a leak, but it was not located. The measurements of the metabolism and other records made during the experiment are given in tables 87 and 91. Table 87. — Measurements of metabolism — Calorimeter experiment No. U9. Date and period. Carbon dioxide eliminated. Average pulse- rate. Total. Per minute. June 2, 1911: 10h 40m a.m. to llh 31m a. 1:1.1 11 31 a.m. 12 16 p.m 12 16 p.m. 1 01 p.m 1 01 p.m. 1 40 p.m gms. 14.6 15.2 14.0 14.5 c.c. 166 171 158 164 87 87 85 89 Total, 3 hours2 58.3 165 1 Subject ate 477 gms. cooked oatmeal and 157 gms. cream between 9h 06m and 9h 25m a.m. 2 Carbon dioxide eliminated per kilogram per minute, 4.45 c.c. Respiration Experiment No. U10. Date, June 2, 1911. Body-weight without clothing, 36.8 kilos. This respiration experiment followed immediately after the experiment with the bed calorimeter (U9) and included seven periods, each of which was approximately 15 minutes long. The intermissions ranged from 35 minutes to Table 88. — Results of respiration experiment No. U 10. Date and time Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. i Average respiration rate. June 2, 1911: min. sec. c.c. c.c. 2h17mp.m.'.... 14 40 142 207 0.69 84 19 3 20 p.m 14 42 147 204 .72 so 19 4 29 p.m 15 2 141 202 .70 84 20 5 47 p.m 14 31 143 202 .71 82 20 6 57 p.m 14 35 140 203 .69 84 21 8 22 p.m 15 2 133 200 .07 82 19 9 43 p.m Average 15 2 134 196 .68 82 20 2 140 2 202 .69 83 20 ■The subject had eaten oatmeal and cream between 9h 06m a.m. and 9h 25m a.m. 2 Carbon dioxide eliminated per kilogram per minute, 3.80 c.c. ; oxygen absorbed per kilogram per minute, 5.49 c.c. 1 hour and 10 minutes. The experiment began at 2h 17m p. m. and ended at 9h 58m p. m. The subject was very quiet and awake throughout the experi- ment. A period was begun in the intermission between the first and second periods, but as the subject moved her head and there was the possibility of a STATISTICS OF EXPERIMENTS. 73 leak, the measurements were discontinued at the end of approximately 2 minutes. Between the second and third, third and fourth, and the fifth and sixth periods she sat up in a chair, lying down on the couch again 13 to 20 minutes before the beginning of the following period. The nurse gave her a massage in the intermission between the fourth and fifth periods. Previous to the experiment the subject drank 120 c.c. of water. She also urinated at lh 50m p. m., and again at 5h 10m p. m., 6h 40m p. m., and 10h 30m p. m. The results of the experiment are given in tables 88 and 91. Calorimeter Experiment No. Ull. Date, June 2-3, 1911. Body-weight without clothing, 36.2 kilos. In this experiment (the fourth of Scries II) the subject remained in the bed calorimeter all night, with one short intermission. At 10 p. m. the nurse in attendance gave her an alcohol rub-down in preparation for the experiment. The subject also drank a glass of water at 10h 50m p. m., just before entering the apparatus, but took no food. The experiment was divided into two parts; the first part began at llh 55m p. m. and continued for one period of 1 hour and 32 minutes, and a second of 1 hour and 47 minutes, ending at 2h 14m a. m. The subject was then taken out of the calorimeter for a short time, but returned to the apparatus at 2h 40m a. m., the second part of the experiment beginning at 4h 01m a. m. In this section of the experiment the measurements were also Table 89. — Measurements of metabolism — Calorimeter experiment No. Ull. Date and period. June 2-3, 1911: llh 55m p.m. to lh 27m a.m. 1 27 a.m. 2 14 a.m. 4 01 a.m. 5 05 a.m. 5 05 a.m. G 05 a.m. Total 4 hrs. 23 min Carbon dioxide eliminated. I Oxygen absorbed. Total. Per minute. Total. Per minute. Respi- ratory quotient. Average pulse- rate. gms. 24.4 15.2 18.3 15.1 c.c. 135 163 145 128 gms. 23.3 15.0 73.0 141 38.9 c.c. 177 183 0.76 .70 83 80 82 83 U79 I I ! I 1 Carbon dioxide eliminated per kilogram per minute, 3.90 c.c. 2 Oxygen absorbed per kilogram per minute (2 hrs. 32 min.), 4.94 c c. made in two periods, the first 1 hour and 4 minutes and the second 1 hour in length. No records of the body-temperature were obtained, and the pneumo- graph was not used, but the pulse-rate was taken by means of the stethoscope. The subject slept throughout the first period, but waked at the end, and her slight movement at this time disturbed the measurement of the oxygen. At the beginning of the next period she fell asleep again, and slept until taken out of the calorimeter. After reentering the apparatus she slept the rest of the night and was very quiet. The experiment did not appear to disturb the sub- ject at all, for she was rested by her night's sleep and said that she had slept better than she did at home. No water was taken during the experiment. Urine was passed at 6h 40m and 10h 30m p. m. June 2, and at 2h 25m and 6h 25m a. m. June 3. The records of the experiment are given in tables 89 and 91. Respiration Experiment No. U12. Date, June 3, 1911. Body-weight without clothing, 35.8 kilos. The last experiment of Series II was preceded by a breakfast of 153 grams of beefsteak, taken at 7h 42m a. m. With the steak, the subject drank 150 c.c. of water. She lay down upon the couch at 8h 15ra a. m., and the experiment began at 8h 41m a. m., continuing for five periods 13 to 15 minutes in length, with intermissions ranging from 17 to 45 minutes. The subject complained 74 METABOLISM IN SEVERE DIABETES. that the nosepieces hurt her a little in the first period. In the second she moved rather more than usual, but was quiet in the other periods. After the third period she sat up, lying down again 20 minutes before the fourth period began. The subject urinated at 10h 17 a. m. and llh 45m a. m. The results of the experiment are given in tables 90 and 91. Table 90. — Results of respiration experiment No. U 12. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory Average Average quotient, pulse-rate. reS^eUon June 3, 1911: 8h41ma.m.i... 9 20 a.m.... 9 50 a.m 10 48 a.m.... 11 26 a.m.... Average min. sec. 14 42 12 41 12 54 14 35 14 20 c.c. 140 165 165 156 156 c.c. 219 240 236 223 0.64 ,6S .70 .70 88 90 90 90 91 21 22 23 21 21 2 156 2 230 . 68 90 22 1 Subject ate 153 gms. of beefsteak between 7h 30m and 7h 42m a.m. 2 Carbon dioxide eliminated per kilogram per minute, 4.36 c.c. ; oxygen absorbed per kilogram per minute, 6.42 c.c. Table 91. -Statistics of urine — Calorimeter experiments Nos. U 9 to U 11, and respiration experiments Nos. U S to U 12. Date and period. Volume. Specific Total g gravity, nitrogen. s June 1-2, 1911: 7hC0mp.m. to 7h00ma.m June 2, 1911: 7h00ma.m. to 9h 30m a.m ' 9 30 a.m. 1 50 p.m 1 50 p.m. 5 10 p.m 5 10 p.m. 6 40 p.m 6 40 p.m. 10 30 p.m June 2-3, 1911: 10h 30m p.m. to 2h 25m a.m June 3. 1911: 2h 25'" a.m. to 6h 25'" a.m 6 25 a.m. 10 17 a.m.2 10 17 a.m. 11 45 a.m c.c. 16S0 209 782 295 118 146 146 108 305 81 1.027 1.024 1.018 1.023 1 023 1.022 1.023 1.024 1.034 gms. 7.37 .94 1.88 .95 .49 .93 .96 .68 1 . 91) .82 gms. 46.5 3.9 18.9 6 4 2.3 1.6 1.2 14 5.3 2 3 1 Subject ate 477 gms. of cooked oatmeal and 157 gias. of cream between 9h 08 m and 9h 25"' a.m. 2 Subject ate 153 gms. beefsteak between 7h 3Um and 7h 42m a.m. and drank 150 c.c. of water. Table 92. — Comparison of metabolism experiments in the bed calorimeter with Case U. EXPERIMENTS WITHOUT FOOD. Experi- ment No. Date. U 5 U 11 1911. Mar. 31 June 2-3 Weight of subject. Length of ex- periment. kilos. 39 9 36.2 hrs. min. 1 30 4 23 Per minute. e.iiZ^d.iabsorbed- Respi- ratory quotient. c.c. 155 141 c.c. U79 '0.73 Average pulse per minute. 84 82 Average respira- tion per minute. 18.5 EXPERIMENTS WITH FOOD. U9 1911. June 2 2 kilos. 37 1 hrs. min. 3 00 c.c. 165 87 1 Oxygen absorbed and respiratory quotient for the time included in the periods llh 55m p.m. to lh 27m a. m and 5h 05m to 6h 05'" a.m. 2 About 1 hour 30 minutes before the experiment began the subject ate 477 gms. of cooked oatmeal and 157 gms. cream. STATISTICS OF EXPERIMENTS. 75 CASE V. DESCRIPTION OF THE CASE. Male; born January 19, 1874; married; proprietor of a grocery; onset of diabetes July 1909; sugar found in the urine October 1909; came under our observation March 7, 1910; died February 6, 1911. Family history. — No history of diabetes in the family. Father and one child well. Wife has had two miscarriages. Mother ill, diagnosis unknown. A brother is not rugged, and one sister died of typhoid fever. Past history. — The patient advanced slowly at school because of "neu- ralgia" and headaches. Measles, mumps, two attacks of diphtheria. "Inflam- mation of the gall-duct," accompanied with severe pain but without jaundice, occurred three or four times at about 32 years of age. At one time consider- able alcoholic liquor was used. General history of the case. — In July 1909, polyuria and polyphagia were manifest, but polydipsia did not occur until October 1909, when sugar was found. The greatest quantity of urine reported was 4,000 c.c. in October 1909. Weakness, vertigo, palpitation, failing eyesight, insomnia, and indigestion were the chief symptoms. On March 8 to 9, 1910, the quantity of sugar amounted to 115 grams in 24 hours. With a fairly rigid diet the patient did not become sugar-free, and, indeed, bore the restriction of diet very poorly. Pneumonia is said to have developed upon February 3, 1911; the patient failed rapidly and death occurred February 6, 1911. Physical examination. — Greatest weight without clothing, 63.5 kilos. Weight without clothing March 7, 1910, 58.3 kilos. Height 173 cm. Tour de taille 72.5 cm. Pupils equal and reacted to light. Knee-jerks normal. No edema of the extremities. Tongue and teeth normal. No cervical, right axil- lary, or inguinal gland. A left axillary gland. Pulse-rate 76, regular. Blood- pressure 100. Heart and lungs not abnormal. Abdomen, nothing abnormal felt. Urine data. — The urinary record is given in table 93. Throughout the observations the urine was acid in reaction. No albumen was present, except on March 27 and 28, when there was a very slight trace. Diacetic acid was also absent, except on March 8-9, and a very slight trace on March 28. Table 93. — Clinical chart — Case V. Date. Volume of urine. Specific gravity. Nitrogen. Sugar. Carbo- hydrate in diet.1 NaHC03 Body- weight without clothing. BIrCT By rota- per re- 1 i- „ duction. tlon- 1910. Mar. 8- 9 10-11 13-14 15-16 18-19 21-22 22-232 25-26 273.... 28 3. . . . 283.... 293.... 303.... 313.... c.c. 2300 2040 1920 2400 1680 1710 586 2400 750 720 1800 1350 1920 900 1034 1034 1031 1028 1014 i023 1021 1025 1018 1016 1023 1025 gins. ni'.z 3.7 gins. + + + + + 41 13 + + gms. 115 82 73 72 7 ... 43 3 3 32 8 46 16 gms. 115 iis 90 50 50 gms. 0 5 2 3 i kilos. 58.8 59.1 58.5 58^9 5^9 'Amounts only approximate. 2From 6 to llh 15m a.m., Mar. 22. » 12-hour record. 76 METABOLISM IN SEVERE DIABETES. EXPERIMENTS WITH CASE V. Only one experiment was made with this subject, the respiration apparatus being used. The vital statistics were as follows: Date of birth, January 19, 1874; height, 173 cm.; body-weight, without clothing, during experiments, 60 kilos. Respiration Experiment No. VI. Date, March 22, 1910. Body-weight without clothing, 60 kilos. The subject had inadvertently eaten some breakfast at 6h 45m a. m. on the day of the experiment, consisting of a 2-egg omelet and a cupful of coffee. He arrived at the laboratory at 8h 40m a. m., lay down on the couch at 8h 45m a. m., and the experiment began at 9h 22m a. m., continuing for five periods, with the usual intermissions. Two pneumographs were used to obtain the respiration rate and the major muscular movements, and the stethoscope was employed Table 94. — Results of respiration experiment No. VI. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. Mar. 22, 1910: 9h22ma.m.i... 9 40 a.m.... 10 02 a.m 10 27 a.m 10 56 a.m Average min. sec. 10 07 14 50 14 36 14 19 14 24 c.c. 222 204 198 204 195 c.c. 285 291 283 274 280 0.78 .70 .70 .75 .70 69 68 66 66 66 11 12 15 13 15 2 205 2 283 .73 67 13 1 Subject ate a light breakfast consisting of a 2-egg omelet and a cup of coffee at 6h 45m a.m. 2 Carbon dioxide eliminated per kilogram per minute, 3.42 c.c. ; oxygen absorbed per kilogram per minute, 4.72 c.c. for securing the pulse-rate. The mouth was covered with surgeon's plaster in all the periods. Just before the close of the third period the subject almost went to sleep. After the experiment he said that he found it more difficult to breathe through the apparatus than into the open air. Before coming to the laboratory in the morning he urinated at 6 a. m., after reaching the laboratory at 8h 45m a. m., and again after the experiment at llh 15ra a. m. The records of the experiment may be found in tables 94 and 95. Table 95. — Statistics of urine — Respiration experiment No. VI. Date and period. Volume. Total nitrogen. Sugar. Mar. 22, 1910: ■6h00ma.m. to 8h 45m a.m 8 45 a.m. 11 15 a.m c.c. 151 435 gms. 1 16 2.57 gms. 4 3 8.7 1 Subject ate a light breakfast consisting of a 2-egg omelet and a cup of coffee at 6h 45m a.m. CASE W. DESCRIPTION OF THE CASE. Female; born June 1, 1892; single; onset of diabetes, November 1908; sugar found in the urine January 1909; came under our observation April 30, 1910; condition November 11, 1912, comfortable. STATISTICS OF EXPERIMENTS. 77 Family history. — No history of diabetes in the family. Father had rheu- matism. Mother, three brothers, and five sisters are well. Two brothers died of cholera infantum; one sister of spinal meningitis. Past history. — Measles, mumps, chicken-pox. March 1907, operation for appendicitis, with good recovery. General history of the case. — In November 1908 the patient was markedly tired, and in January 1909 pruritus appeared and sugar was found in the urine. In February 1909 she suffered from periods of weakness, but was not uncon- scious. Micturition was painful. Polyuria and polydipsia were present, but not polyphagia. During the summer of 1909 she suffered pain in the left iliac fossa, which was constant in character and accompanied by abdominal tender- ness, but no fever. The pain was worse before catamenia, which was reported as normal in April 1910. Although suffering from indigestion, she vomited but once. She was nervous, and complained of dizziness, dyspnea, and palpitation. August 1909 an obstruction was found in the ureter by Dr. Chute. April 16, 1912, the patient was in comfortable health. Table 96. — Clinical chart — Case W. Sugar. Date. Volume of urine. Specific gravity. Nitrogen. Carbo- hydrate in diet.1 Carbo- hydrate balance. Body- weight without clothing. By cop- per re- By rota- tion. duction. 1910. c.c. gms. gms. gms. (/ms. gms. kilos. Apr. 29-30 2000 1038 104 May 9-10 1023 = 0.6 60.6 May 10-11 1170 1026 26 iro +145 60.7 May 11-12 1305 1021 23 170 +145 59.7 May 12-13'.... 1980 1017 8 4 33 28 130 + 95 60.1 May 13-14* 1575 130 59 1 May 14-15* 125 58.2 May 15-16* .... 125 58.5 May 16-17 1440 1017 . 14 125 +iio 58.5 May 17-18 1140 1021 8.8 23 16 125 +100 58.6 May 18-19 1020+ 1018 20.8 90 58.8 May 19-20 1140 1015 8.0 7 2 60 + 55 58.9 May 20-21 1230 1015 tr. 1 60 + 60 59 0 May 21-22 1740 1010 8.1 1 60 + 60 58.6 May 22-23 1440 1014 8.8 1 60 + 60 58.5 May 23-24 1350 1014 9.1 2 65 + 65 58.9 May 24-25 600+ 1015 0 . . . 58 7 June 1- 2 2100 1035 62 Julv 5-6 1023 6 .... 1911. Aug. 9-10 1039 + 26.8 1 No sodium bicarbonate given except 8 gms. on May 23-24. 2 Per cent. NH3— N 8 Ammonia, 1.2 gm8.;_ , , __ =11.8 per cent. 4Catamenia. 6Per cent by fermentation. lotal N Physical examination. — Greatest weight without clothing, 63.5 kilos.; August 1909, 51.7 kilos.; April 30, 1910, 61.1 kilos. Height, 161 cm. Red cheeks. Pupils equal and reacted to light. Knee-jerks normal. No cervical, axillary, or inguinal glands felt. Pulse-rate, 112 to 128. Blood-pressure, 130. Heart 13 cm. to the left of the median line. No murmurs. Lungs normal. Liver extended 2 fingers' breadth below the costal margin. Spleen and kidney not felt. No abdominal tenderness. Scar in appendix area. Urine data. — The greatest quantity of urine recorded was in July 1909 i. e., 4500 c.c. The urinary record during observation is given in table 96. Throughout this period the reaction was acid, with an occasional slight trace of albumen. Diacetic acid was not present. The sugar in the urine decreased rapidly with moderate restriction of the diet, and disappeared within three weeks. A subsequent report, however, showed a return of sugar a few months later. Sodium bicarbonate was given only once — 8 grams on May 23-24, 1910. 78 METABOLISM IN SEVERE DIABETES. EXPERIMENTS WITH CASE W. Two respiration experiments were made with this subject, in both of which she fasted. The vital statistics were as follows: Date of birth, June 1, 1892; height, 161 cm.; range of body-weight without clothing during experiments, 58.9 to 60.1 kilos. Respiration Experiment No. Wl. Date, May 13, 1910. Body-weight without clothing, 60.1 kilos. The subject came to the laboratory fasting at 7h 45m a. m., and lay down upon the couch at 7h 55m a. in. The experiment began at 8h 07m a. m., con- tinuing for four periods of 10 to 11 minutes each, with intermissions of 10 to 14 minutes. The subject was nervous throughout the whole experiment, espe- cially in the last period; the respiration was consequently irregular. At the close of the second period she said that her nose felt as if it were bleeding. Just after the beginning of the third period she opened her mouth. After the experi- ment was over the subject felt a little faint. She seemed to breathe easily through the nose, and but for the nervousness was a very good subject. The records of the experiment are given in table 97. Table 97. — Results of respiration experiment No. W 1. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory' Average Ijjjg, quotient. pulse-rate. rote May 13, 1910: 8h 07° a.m 8 28 a.m 8 53 a.m, 9 13 a.m Average min. sec. 10 24 10 39 10 17 10 27 c.c. 171 170 161 165 c.c. 238 228 239 0.72 110 .75 100 106 .69 100 18 16 16 16 U67 1235 .72 104 17 'Carbon dioxide eliminated per kilogram per minute, 2.78 c.c; oxygen absorbed per kilogram per minute, 3.91 c.c. The urine collected between 7 and 10h 10m a.m. amounted to 197 c.c. and contained 0.94 gm. nitrogen and 1.6 gms. sugar. Respiration Experiment No. W2. Date, May 24, 1910. Body-weight without clothing, 58.9 kilos. This was also a fasting experiment, the subject having taken no food since the evening meal of the day before. She arrived at the laboratory at 8h 15m a. m., lay down on the couch at 8h 30m a. m., and the experiment began at 8h 43m a. m., continuing for three 10-minute periods, with intermissions of 11 to 14 minutes. She was not nearly so nervous as in the previous experiment, but as the periods continued became more restless, and at the close of the last period felt faint. The results of the experiment are given in table 98. Table 98. — Results of respiration experiment No. W2. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration rate. May 24, 1910: 8h43ma.m 9 07 a.m 9 28 a.m Average min. sec. 10 0 9 40 9 53 c.c. 157 160 164 c.c. 207 219 0.76 .73 91 91 99 16 16 16 M60 '213 .75 94 16 1 Carbon dioxide eliminated per kilogram per minute, 2.72 c.c; oxygen absorbed per kilogram per minute, 3.62 c.c. The urine collected between 7 and 9h 45m a.m. amounted to 162 c.c. and contained 0.57 gm. nitrogen and 0.1 gm. sugar. STATISTICS OF EXPERIMENTS. 79 CASE X. DESCRIPTION OF THE CASE. Male; born October 1875; married; clerk in grocery store; onset of dia- betes, July 1908; sugar found in urine September 1908; came under our obser- vation, February 28, 1910; condition, May 8, 1912, comfortable. Family history. — No history of diabetes in the family. Father, mother, three brothers, four sisters, and one child well. A brother and a sister died soon after birth. Past history. — Measles, mumps, whooping-cough, jaundice at 8 or 10 years of age. Twelve years and three years previous to observation, there was a swelling in the right knee for periods of 6 weeks and 10 days, respectively. Table 99. — Clinical chart — Case X. Date. of urine. gravity. 2 '8 d Sugar. Diet.1 1 3 . ±; ® 1 -i -> •3° D. O J a i o 'S a CD O 03 s o M 3 T3 2 >> e3 CD 60 O M ■CJ o o 3 A OS o u a J *» T3 O O > CO 0 2 &U H O s < o m 1910. c.r. gms. gms. gms. gms. gms. gms. gms. kilos. Feb. 27-28 2 2850 1039 0 25.9 209 194 62.3 Feb. 28- Mar. I3.. 2625 1041 0 23.8 182 179 62 3 Mar. 1-2 1740 1042 0 20.7 109 101 115 + 5 62.7 Mar. 2-3 2070 1040 0 22.9 124 116 115 -10 63 1 Mar. 3-4 2565 1038 0 133 115 -20 62.3 Mar. 4- 5 1890 1033 0 49 15 -35 63 0 Mar. 5-6 2115 1029 0 72 75 + 5 62.8 Mar. 6-7 1650 1030 0 36 50 + 15 63.1 Mar. 7-8 1455 1031 S1.+ 38 50 + 10 63.2 Mar. 8-9 1530 1027 S1.+ ... 28 35 + 5 63.6 Mar. 9-10 2070 1023 0 21 25 + 5 63.4 Mar. 10-11 1710 1023 0 17 20 12 + 5 63.1 Mar. 11-12 1200 1026 S1.+ 11.0 15 5 18 + 5 63.6 Mar. 12-13 1620 10?1 0 12.9 15 8 18 +10 64.0 Mar. 13-14 1770 1017 0 11.3 6 15 8 18 +10 63.4 Mar. 14-15 2280 1020 0 12.8 15 10 18 +10 64.4 Mar. 15-16 2640 1025 0 12.9 6 15 12 18 +15 64.7 Mar. 16-17 2670 1019 0 19.3 15 14 18 +10 64.6 Mar. 17-18 1730 1017 0 13.0 > * . 15 +10 Apr. 3-4 1029 0 <0.8 15 , . 64.6 Apr. 10-11 1470 0 , . 65.5 Apr. 14-15 2000 1023 0 .... + 4 15 . , +io 1625 1028 0 • . * • + (5) t . . .... Oct. 23-24 720 1028 0 70.9 Dec. 1-2 625 1028 S1.+ 0 < • • 20 . , +20 70.9 1912. Apr. 26-27 1750 1028 + + 39 25 •• -15 70.5 1 No sodium bicarbonate was given, except 15 gms. on Mar. 14-15 and 15-16. NHa— N h 'Ammonia, 1.9 gms.; = p^-r =6.0 per cent. 'Period was 22| hrs, t. e., 8n 15m to 7 a.m. lotal N 4 Per cent. 6 Less than 0.1 per cent. The patient used considerable tobacco and ate excessively of candy and cookies, both in the grocery store and at home. Ten years previous to observation considerable alcoholic liquor was used. General history of the case. — While the onset of the diabetes was in July 1908, the disease first attracted particular attention and was diagnosed in September 1908, because of polyuria at a horse-race. 5000 c.c. of urine were voided during the night at the onset. Other symptoms were polydipsia, poly- phagia, weakness, loss of weight, a parched tongue, pain in the back, extreme constipation, impotence, and failing eyesight. Under the advice of his physi- cian the patient ate no pork, fat, or vegetables, but drank skim milk ! The unusually favorable course of the case, despite the unpromising con- dition of the patient when first seen, is probably due to the change in diet, as 80 METABOLISM IN SEVERE DIABETES. prior to the time of observation his diet had been unfortunate. The case illus- trates the unreliability of prognosis without repeated observations upon the same patient. Physical examination. — Greatest weight without clothing, 90.7 kilos.; July 1908, 85.3 kilos.; February 23, 1910, 64.5 kilos. Height, 170 cm. Tour de taille, 76 cm. Pupils equal and reacted to light. Knee-jerks normal. No edema of extremities. A few small left axillary glands. No acetone odor to breath. One-third of the teeth missing. Lungs and heart normal. Pulse-rate, 80. Blood-pressure, 90 (two estimations, Riva Rocci). Abdomen, nothing abnormal felt. Urine data. — The urinary record for the period of observation is given in table 99. The reaction was acid throughout, except March 14-16, 1910, when it was alkaline. There were occasional slight traces of albumen. The quan- tity of sugar in the urine on February 27-28, 1910, amounted to 209 grams in 24 hours, and the ammonia to 1.9 grams. Under strict dieting, sugar disap- peared from the urine after 12 days and the urine was sugar-free on December 1, 1910, the weight having risen to 71 kilos. No sodium bicarbonate was given the patient, except 15 grains on both March 14 and March 15. On April 26, 1912, the quantity of sugar reached 39 grams in 24 hours, and there was a trace of diacetic acid. The patient reported having successfully withstood an attack of pleurisy, and that the 6.8 kilos, of weight lost during that illness had been regained. EXPERIMENTS WITH CASE X. With this subject 3 calorimeter experiments were made, in all of which the chair calorimeter was used. The third experiment was preceded by a respira- tion experiment. No food was taken in any of the experiments, and a fast of at least 12 hours preceded them. A comparison of the results obtained in the calorimeter experiments is given in table 107. The vital statistics of the sub- ject were as follows: Date of birth, October 1875; height, 170 cm.; range in body-weight with- out clothing during the experiments, 62.3 to 64.6 kilos. Table 100. — Measurements of metabolism — Calorimeter experiment No. XI. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. feT, minute. 1 Feb. 28, 1910: 10h 10™ a.m. tollh 10ma.m 11 10 a.m. 12 10 p.m 12 10 p.m. 1 10 p.m Total3hrs.> gms. 27.6 24.8 25.4 c.c. gms. c.c. 234 27.4 320 211 , 24.7 288 215 24.9 290 0.73 .73 .74 70 68 66 22 22 20 77.8 220 77 0 299 •• 1 Carbon dioxide eliminated per kilogram per minute, 3.53 c.c; oxygen absorbed per kilogram per minute, 4.80 c.c. Calorimeter Experiment No. XI. Date, February 28, 1910. Body-weight without clothing, 62.3 kilos. The subject came to the laboratory without breakfast at 8h 10m a. m. and entered the chair calorimeter at 8h 41m a. m. The experiment began at 10h 10m a. m., and continued for three 1-hour periods, ending at lh 10m p. m. Records of the pulse and respiration rates were obtained by means of the steth- oscope and pneumograph, while body-temperature records were secured with STATISTICS OF EXPERIMENTS. 81 the rectal thermometer. The subject also used a clinical thermometer at llh 10m a. m., 12h 10mp. m., and lh 10m p. m. In this and the succeeding experiments an attempt was made to obtain some record of the muscular activity of the subject by the use of a pneumatic cushion connected with a kymograph. Throughout the experiment there was but little muscular move- ment aside from the activity incidental to telephoning several times during Table 101. — Statistics of urine — Calorimeter experiment No. XI. Date and period. Volume. Total nitrogen. Sugar. Feb. 28, 1910: 8h 15m a.m . to lh 20™ p.m Feb. 28 to Mar. 1. 1910: lh 20m p.m. to 7 a.m... c.c. 227 2400 gms. 3.43 gms. 8.9 182.1 each period, and drinking 64 c.c. of water at 10h 20m a. m. Previous to the experiment the subject urinated and defecated at 8h 15m a. m., and urinated again at lh 20m p. m. after the experiment was over, but was unable to urinate during the experimental period. The records of the experiment are given in tables 100 and 101. Table 102. — Measurements of metabolism — Calorimeter experiment No. X2. Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Mar. 1,1910: '9h 18ma.m. to 10h 18m a.m 10 18 a.m. 11 18 a.m 11 18 a.m. 12 18 p.m Total 3 hrs.2 gms. 24.2 24.5 23.5 c.c. 205 208 199 gms. 20.3 23.0 22.5 c.c. 236 268 262 0.87 .78 .76 67 63 59 21 20 21 72.2 204 65.8 256 .... •• •• 1 Subject drank a cup of coffee about 2 hours before the experiment began. 2 Carbon dioxide eliminated per kilogram per minute, 3.25 c.c. ; oxygen absorbed per kilogram per minute, 4.08 c.c. Calorimeter Experiment No. X2. Date, March 1, 1910. Body-weight without clothing, 62.7 kilos. With the exception of a cup of coffee, no food was taken by the subject before he came to the laboratory at 7h 50m a. m. At 8h 08m a. m., the subject entered the chair calorimeter; the experiment began at 9h 18m a. m., continued for three 1-hour periods, and ended at 12h 18m p. m. The records of the pulse and respiration rates were obtained as in the preceding experiment, but the rectal thermometer was not used, although records were taken by the subject with a clinical thermometer at 9h 28m a. m., 10h 32m a. m., llh 28m a. m., and Table 103. — Statistics of urine — Calorimeter experiment No. X2. Date and period. Volume. Total nitrogen. Sugar. Mar. 1. 1910: i7h00ma.m. to 9h 28m a.m ,,., 9 28 a.m. 10 32 am 10 32 a.m. 11 35 a.m 11 35 a.m. 12 25 p.m Mar. 1-2, 1910: 12h 25°° p.m. to 7h00ma.m ex. 143 58 48 37 1455 gms. 1.90 .77 .66 .56 16.78 gms. 9 8 3.1 2 1 1.3 82.9 'Subject drank a cup of coffee at about 7° 15m (?) a.m. 82 METABOLISM IN SEVERE DIABETES. 12h 18m p. m. Near the end of the first period the subject was asleep, waking just after the beginning of the second period. He telephoned once in each period. The subject urinated before coming to the laboratory at 7 a. m., and three times during the experiment, i. e., at 9h 28m a. m., 10'1 32m a. m., and 1 1 h 35m a. in., also at 12h 25m p. m., after the experiment was over. He drank no water. The records of the experiment are given in tables 102 and 103. Respiration Experiment No. X3. Date, March 17, 1910. Body-weight without clothing, 64.6 kilos. On the experimental day the subject drank a cupful of coffee before com- ing to the laboratory, but ate no breakfast. He reached the laboratory at 7h 40m a. m., lay down on the couch at 7h 45m a. m., and the experiment began at 8h 58m a. m. The three periods ranged from 12 to 15 minutes in length, with intermissions from 8 to 10 minutes, the last period ending at 9h 56m a. m. After the experiment began the subject breathed slower and possibly deeper than he had previously. In the second period he took several very deep breaths. In this period, also, there was a slight leak in the nosepiece, and a new nosepiece was accordingly used for the next period. Immediately after the experiment was over the subject urinated at 9h 56m a. m., the last period being shortened on account of the pressure of urine. The records of the experi- ment are given in tables 104 and 106. Table 104. — Results of respiration experiment No. X3. Date and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory Average quotient. , pulse-rate. Average respiration rate. Mar. 17, 1910: 1 8h 58m a.m . 9 22 a.m 9 44 a.m Average2 min sec. 14 54 14 42 12 23 c.c. c.c. 178 247 0.72 179 245 .73 189 243 .78 72 73 72 11 16 15 182 245 0.74 72 14 1 Subject drank a cup of coffee about If hours before experiment began. 2 Carbon dioxide eliminated per kilogram per minute, 2.82 c.c; oxygen absorbed per kilogram per minute, 3.79 c.c. Calorimeter Experiment No. X4. Date, March 17, 1910. Body-weight without clothing, 64.6 kilos. This experiment was preceded by a five-period respiration experiment (experiment No. X3). The subject drank a cupful of coffee on the morning of the experimental day, but aside from this took no food after the evening meal of the day before. He entered the chair calorimeter at 10h 08m a. m.; the experiment began at 10h 45m a. m., continued for three 1-hour periods, and ended at lh45rap. m. The rectal thermometer was not used, but the Table 105. — Measurements of metabolism — Calorimeter experiment No. X4- Date and period. Carbon dioxide eliminated. Oxygen absorbed. Respi- ratory quotient. Average pulse- rate. Average respira- tion rate. Total. Per minute. Total. Per minute. Mar. 17, 1910: 10h45ma.m. tollh45ma.m 12 45 p.m. 1 45 p.m Total 3 hrs.1 gms. 20.9 23.1 22.9 c.c. 177 196 194 gms. 17.5 22.8 19.9 c.c. 204 266 232 0.87 .74 .84 69 70 71 19 20 20 66.9 189 60.2 234 •• 1 Carbon dioxide eliminated per kilogram per minute, 2.93 c.c.; oxygen absorbed per kilogram per minute, 3.62 c.c. STATISTICS OF EXPERIMENTS. 83 pulse and respiration records were taken in the usual way. By means of the clinical thermometer the subject made a few records of the body temperature at 10h 55m a. m., llh 55ra a. m., 12h 55m p. m., and lh 50m p. m. During the latter part of the second period the subject was apparently asleep, and was sound asleep near the end of the third period, but awoke before the close of the Table 106. — Statistics of urine — Respiration experiment No. X3 and calorimeter experiment No. X4- Date and period. Volume. Total nitrogen. Sugar. Mar. 17, 1910: 7h 00" a.m. to 9h 55m a.m.i 9 55 a.m. 1 00 p.m c.c. 627 142 960 gms. 1 61 1.09 10.38 gms. 0.5 .2 2.1 Mar. 17-18, 1910: lh 00™ p.m. to 7h 00m a.m 1Subject drank a cup of coffee at about 7h 15m (?) a.m. experiment. He telephoned twice during each period. Before the experiment he urinated at 9h 55m a. m., but was unable to urinate again until 1 p. m. No water was taken during the experimental period. The records of the experi- ment are given in tables 105 and 106. Table 107. — Comparison of metabolism experiments in the chair calorimeter with Case X. Experiments without food. Experi- ment No. Date. Weight of subject. Length of experiment. Per minute. Respi- ratory quotient. Average pulse per minute. Average respiration per minute. Carbon dioxide eliminated. Oxygen absorbed. XI X2 X4 1910. Feb. 28.... Mar. li... Mar. 17.... kilos. 62.3 62.7 64.6 hrs. min. 3 00 3 00 3 00 c.c. 220 204 189 c.c. 299 256 234 0.73 .80 .81 68 63 70 21.5 20.5 19.5 'About 2 hours before the experiment began the subject drank a cup of coffee. PART III. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. While in general the order and method of discussion of the subjects in this publication follow that in the earlier report, as experimental evidence accumu- lated certain topics which were much more completely studied warranted more extensive consideration. Furthermore, while in the earlier publication it was important to emphasize more especially the relationship between the respira- tory exchange and the character of the metabolism, particularly with normal individuals, here it is necessary to pay but little attention to normal metabo- lism, because it is believed that this phase of the study was amply treated in the earlier report. None of the experiments with food are discussed in this report pending further investigation, but the statistics for these experiments have been presented in order to record the data permanently for subsequent use. Pulse-Rate. In the earlier series of experiments a cursory examination of the pulse-rate taken from time to time indicated that there was apparently no marked differ- ence between the pulse-rate of normal individuals and that of diabetics, the fluctuations in the pulse-rate of the diabetic subjects being within normal limits. It would appear from the lack of data upon the subject in the text- books of medicine and in the monographs upon diabetes mellitus that this coincides with the opinion of most clinicians, but such a conclusion rests upon negative evidence alone, since usually little attention is paid to the pulse-rate in chronic afebrile diseases of a non-circulatory type. It is quite possible that a closer study of this factor may supply much information of value. In physiological experimentation it is frequently difficult to distinguish between the normal and the abnormal. The popular conception of a normal pulse-rate is the observation usually made by a physician in his office, which may often be affected by the muscular exercise of the patient in walking to the office, or the excitement incidental to consulting a physician. To obtain a true normal value, however, the observation should be made under conditions which would insure its being unaffected by food, exercise, or mental stimulus of any kind. Such conditions are obtained when the record is taken with the subjects lying quietly in bed without food. It seemed therefore desirable in the later researches to make a more detailed record of these values, and study carefully not only the pulse-rate of the diabetic subjects, but also of the normal subjects used for comparison. An abstract of the results is presented in tables 108 and 109, in which are given the minimum and maximum pulse-rates recorded while the subjects lay quietly without food in the bed calorimeter or on a couch in respiration experiments. The values given for the diabetics include those obtained for all of the subjects in both the earlier and the later experiments, with the exception of E and F, no records of pulse-rate being available which were taken while these subjects were lying down. 85 86 METABOLISM IN SEVERE DIABETES. The average for all of the diabetic subjects shows a minimum pulse-rate of 65 beats per minute, and a maximum of 81 beats. The average maximum and minimum pulse-rates for the normal subjects are 54 and 74 respectively, both materially lower than the averages found for the diabetic subjects. In prepar- ing these tables, care was taken not to include any records obviously affected by excitement or other untoward incident in connection with the experiment, three records approximately constant usually being taken as indicating the maximum or minimum. The values given can therefore be considered as repre- senting the average normal variations in pulse-rate to be expected for normal Table 108. — Pulse-rate of diabetic subjects. Subject. Minimum. Maximum. Subject. Minimum. Maximum.' Subject. Minimum. Maximum. A 65 56 50 52 69 64 117 60 86 72 84 58 74 90 122 84 K 73 54 64 53 83 73 80 84 69 82 83 73 S 57 63 72 62 90 72 60 71 97 69 111 75 B.. L T C. M U.... D.... N V G O 57 W H I J P 64 61 64 X o Average . R... 65 81 individuals under the conditions of experimenting as employed in this labora- tory, and for patients with severe diabetes. It will be seen, therefore, that both the minimum and maximum pulse-rates of normal individuals are markedly lower than those of diabetics. It must furthermore be remembered that in practically every instance the normal individual led a much more active life, had much greater muscular tone, and was more restless than were the diabetics. This makes the difference in pulse-rate all the more striking, since one would ordinarily expect a somewhat higher value with the more active and restless normal subjects than with the Table 109. — Pulse-rate of normal subjects. Subject. Mb. Max. A.F.G 59 56 56 61 74 58 54 46 53 62 82 73 75 90 70 96 76 66 T. M. C Misa J Miss A MissE. W Mrs. S C H.H. A S A. R Dr.P.R Subject. C. H. H.. M. A. M.. Miss B . . . Dr. S.... H. F. T.. E. P. C. K. H. A.. J. R O. F. M.. Min. Max. 53 69 49 82 70 82 50 61 37 64 45 59 40 62 52 74 49 66 Subject. Min. Max. Prof. C 48 54 48 50 55 74 48 68 79 80 68 74 97 72 Miss L V. G M.B H.B. L MissB. VV D. M Total average.. 54 74 weak, sick diabetics, disinclined to any extraneous muscular motion. An examination of tables 108 and 109 shows no regularity in either the minimum or maximum pulse-rates when individual diabetics are compared with normal individuals, since some of the diabetic subjects show a minimum pulse-rate con- siderably lower than the average minimum pulse-rate of the normal subjects; and similarly, the normal individuals in some instances show a pulse-rate con- siderably higher than the average maximum pulse-rates of the diabetics. On the whole, however, a distinct tendency toward an increased pulse-rate in diabetics is here clearly shown. This increase is fully in conformity with the DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 87 increased metabolism previously noted and further substantiated by the evi- dence set forth in this report. Yet in this discussion of the pulse-rate it should be stated that it is questionable whether sufficient information with regard to normal pulse-rate has accumulated to indicate that a variation above normal of 15 per cent could be recognized. While the metabolism may be 15 per cent above normal and be accurately measured, since normal metabolism is fairly well established, a 15 per cent increase in pulse-rate could not be so easily identified. The intimate relationship between pulse-rate and metabolism is increasingly evident in practically every new publication on metabolism and shows that to-day the pulse-rate is taking on a new significance; it is not at all impossible that the degree of acidosis and the degree of metabolism may be at least approximately estimated in diabetics by a careful examination of the pulse-rate. In this connection, a reference to the later discussion on the rela- tionship between acidosis and metabolism will be of interest. (See page 123.) While an increased pulse-rate is invariably accompanied by an increased metabolism, it is by no means to be inferred that the increased metabolism is due exclusively to the work of the heart. In fact, from what is known of the work of the heart, it can be seen that probably but a very small proportion of the total increase can be properly ascribed to the actual muscular action of the heart itself, but that the increased pulse-rate is an excellent index of gen- eral tonus is highly probable. Unquestionably, during increased metabolism and increased pulse-rate, there is some tendency toward an increased respira- tion rate, but here again it is highly improbable that the muscular action involved in raising the chest-wall can in any considerable proportion account for the total increase in metabolism. On the other hand, both the increased muscular activity of the heart and the increased work of the respiratory mus- cles unquestionably contribute some small quota to the total increase in metab- olism. We commend to the attention of the physician the importance of the pulse-rate in diabetes and particularly the value of changes in the pulse-rate in the same patient during the progress of the disease. We likewise commend to all experimenters the practice first established by Prout1 of reporting the pulse-rate with the chemical data of each experiment. Body -Temperature. In a research of this kind, measurements of body-temperature have two purposes. First, to learn whether the temperature measurements are within normal limits and, second, for use in computing the heat production. The variations in body-temperature necessitate proper corrections for heat stored when the body-temperature rises, or for heat given off, and thus not produced, as the body-temperature falls. An ideal experiment, therefore, would call for continuous measurements of body-temperature, particularly at the beginning and end of each experimental period. In this laboratory and in the laboratory of Wesleyan University, Middletown, Connecticut, much attention has been paid in the last ten years to such measurements. To obtain the most accurate 1 Prout, Ann. Philos., 1813, 2, p. 328. 88 METABOLISM IN SEVERE DIABETES. calorimetric measurements, an electrical resistance thermometer which can be inserted deep in the rectum has been used for measuring rectal temperatures, but a number of the diabetic subjects found this somewhat objectionable, although in no sense painful. Accordingly, in many instances we were obliged to content ourselves with temperatures taken in the mouth by means of a mercurial clinical thermometer of good grade. With a number of subjects, however, we were able to determine the rectal temperature by the electrical resistance method. In general, the fluctuations and actual temperature measurements ranged well within what are commonly supposed to be normal limits; only one of the diabetic subjects showed a body-temperature that could be considered in any sense above normal, and even normal individuals have indicated equally as high a temperature as did this diabetic subject. Table 110. — Body-tem-perature of diabetic subjects. Subject. Sublingual.1 Rectal.2 Maximum.3 Minimum.3 Maximum. Minimum. A op 98.4 (36.90) 98.0 (36.65) °F 97.2 (36.20) 97.6 (36.45) °C. 37.07 36.30 B C .. 37.32 E... 99.0 (37.20) 98.95 (37.20) 98.0 (36.65) 97.95 (36.65) 38.05 37.14 37.71 37.11 37.70 36.93 36.56 36.44 F G H I 98.6 (37.00) 98.65 (37.05) 98.55 (36.95) 97.6 (36.45) 97.75 (36.55)* 98.25 (36.80) J . K L M N U X 98.3 (36.85) 97.90 (36.60) 98.7 (37.05) 98.6 (37.00) 98.2 (36 80) 97.02 (36.10) 98.4 (36.90) 97.1 (36.15) 1 Records taken with a clinical thermometer. 2 Records taken with an electrical resistance thermometer. 3 Centigrade equivalents given in parentheses. "For Case I there was also 97.3° F. (36.28° C.) on Feb. 23, 1911, sitting in chair after the experiment. To give an indication of the minimum and maximum temperatures observed with the diabetics, we have collected in table 110 the values for both the sublingual temperatures taken with a mercurial thermometer and likewise the rectal temperatures taken with the electrical resistance thermometer. An inspection of the data shows that the sublingual temperatures are practically those ordinarily experienced with normal individuals in health. The rectal temperatures are almost invariably somewhat higher than are the sublingual temperatures, as would be expected from the well-known fact that tempera- tures in the rectum are considerably higher than those in the mouth. With one subject, Case G, the temperature was somewhat higher than normal, averaging close to 38° C. throughout the whole experiment. Since the publication of our first report on metabolism in diabetes, a research has been concluded in this laboratory,1 demonstrating what has hitherto been assumed, namely, that fluctuations in temperature taken deep 'Benedict and Slack, A comparative study of temperature fluctuations in different parts of the human body, Carnegie Institution of Washington Publication No. 155, 1911. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 89 in the rectum are accompanied by similar fluctuations in different parts of the body. For purposes of computing the heat production, it is most necessary to know if an alteration in temperature of 0.1 degree in any one part of the body shows a like alteration in the temperature of the body as a whole, the absolute temperatures not being so significant. The investigation referred to has shown that when the rectal temperature falls 0.1 degree, there is a corre- sponding fall in all other parts of the body ; hence it is logical to assume that a change of temperature measured in the rectum may be ascribed to that of the whole body. In computing the heat production, therefore, correction can be made for the heat lost from the body when there is a lowering in the tempera- ture by multiplying the specific heat of the body by its weight and by the loss in temperature as measured in the rectum. The importance, therefore, of this table is that it establishes the fact that the temperatures of diabetics as a rule range well within what are commonly supposed to be the normal limits. We wish, however, to point out here the difficulties experienced by Benedict and Slack in securing adequate and proper records of the body-temperature by means of the mercurial thermometer in the mouth. As a means of indicating the presence or absence of a high fever this method is certainly rational, but for all physiological purposes and especially for the measurement of small differences in temperature, observations taken in the mouth are wholly unsatisfactory and no reliance should be placed upon them. On the other hand, rectal temperatures should be taken deep in the rectum, the thermometer being inserted at least 5 cm. if the true internal temperature of the body is to be recorded. BODY-WEIGHT. Perhaps no one gross observation made during the course of diabetes melli- tus is of greater significance and causes greater alarm, both to patient and physician, than the persistent loss in body-weight. On the other hand, slight changes in body-weight which may accompany dietetic alterations or the inges- tion of sodium bicarbonate are looked upon as material gains and of diagnostic value, and are thus liable to be misunderstood by the patient. To interpret intelligently these changes it is necessary both for the physician and for the patient to realize the factors affecting the body-weight of normal as well as pathological cases. Few realize that the normal individual is continually undergoing changes in body-weight throughout the 24 hours. The extent and rapidity of these fluctuations may best be shown by means of a chart obtained from observations made every hour for 24 hours. (See fig. 1.) The subject was weighed on a sensitive platform balance ; the total weight of food eaten at different times was recorded, also the total weight of drinking-water when it was taken, and the weight of urine and the weight of feces when passed. In addition to being weighed every hour, the subject was weighed immediately before and after eating or drinking, passing urine, or defecating. Two series of observations were made, the results of which are shown in curves I and II. Curve I gives 90 METABOLISM IN SEVERE DIABETES. a record of hourly weighings taken when the subject was awake the whole 24 hours; curve II shows the results of hourly weighings made during the waking hours, also a record of the total loss during the night sleep. In curve I it can be seen that except at the times when food was taken there was a downward tendency of the curve throughout the whole 24 hours. As a matter of fact, the general angle of the curve with the base-line is essen- tially the same throughout the whole day. During this experiment the subject was engaged in experimental work in the laboratory which necessitated con- tinous observation during the 24 hours, and hence we find no variations in the rapidity of the combustion of materials during the day or during the night. On the other hand, when the same subject spent a normal amount of time in bed asleep, the course of the curve (curve II) is somewhat different. During the day its course is essentially the same as that of curve I, but during the night 7-AM 12 M 6-PM I2M Fig. 1. — Curves showing hourly changes in body-weight for 24 hours. 6AM Curve I shows the changes in body-weight when the subject was awake the entire 24 hours. Curve II shows the changes in body-weight when the subject was awake from 7 a.m. to 10 p.m., and asleep from 10 p.m. to 6 a.m. the loss is much less; this would be expected from the fact that instead of being engaged in rather active muscular work about the laboratory, the subject was in bed asleep. Curve I furthermore shows that the long night work was rather severe and the body-weight was noticeably less at the end than it was at the beginning of the experiment. In curve II the body-weight returned to essen- tially the same point at the end of the 24 hours, notwithstanding the fluctua- tions due to the ingestion of food and drink and the loss in feces and urine. The second curve shows clearly, therefore, that the body-weight varies at different times of the day, but it may be noticeably different on different days, easily varying 1 or 2 pounds in the course of a single day. It is obvious that, aside from the loss in weight due to the passing of urine or feces, there is a general tendency for the body to lose weight from hour to DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 91 hour. This is due to a loss which has been known since the days of Sanctorius1 as insensible perspiration. One of the best methods of observing this loss in weight in the form of insensible perspiration is during the night. If, for example, the subject is weighed just before going to bed and again in the morn- ing immediately on rising and before the bladder is emptied, the loss in weight will be due to insensible perspiration. Two such experiments were made with a normal man weighing approximately 85 kilos, without clothing and a normal woman weighing 65 kilos, without clothing. The results are shown in table 111, which gives the number of hours spent in bed and the loss in weight in grams. The loss in weight was found to be directly proportional to the restless- ness of the sleep, as on a hot, uncomfortable night it was much greater than on a cold night when the person slept quietly beneath bedclothes, instinctively moving no more than was necessary. On the average the man lost 39 grams per hour and the woman 29 grams. The insensible perspiration, therefore, was not far from 30 to 40 grams. Table 111. — Loss in body-weight during night. Man, 85 kilos. Woman, 65 kilos. Date. In bed. Loss in weight. Date. In bed. Loss in weight. 1898. Oct 7.. Oct. 8.. Oct 9.. Oct. 10.. Oct. 11.. Oct. 12.. Oct. 13.. hrs. min. 8 45 8 0 8 15 9 0 9 0 8 15 8 0 gms. 330 360 300 310 390 360 250 1898. Oct 13.... Oct. 14.... Oct. 31.... Nov. 1.... hrs. min. 8 0 9 45 7 15 9 0 gms. 170 270 230 290 Average loss per hour: Man, 39 grams; woman, 29 grams. This observation, made with a platform balance, of the loss of 30 to 40 grams of weight by insensible perspiration received substantiation from the results of 50 or more experiments carried out in the Nutrition Laboratory by more refined and exact methods. With a considerable number of individual subjects it was found that the loss due to insensible perspiration, during wak- ing hours, when the subject was sitting still2 inside the respiration chamber, averaged 40 grams per hour. In certain work experiments this insensible perspiration was greatly increased, but it is safe to say that a normal person, sitting still and reading quietly, will lose in weight approximately 40 grams per hour. With severe muscular work the loss may be increased tenfold, or, indeed, during the time of strenuous muscular exercise, as in athletic contests, even a hundredfold. Although the amount of this insensible perspiration can be obtained by accurately weighing the subject on scales, the character of the loss can be determined only by careful respiration experiments, which show that carbon dioxide and water-vapor are continually being given off from the 'Sanctorius, De medicina statica aphorismi, Venice, 1614. Translated by John Quincy, M. D., London, 1737. 2 Benedict and Carpenter, Carnegie Institution of Washington Publication No. 126, 1910. p. 114. 92 METABOLISM IN SEVERE DIABETES. body and oxygen consumed. The loss in insensible perspiration is, then, not simply an evaporation of water from the body, but consists, in part at least, of an actual loss of organized body-tissue that has been oxidized by the oxygen taken into the lungs and given off both as carbon dioxide and as water result- ing from the oxidation of organic hydrogen. Referring again to curves I and II in fig. 1, it will be seen that the increase in weight found after taking food was due simply to the weight of the food taken into the intestinal tract, and that the noticeable losses in weight follow- ing the passage of urine and feces were due to the loss of these materials from the body. In discussing changes in body-weight, the important point to note is whether there are additions to or losses from the total body-mass, the inci- dental fluctuations due to the taking on of food or the passage of urine or feces being of no great importance. If, then, during a period of one year, the body gradually increases in weight a number of pounds or loses a number of pounds, it is clear that these changes in weight can not be due to minor fluctuations in the quantity of water or food taken, of urine passed, or of feces excreted. A factor which should be taken into consideration in interpreting changes in body-weight is the fluctuation in the water-content of the body. Under certain conditions it is possible for the body to retain considerable quantities of water and, indeed, to be deprived of considerable amounts of water that would normally be retained. Since about 60 per cent of the body is water, any change of water-content may result in material gains or losses in body-weight. A man weighing, for example, 65 kilos, may have an absolute water-content of 40 kilos., so that a relatively small change in the percentage of water in the body may produce a change in body-weight of 1 kilo. It was observed many years ago by Bischoff and Voit,1 in a series of experi- ments with animals, that when the diet was in large part carbohydrate there was a tendency for the body to retain water in that the muscular tissues became more moist. By means of the respiration calorimeter at Wesleyan University, Middletown, Connecticut, an interesting experiment was made on a man which showed conclusively the effect of the constituents of a diet on the water- content of the body.2 During the experiment, which lasted 6 days, the sub- ject was confined inside of a respiration chamber and spent 8 hours of the day riding a stationary bicycle ergometer, thereby doing a considerable amount of muscular work. The daily routine and the quantity of work performed were adjusted so that they would be the same on all days. During the first three days the subject was given a diet containing a large amount of carbohydrate, the total diet being nearly, although not quite, sufficient to supply him with energy for the amount of work he was to do. In this period, which was pre- ceded by a preliminary period with the same diet, the body retained its weight for a number of days. On the fourth day the character of the diet was materi- ally altered by decreasing the carbohydrate and increasing the fat. Singularly enough, although the actual total weight of food ingested was somewhat more 'Bischoff und Voit, Die Gesetze der Erniihrung des Fleischfrcssers, Leipsic, 1860. 'Benedict and Milner, U. S. Dept, Agr., Office Exp. Stas. Bui. 175, 1907, p. 225. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 93 than on the first three days, nevertheless the body actually lost in weight 950, 839, and 952 grams on the first, second, and third days, respectively, thus showing that with the carbohydrate diet the body of the subject had a ten- dency to retain a much larger amount of water than with the fat diet. The results of this experiment are presented in table 112. The chemical analyses of food, feces, and excreta, including especially the determination of carbon dioxide produced, oxygen consumed, and water vapor- ized, give the data for the exact computation of the kind and amount of material lost from the body. The results from this G-day experiment show that the quantities of the food had been so adjusted to the needs of the body that there was practically no draft upon body-material or storage of either pro- tein, fat, or carbohydrates, but that there were great changes in the amount of water. It was found on the average that the body actually stored 165 grams of water per day during the carbohydrate period and actually lost on the aver- Table 112.— Changes in body-iccight due to diet. CARBOHYDRATE DIET. Date and diet. Food and drink. Body- weight. Gain (+) or loss (-)• Solid matter. Water. Total. 1904. Apr. 16 16-17.. 17-1S.. 18-19.. gms. 970 966 966 gms. 3577 3553 3491 gms. 4547 4519 4457 kilos. 75.086 75.443 75.414 75.269 gms. +357 - 29 -145 FAT DIET. Apr. 19-20.. 20-21.. 21-22. . 750 745 747 3108 4150 4152 3859 4896 4899 74.319 73.480 72.528 -950 -839 -952 grams. Average gain per day, carbohydrate diet +61 Average loss per day, fat diet —914 Water stored per day, carbohydrate period +165 Water lost per day, fat period —906 age 906 grams of water per day during the fat period. This loss during the fat period corresponds almost exactly with the loss in body-weight, and shows that the loss is due to water. Similar experiments have shown that the reverse is true, i. e., when the previous diet contained a preponderance of fat and the change was suddenly made to a carbohydrate diet, there was a marked increase in weight. Obviously, there would be a limit to such retention of water, since the body would not continue indefinitely to accumulate water at the rate of 500 or 600 grams a day, as it would soon become "waterlogged" under these conditions. There is, however, something in the character of a rich carbo- hydrate diet which seems to demand a larger proportion of water, and this demand is provided for by a storage of water in the body-tissue; when the carbohydrate diet is changed to a fat diet, this water is freely excreted. The restriction of carbohydrate and the increase of fat which are prescribed when diabetic patients are first started upon dietetic treatment duplicate the above 94 METABOLISM IN SEVERE DIABETES. experiment and the loss of weight which such patients usually undergo at once is thus in part explained. Conversely, a gain in weight almost universally accompanies the oatmeal cure. That other conditions also play an important role in the storage of water in the body has been shown in our extensive experience with diabetics. It has been frequently found that when diabetics are on a strict diet and are given relatively large amounts of sodium bicarbonate to counteract the ever-present tendency to acidosis, there may be a considerable retention of water and con- sequent increase in body-weight inside of a few days. An abstract of the results with one of the cases (Case A) is given in table 113. The records of the body-weights were made in the early morning before food was taken. Beginning November 6, 20 grams of sodium bicarbonate were given daily, and the results show that while the body-weight, on the morning of November 6, was 49.3 kilos., on the morning of November 11 it had increased to 53.3 kilos., or a gain of 4 kilos. Since at this time the subject was living on a very restricted diet, with barely enough energy in the diet for daily maintenance, it can be seen that this increase must have been due not to the retention of organ- ized body-material, either protein or fat, but simply to water. If the dietetic conditions had been reversed, an equally rapid loss in weight would have been expected, corresponding to the amount of water lost. Table 113. — Gain in weight of a diabetic with administration of sodium bicarbonate* Date. Sodium bicar- bonate. Body- weight. Date. Sodium bicar- bonate. Body- weight. Nov. 2 3 4 5 6 gms. 0 0 0 0 20 kilos. 4S 1 48.6 49 0 48.6 49.3 Nov. 7... 8... 9... 10... 11... gms. 20 20 20 20 20 kilos. 50 7 51 5 52 4 53.3 53.3 *The proportions of protein, carbohydrate, and fat, as well as total calories, were nearly constant throughout. While a knowledge of the fluctuations in body-weight due to the retention or loss of water plays an important role in gaining a correct understanding of the significance of changes in body-weight, we need pay particular attention only to drafts upon organized body-material. Of the four remaining constit- uents of the body — the protein, fat, carbohydrate, and the mineral matter — the largest addition or depletion can be made in the case of fat. Additions to the protein content of the body are not so easily made as are additions to the fat. Experiments in the laboratory of Professor von Noorden1 have shown, however, that considerable quantities of nitrogenous material can be stored in the body, but how this is stored and in what form is by no means certain. It is, however, reasonably certain that the protein is not stored in the form of active protoplasmic tissue which necessitates an active metabolism. After the body has been subjected to a fast it seems to have an especial ability to restore the loss of nitrogenous material and even take on a greater amount. While under lSee Miiller, Zentralblatt f. die ges. Path. u. Pharm. des Stoffwechsels, 1911, 6, p. 617. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 95 special experimental conditions it is possible for us to add to or take from the store of nitrogen in the body to the extent of several hundred grams, never- theless this is rarely accomplished. Consequently, in studying fluctuations of body-weight ordinarily occurring outside of those attendant upon wasting dis- eases, we do not need to consider any alterations in the storage of body nitrogen. One of the most important compounds in the human body is the relatively small quantity of carbohydrate material, chiefly in the form of glycogen in the liver and muscles. While it is believed that there may be, relatively speaking, a large draft upon this storage of body-glycogen, which has been estimated by some writers to be not more than 400 grams, the total fluctuation one way or the other is not of sufficient moment to play any part in considering the major changes in body-weight. It is possible, indeed probable, that varying amounts of glycogen may indirectly control or influence the presence of varying amounts of water, but glycogen per se can not be materially added to the body or taken from the body, since the total storage is small — probably not far from 400 grams. The remaining compound of the body, i. e., fat, can, however, be enormously added to or taken from. It is with changes in the storage or loss of fat that we have chiefly to do when discussing the question of the gains and losses in body-weight, particularly losses that are the result of a progressive change covering some weeks or months. It has already been pointed out how by certain abnormal conditions we can produce rapid fluctuations in the water-content of the body, but it is prac- tically impossible to secure any rapid change in the amount of fat stored or lost by the body. Even fasting for a day does not lead to any appreciable draft upon the storage of fat. It has been proved that in a normal healthy indi- vidual undergoing a complete fast for 24 hours, the glycogen may be depleted to the extent of possibly one-half of its original value. Then after this deple- tion of glycogen has taken place, the fat is drawn upon, and after the third day the draft is chiefly upon the fat-content of the body, with a relatively small but constant depletion of the glycogen and protein ; thus it is seen that any changes in weight having to do with 1 or 2 pounds inside of 24 hours can not in any way be considered as changes in the fat-content of the body. To studjr the character of these changes, respiration experiments are essen- tial, in which the carbon-dioxide production is determined as well as the oxygen intake and, if possible, the vaporization of water. If we were to collect all of the products of expiration from the body, namely, the carbon dioxide and water-vapor, we would not even then have an equivalent of the material lost from the body, for of the carbon dioxide and that portion of the water which is formed by the oxidation of organic hydrogen, a not inconsiderable amount is due to the weight of the oxygen absorbed from the air. For instance, assuming that a man at rest in 24 hours produces 700 grams of carbon dioxide and gives off 900 grams of water by sensible and insensible perspiration, this total weight of 1,600 grains does not by any means represent the loss from the body, since of this amount at least 700 grams is due to the oxygen absorbed out of the air, and the actual loss from the body would therefore be approximately 900 grams of water and organic material. 96 METABOLISM IN SEVERE DIABETES. Here again we find the ever-occurring changes in water-content com- pletely masking all information with regard to the loss of organized body-tissue. The water given off from the body is from two sources, first, the preformed water existing as such in the tissues, and, second, the water resulting from the oxidation or burning of organized body-material. The respiration calorimeter with its accessory appliances shows us the method by which the water leaves the body, but it does not tell us whether the water from these two sources has any selective method of discharge; thus, all the water formed from the combus- tion of organic tissue is not excreted through the lungs and skin, nor is the water drunk all excreted through the kidneys. The data for the losses in gross weight cease to be of any service to us, therefore, in telling us what pro- portion of the daily loss is due to the oxidation of organized tissue. As a result of a large number of calorimetric experiments on men, both fast- ing and with food, it can be shown that the average man at rest without food may oxidize per day about 75 grams of protein, 25 grams of glycogen, and 200 grains of fat, a total of 300 grams of water-free organized body-tissue. It can be readily seen, therefore, that with subjects at rest large changes in weight must be due not to the oxidation of organic matter, which amounts to only 300 Table 114. — Loss in body-weight after severe muscular exercise. Subject. Football player Marathon runner College 8-oared boat crew Duration of work. hrs. min. 1 10 3 0 0 22 Loss in weight. lbs. 14.0 8.5 5.5 kilos. 6.4 3.9 2.5 grams per day, but to large excretions of water. With increased muscular activity we have both increased destruction of organized tissue and likewise very large increases in the amount of water lost from the body. This is well shown by the records of losses in body-weight due to the excessive exercise of athletes, and while the observations lack that finality in conclusions that experi- ments in the calorimeter have, yet they are of great interest. The strenuous exercise incidental to eight-oared boat racing and to football games, particu- larly in the early fall, when the subjects are not perfectly trained and when the weather is liable to be hot, has frequently been made the subject of more or less observation. Thanks to the kindness of Prof. William G. Anderson, of the Yale University gymnasium, we are able to present authoritative figures on this subject. A number of years ago a well-known football player at Yale was weighed before and after a contest which lasted in all about an hour of actual playing. During the period this man, whose original body- weight was 191 pounds, actually lost 14 pounds. This observation, together with some others likewise furnished by Professor Anderson, are given in table 114. As pre- viously stated, a man sitting quietly loses weight as the result of insensible perspiration approximately 40 grams per hour. The football player lost 6,000 grams, or 150 times as much. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 97 It is impracticable inside the narrow confines of a respiration calorimeter to study the metabolism of Marathon runners or a college eight-oared boat crew, but a bicycle rider, riding to the limit of human endurance, has been studied.1 If we use the figures for carbon-dioxide production and oxygen con- sumption determined on this professional rider, we shall be able to compute the probable loss in weight from the body of the football player which was due to the oxidation of organic material; by deducting this loss from the total weight, we can find the loss due to the insensible and sensible perspiration. The bicy- clist produced 200 grams of carbon dioxide per hour and absorbed 121 grams of oxygen. Since practically all of the oxygen absorbed was immediately given off in combustion products, we may infer that of the total loss in weight from the body the carbon sufficient to produce 200 grams of carbon dioxide repre- sents approximately the amount of organic material lost from the man's body during one hour of severe muscular work, although there should also be a small allowance for hydrogen. It is safe to say, therefore, that during an hour of exceedingly hard muscular work, such as this strenuous football player indulged in, there would be burned in the body not far from 100 grams of dry organic material. This is approximately a quarter of a pound, leaving a total of 13.75 pounds of lost weight due to water. However, eating and drinking caused the body- weight of the subject to return to normal inside of 48 hours. This illustration not only serves admirably to show the enormous fluctua- tions that can take place in the body in a very short time, but also gives us a hint as to the possible cause of sudden changes in body-weight such as may be experienced inside of 24 or 48 hours, namely, that these changes in body-weight must of necessity be due to changes in the water-content and not to changes in the organic constituents of the body. In mild diabetes the initial loss in body- weight may therefore well be due in large part to loss of water, and although there may be a rapid fall in body-weight, sufficient to alarm both patient and physician, it need not necessarily represent the loss of organized tissue; it may simply be due to the restriction of carbohydrate during the process of getting the patient sugar-free. During the initial course of the disease, therefore, changes in body-weight are liable to be peculiarly deceptive, both qualitatively and quantitatively, since an apparent large loss in body-weight may be due exclusively to changes in water-content, with material drafts upon the organ- ized tissues. After this preliminary period with marked loss in body-weight has passed, it is probable that the loss is then due to tissue disintegration. While it is true that sudden initial changes in body-weight may reasonably be ascribed to fluctuations in the water-content of the body, it nevertheless remains a fact that an inevitable consequence of diabetes, especially when severe, is a persistent and considerable loss in weight. Although it is difficult to obtain accurate data from patients with regard to their greatest body- weight in health, particularly without clothes, we have attempted in all these cases to secure information with regard to this important factor. These weights are given in table 115, together with the minimum weight observed by 'Benedict and Carpenter, U. S. Dept. Agr., Office Exp. Stas. Bui. 208, 1909, p. 29. 98 METABOLISM IN SEVERE DIABETES. us or at death. From these the loss in body- weight has been computed, as well as the percentage loss. It is seen that in these cases the loss in body- weight varied from 5.4 to 48.3 per cent of the initial highest body-weight, with an average loss of 22.7 per cent. It is thus clear that a large percentage loss in body-weight is almost regularly observed in severe diabetes. On some 200 cases taken from several hundred in the practice of one of us (E. P. J.) we have likewise computed the percentage loss in body-weight, using the highest and minimum body-weights observed. These are given in table 116. It so happens that the maximum percentage loss observed in these 200 cases (that of Case No. 3, an excessively fat individual) was but slightly greater than that observed in our Case R, who had an initial body-weight essentially one-half that of Case No. 3. We have also computed the loss in weight experienced by these patients before being seen by E. P. J. as an index of the degree of emaciation which patients usually reach before coming under special treatment for diabetes. It should be borne in mind that these losses in Table 115. — Comparison of body-weights of subjects in health and disease. Greatest body- weight in health. Minimum Loss in Per cent ! loss of Subject. weight body- original j observed. weight. best weight. kilos. kilos. kilos. p. ct. Case A 68.0 46.1 21.9 32.2 B 50.7 37.5 13.2 26 0 C 73.5 54.9 18.6 25.3 D 57.3 45.9 11.4 19.9 F 80.5 54.5 26.0 32.3 G 73.6 53.1 20.5 27.9 H 57.7 49.2 8.5 14.7 I 56.8 39.3 17.5 30.8 J 59.1 51 5 7.6 12.9 K 73.2 55.6 17.6 24 0 L 79.1 62.2 16.9 21.4 M 86.4 80.6 5.8 6.7 N 34.5 29.6 4.9 14.2 Subject. Greatest body- weight in health. Minimum weight Loss in body observed, weight. kilos. Case O 60.8 P 49.9 Q 54.0 R 66.7 s 71.1 T 71.2 U 53.1 V 63.5 w 63.5 x 90.7 kilos. Average . 49. 38. 51. 34 57. 50. 35.8 58.3 51.7 62.3 kilos. 11.6 11.5 2.9 32.2 13.6 20.6 17.3 5.2 11.8 28.4 Per cent loss of original best weight. p. ct. 19.1 23.0 5.4 48.3 19.1 28.9 32.6 8.2 18.6 31.3 22.7 weight of diabetic patients are not necessarily the result of a sudden change in 1 or 2 weeks, but usually extend over a period of several months; the only inference that can be drawn is that patients undergoing such losses in body- weight are prone to delay dietetic treatment too long. The gains in weight of diabetics noted on the administration of sodium bicarbonate or following a change in the diet with the ingestion of large amounts of carbohydrate in the form of oatmeal may be and probably are due wholly to the variations in composition of the water-content of the body; hence such gains are not to be considered as additions to organized body-tissue. The tendency of optimistic patients to consider the gain in weight of a pound or more as an advantageous sign must, in certain instances at least, be dispelled by the attending physician, who should explain that the change in body- weight is probably due to a change in the water-content of the body, and in some cases can demonstrate this by calling attention to the appearance of edema. With the diabetic cases, therefore, we have practically two fundamentally different alterations in body-weight to be considered : first, an initial rapid loss in weight DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 99 Table 116. — Losses in body-weight by diabetics. [Weights without clothing.] (a) G reatest weight. (b) Loss in weight previous to observation. (•) Maximum loss in weight. Case No. Weight at our first observation. Minimum weight observed. (c) Amount w Per cent (/) Amount (?) Per cent (a-b). (c+a). (o-e). (f+a). kilos. kilos. kilos. kilos. kilos. '3 110.3 62.3 48.0 43 5 56.5 53.8 48.8 '5 113.9 111.2 2.7 2.4 98.5 15.4 13.5 '7 64.0 51.1 12 9 20.2 49 1 14.9 23.3 8 79.9 70.8 9.1 11 4 63.8 16.1 20.2 '10 86.7 68 6 18.1 20.9 61.8 24.9 28.7 '12 64.0 47.8 16.2 25.3 45.4 18.6 29.1 »13 91.3 79.5 11.8 12 9 76.1 15.2 16 6 '14 86.7 69.0 17.7 20.4 55.4 31.3 36 1 >15 61.8 39.1 22.7 36.7 '16 98.5 87.0 11.5 11.7 86'3 i2]2 12^4 U7 71.8 59.5 12.3 17.1 59 5 12.3 17.1 IS 73.1 57.2 15 9 21.8 57.2 15.9 21.8 '19 95.8 80.0 15.8 16.5 73.6 22.2 23.2 21 63.1 50.6 12.5 19.8 50.6 12.5 19.8 25 63.1 45 3 17.8 28.2 45.3 17.8 28.2 26 109.4 99.9 9.5 8.7 99.9 9.5 8.7 '28 39.7 34.2 5.5 13 9 31.8 7.9 19.9 '31 30 4 26 8 3.6 11.8 '32 82.2 56.7 25.5 31.0 33 95.8 94.9 0.9 0.9 82!6 i3 8 14.4 34 65.5 65 5 0 0 61.8 3 7 5 6 '36 93 5 83.8 9.7 10.4 78.9 14 6 15.6 37 82.2 67.6 14 6 17.8 67.6 14.6 17.8 '38 49.5 45.0 4.5 9.1 45.0 4.5 9.1 '39 65.9 59 7 6.2 9.4 57.7 8.2 12.4 '40 64.9 55 4 9.5 14 6 38.9 26.0 40.1 '41 103.5 75.4 28 1 27.2 75.4 28.1 27 1 '42 84 9 68.1 16 8 19.8 61.8 23.1 27 2 '44 64 9 56.8 8.1 12 5 49.1 15.8 24.3 '45 40.6 34.5 6.1 15.0 34.5 6.1 15.0 46 108.0 79.9 28.1 26.0 79.9 28.1 26.0 '48 109.4 74.7 34.7 31.7 72.2 37 2 34 0 49 94.9 82.4 12.5 13.2 82.4 12 5 13.2 '51 88.5 65.7 22.8 25.8 60.9 27.6 31.2 152 66 3 50.1 16.2 24.4 49 5 16 8 25.3 ■54 86.7 49.8 36.9 42.6 48.6 38.1 43 9 ■55 55 0 52.7 2.3 4.2 52.7 2.3 4.2 156 79.9 61.7 18.2 22.8 61.7 18.2 22 8 157 68 6 56.6 12.0 17.5 55.9 12 7 18.5 59 68.6 59.3 9.3 13.6 55.9 12.7 18.5 '62 63.6 46.3 17 3 27.2 46.3 17.3 27.2 '64 68.6 48.6 20.0 29.2 42.3 26 3 38 3 65 59.5 58.3 1.2 2 0 58.5 1.0 1.7 '66 112.1 89.9 22.2 19.8 87.0 25.1 22.4 70 118.5 107.8 10.7 9.0 103.0 15.5 13.1 71 80.8 78.0 2.8 3.5 78.0 2.8 3.5 ■72 58.6 55.2 3.4 5.8 50.0 8.6 14.7 '73 94 9 77.8 17.1 18 0 73 1 21.8 23.0 75 73.1 58.6 14.5 19.8 58.6 14.5 19.8 76 68.6 55 3 13.3 19 4 54.5 14.1 20.6 77 63.1 44.6 18.5 29.3 42.7 20.4 32 3 78 59.5 55.5 4 0 6.7 53.5 6 0 10 1 '79 77.6 60.4 17.2 22.2 53 1 24 5 31.6 '81 75.8 60 8 15.0 19.8 60.8 15.0 19 .8 '82 58 4 49.3 9.1 15.6 49.3 9.1 15.6 83 62.2 54.1 8.1 13 0 54.1 8.1 13.0 84 107.1 79.5 27.6 25.8 73.2 33.9 31.7 '85 93.5 56.8 36 7 39 .3 56.8 36 .7 39.3 89 97 .2 77 6 19 6 20.2 73.1 24.1 24.8 '91 64 0 51 1 12.9 20.2 44.1 19.9 31.1 92 95.8 82.8 13.0 13.6 78.2 17 6 18.4 93 79.9 64.8 15.1 18.9 62 9 17 0 21.3 '94 64 0 48.7 15.3 23 9 47.1 16.9 26.4 97 93.5 75.8 17.7 18.9 72.2 21.3 22.8 98 77.6 67 5 10 1 13.0 65 4 12 2 15.7 100 70.8 63 .6 7.2 10.2 63.6 7.2 10.2 '101 75.4 55.8 19.6 26.0 55.8 19.6 26.0 102 79.9 71.9 8.0 10.0 66.8 13.1 16 4 103 104 9 95.3 9.6 9.2 75.4 29.5 28.1 '105 43.6 41.5 2.1 4.8 41.5 2.1 4.8 107 70.8 44 5 26 3 37.1 44.5 26.3 37.1 '108 61.8 61 8 0 0 57.2 4.6 7.4 'Dead. 100 METABOLISM IN SEVERE DIABETES. Table 116. — Losses in body-weight by diabetics — Continued (a) Greatest weight. (b) Loss in weight previous to observation. (e) Maximum loss in weight. Case No. \\ eight at our first observation. Minimum weight observed. (c) Amount Per cent Amount to) Per cent (o-6). (c+a). (a-e). (Z-5-o). kilos. kilos. kilos. kilos. kilos. '109 39.7 39.1 0.6 1.5 39.1 0.6 1.5 111 116.2 108.8 7.4 6.4 107.7 8.5 7.3 '112 104 4 82.6 21.8 20 9 79 6 24.8 23.8 113 82 2 82.4 + 0.2 + 0.2 82.2 0 0 114 65.9 56 1 9.8 14 9 56.1 9.8 14 .9 U19 32.0 31 0 1.0 3 1 31.0 1 0 3.1 120 100.3 85.6 14.7 14 7 79.7 20.6 20.5 '121 66 3 39 2 27.1 49.9 38 4 27.9 42 1 122 86.7 77.1 9.6 11.1 74.1 12.6 14.5 124 88.5 73 4 15.1 17.1 73 4 15.1 17.1 126 82.2 72.7 95 11.6 72.5 9.7 11.8 U29 15.2 13.4 1 8 11.8 12 .9 2.3 15.1 130 70.4 55.1 15.3 21.7 55 . 1 15 3 21.7 131 102 6 92 4 10.2 9.9 80.4 22.2 21 6 '132 79.0 61 8 17.2 21.8 53.6 25.4 32.2 '133 90.3 69.8 20.5 22.7 65 9 24.4 27.0 ■134 81.7 58.6 23.1 28.3 50.2 31.5 38.6 1135 58.6 54.8 3.8 6.5 33.1 25.5 43.5 1137 67.2 51 0 16.2 24.1 50.8 16.4 24.4 U38 61.8 50.9 10.9 17.6 50.9 10 9 17 6 U39 58.6 52 .2 6.4 10 9 47.7 10.9 18.6 ■140 77.6 57.4 20.2 26.0 57 4 20.2 2S.0 141 102 6 82.0 20.6 20.1 81.7 20.9 20 4 143 62.7 63 5 + 0.8 + 1.3 57 2 5.5 8.8 1145 76.7 63.8 12.9 16.8 54.1 22 6 29.5 1146 60.4 49.8 10 6 17 6 49.8 10.6 17.6 1147 79.9 65.5 14.4 18.0 61 0 18.9 23 7 149 53.1 53 4 + 0.3 + 0.6 53 4 + 0.3 + 0.6 317 90.7 64 5 26 2 28.9 62.3 28.4 31 3 ■320 63 5 58.3 5.2 8.2 5S.3 5.2 8.2 321 102 6 88.2 14.4 14 0 86.7 15.9 15.5 '324 64.0 38.4 25.6 40.0 38 4 25.6 40.0 '325 25 2 20 3 4.9 19 4 20.2 5.0 19.8 326 97.1 78.7 18.4 19 0 78.7 18.4 19.0 327 109.4 90.7 18.7 17.1 90.7 18.7 17 1 ■328 92.2 78.5 13.7 14 9 68.8 23.4 25 4 329 102.6 91 5 11.1 10.8 85.1 17.5 17 1 330 54.1 47.2 6.9 12.8 47.2 6.9 12.8 331 87.2 87.8 +- 0 6 + 0 7 69.0 18.2 20 9 '332 53.1 39 7 13.4 25.2 35.8 17.3 32 6 333 63.5 61.1 2.4 3.8 51.7 11.8 18.6 337 112 6 82.2 30.4 27 0 82.2 30.4 27.0 339 69 5 59 3 10.2 14.7 56 3 13 2 19.0 ■340 76.7 63.8 12.9 16.8 63.8 12.9 16 8 341 64 0 59.8 4.2 6.6 59 6 4 4 6 9 343 99.9 73 6 26.3 26 3 73 6 26.3 26 3 '344 66.7 60.5 6.2 9.3 34.5 32.2 4S 3 345 77.6 63.8 13.8 17.8 63.8 13.8 17.8 '347 68.6 56.6 12.0 17.5 56.6 12.0 17.5 348 73.1 64.4 8.7 11.9 64 4 8.7 11.9 349 79.9 68.2 11.7 14.6 66.2 13.7 17 1 351 82.2 69.9 12.3 15.0 69 9 12.3 15.0 352 86.7 69 0 17.7 20.4 67.8 18.9 21.8 356 98.1 88 2 9.9 10.1 87.0 11 1 11.3 ■357 95.8 68.1 27.7 28.9 68.1 27.7 28 9 358 102.6 86.6 16.0 15.6 86.6 16.0 15.6 359 70.8 58.7 12 1 17.1 58.7 12.1 17.1 360 84.9 78.8 6.1 7.2 75.7 9.2 10.8 361 68.6 62 1 6.5 9 5 60 4 8.2 12.0 ■364 45.9 43.4 2.5 5 4 43.4 2.5 5 4 365 41.0 40.9 0.1 0.2 40.9 0.1 0.2 366 64.9 61.7 3.2 4.9 58.5 6.4 9 9 367 49.5 41.4 8.1 16.4 41.4 8.1 16.4 ■369 104.9 80.4 24.5 23.4 80.4 24.5 23 4 370 65 4 63.5 19 2.9 63.5 1.9 2.9 '372 60.9 50.7 10.2 16.7 43 1 17.8 29.2 376 84.5 59.1 25 4 30.1 59.1 25.4 30.1 377 31.5 31.0 0.5 1.6 31.0 0.5 1.6 378 80.8 61.7 19.1 23.6 54.7 26.1 32 3 379 93.5 75.8 17.7 18 9 71.8 21.7 23.2 ■381 71.2 52.7 18.5 26.0 50.6 20.6 28.9 382 44.1 38 0 6.1 13 8 38.0 6.1 13.8 386 84.5 66.8 17.7 20.9 66. S 17.7 20.9 ■387 55.0 44.8 10.2 18.5 44.1 10 9 19.8 ' Dead. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 101 Table 116. — Losses in body-weight by diabetics — Continued. (6) Weight at our first observation. Loss in weight previous to observation. («) Maximum loss in weight. Case No. (a) Greatest Minimum weight weight. (c) (At 6b 45m a.m. the subject ate a light breakfast consisting of a 2-egg omelet and a cup of coffee. The experiment began at 9h 22m a.m., the last period ending at llh 10m a.m. tially higher metabolism, although with considerably less extraneous muscular activity. Probably an average of the results obtained with the bed calo- rimeter and the respiration apparatus will represent more nearly the grand aver- age of the carbon-dioxide production of subjects with severe diabetes lying quietly at rest. This average value, 3.33 c.c. per kilogram of body-weight, may be taken therefore as the average carbon-dioxide production of subjects with severe diabetes. The number of cases of moderately severe and light diabetes are too few from which to draw any general deductions, although a distinct tendency is shown for the carbon dioxide to be somewhat lower in these cases. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 107 Table 121. — Average carbon dioxide eliminated per kilogram of body-iveight per minute hj diabetics in experiments without food, 1908-1911. Subject. Severe diabetes Case A B C D E F G H I J K (1910)... L (1910)... N O P Q R S T Chair calorim- eter. 28 i(j 29 41 32 72 Bed calo- rimeter. c.c. 3.22 3.23 2.95 3 22 3.10 4.33 4.11 3.36 3.51 3^29 Respiration apparatus. c.c. 2.89 3.05 2.90 3.11 3.04 3'48 3 31 3.08 3 '.00 3.75 2.64 Subject. Severe diabetes — Con. CaseU V Av. severe cases. . Av. all expts.with bed calorimeter and respiration apparatus , Moderately severe diabetes. CaseK (1909) L (1909) W X Av. moderately severe cases . . Light diabetes. CaseM OXYGEN CONSUMPTION IN DIABETES. The quantitative measurement of the oxygen consumption of diabetics has been attempted only by means of the Zuntz-Geppert apparatus/ by Weintraud and Laves with the Hoppe-Seyler apparatus,2 and by us3 in our earlier investi- gations.4 The difficulties incidental to the accurate determinations of the oxy- gen consumption have precluded a more general measurement. On the other hand, exact determinations of the oxygen used by the subject have greater significance as an index of the calorific output of the body than have the deter- minations of the carbon-dioxide excretion, especially with normal individuals. With diabetics, as we have shown earlier, particularly with severe cases, the carbon-dioxide determinations, if accurately made, may be considered equally as good an index of the heat production as is the oxygen. Nevertheless it remains a fact that quantitative determinations of oxygen have a special sig- nificance and are of unusual importance and interest. Since especial emphasis is laid in this report upon the severity of diabetes, in connection with the dis- cussion of the metabolism during diabetes mellitus we have deemed it advis- able in table 122 to present again the oxygen determinations obtained in our earlier investigations, accentuating here the oxygen determinations found with the severe cases rather than the total average. 'Leo (1891), Stiive (1894), Nehring and Schmoll (1897), Magnus Levy (1905), Mohr (1907). 'Weintraud and Laves, Zeitschr. f. physiol. Chem., 1S94, 19, p. 603. ' Benedict and Joslin, Publication No. 136, Carnegie Institution of Washington, 1910. 4 Two articles have recently appeared giving reports of studies made by Roily and by Leimdorfer of the oxygen consumption of diabetics. Unfortunately these did not come to our attention until after this report had been sent to the printer, and therefore scant com- ment only is possible in the proof. Roily in Leipsic used a modified Benedict respiration apparatus. See Roily, Deutsch. Archiv f. klin Med., 1912, 105, p. 494. Leimdorfer in von Noorden's laboratory used the Zuntz-Geppert method. See Leimdorfer, Biochem. Ztschr., 1912, 40, p. 326. 108 METABOLISM IN SEVERE DIABETES. The agreement between the results found with the bed calorimeter and those with the respiration apparatus is obvious, the greater increase noted with the chair calorimeter being explained in part by the fact that there is an actual increase in the metabolism due to the sitting up in the chair, and in part to the fact that the abnormally high values found with Cases I and J were not accom- panied by similar experiments with either the bed calorimeter or the respiration apparatus. From this earlier work, therefore, one can conclude that for sub- jects with severe diabetes, lying quietly, without food, there is approximately a consumption of 4.22 c.c. of oxygen per minute per kilogram of body-weight. Table 122. — Oxygen absorbed per kilogram of body-weight per minute in experiments with diabetics without food, 1908-1910. Subject. Chair calorimeter. Bed calorimeter. Respiration apparatus. Oxygen absorbed. Aver- age. Oxygen absorbed. Aver- age. Oxygen absorbed. Aver- age. Severe diabetes. Case A 4.86 4.34 4.38 4.92 4.86 4.50 5.17 4.13 4.44 4!20 4!3i 472 4.80 4.55 4.08 4.40 4.54 4'73 i'.32 '..'.'. 4.66 5.65 5.98 .... 5.01 4.06 4.55 4.58 4.64 4.35 3.09 3.20 .... c.c. 4.62 •T45 4.53 4.66 5.82 5.01 4.22 4.42 4.15 4^38 '.'.'.'. '.'.'.'. 4.34 3.88 3.63 4.32 4.17 c.c. 4.22 .... 4.42 4.15 i'is 4.07 4.27 4.04 4.31 4.47 4.01 4.44 4.08 3.82 4.23 3.93 4.85 4.28 4.52 4.44 4.19 4.06 4.14 4.44 4.14 4.00 .... 4!63 '.'.'.'. '.'.'.'. '.'.'.'. c.c. 4.27 4.23 4.19 4!63 B C D E F G H I J Av. severe cases Light diabetes. Case K 4.85 4.25 4.04 4.18 4.06 4!4i 3.28 4.04 L M Av. light cases. . 4 53 3.15 4.41 3.28 3.91 3.85 4.04 The later experiments were almost exclusively made with either the bed calorimeter or the respiration apparatus. The results obtained in these experi- ments are given in table 123 herewith. As was pointed out in our discussion of the carbon-dioxide consumption, the agreement between the average results found with the bed calorimeter and the respiration apparatus is not what would be expected, because the abnormally high values of subjects I and N as determined in the bed calorimeter are not accompanied by similar obser- vations on the same subject with the respiration apparatus. Likewise, the recent experiments differ from the earlier investigations chiefly in the fact that with practically no subject were experiments made with both the bed calo- rimeter and the respiration apparatus; therefore the comparison is obviously not as simple as it was in the earlier report. If we consider the average of the results found with the cases of severe diabetes in the bed calorimeter and on the respiration apparatus as representing the truest average, we may state that with these subjects lying quietly at rest without food, 4.73 c.c. of oxygen are DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 109 absorbed per kilogram of body-weight per minute. The paucity of experi- mental data with regard to light cases prevents any general deduction, although it is again obvious that there is on the average a much smaller oxygen con- sumption per kilogram of body-weight than with the severe cases. Finally, it should be noted that in the experiment with Case X, the value found with the chair calorimeter (4.17 c.c.) is higher than that found with the respiration apparatus (3.79 c.c.) and can be wholly explained by the difference in the mus- cular activity incidental to experiments in the chair calorimeter. Table 123. — Oxygen absorbed per kilogram of body-weight per minute by diabetics in experi- vients without food, 1910-1911. Subject. Severe diabetes. Case A H I K L N O. P. Q. R. S.. T. U. V. Av. severe cases Moderately severe and light diabetes. Case M . W. X. Av. moderately severe and light cases. . . . Chair calorimeter. Oxygen absorbed. 4.80 4.08 3.62 Aver- age. Bed calorimeter. 4.17 4.17 Oxygen absorbed. Aver- age. 3.97 6.03 5.74 5.25 5.39 5.50 5.88 5.71 5.54 4.51 4.23 4.90 4.66 4.35 c c. 3.97 6.03 5^57 4.37 4.90 i'.ii 4.89 2.93 2.93 2.93 Respiration apparatus. Oxygen absorbed. Aver- age. 4.08 c.c. 4.08 4.62 4.57 4.77 .... 4.23 4^65 4.23 4.28 4.44 4.01 .... 5.26 5.24 5.40 5.60 5.22 4.24 5.34 3.67 3.67 4 95 5 21 5.15 5.47 4.721 5^6 4.72 4 57 3.21 3.91 3.62 3 79 3.21 3 77 3.79 3.59 'At 6h 45nl a.m. the subject ate a light breakfast consisting of a 2-egg omelet and a cup of coffee. The experiment began at 9h 22m a.m., the last period ending at llh 10ra - 1 a.m. In table 124 are given the averages of the values found in both series of experiments with the different subjects and with the different forms of experi- mental apparatus, i. e., the bed calorimeter, chair calorimeter, and respiration apparatus, these showing that 4.85 c.c. of oxygen were absorbed and measured in the chair calorimeter, 4.66 c.c. with the bed calorimeter, and 4.41 c.c. with the respiration apparatus. Admitting that the chair-calorimeter results are affected somewhat by increased muscular activity incidental to experiments in this apparatus, we may average the results found in the bed calorimeter and the respiration apparatus and consider the average value of 4.54 c.c. per minute as the best average value for severe diabetics lying quietly at rest without food. The subjects with moderately severe and light diabetes have relatively less oxygen consumption under the same conditions, although in this discussion attention is particularly directed to the values found with the severe cases. 110 METABOLISM IN SEVERE DIABETES. Table 124. — Average oxygen absorbed per kilogram of body-weight per minute in experiments with diabetics without food, 1908-1911. Subject. Chair calori- meter. Bed calori- meter. Respiration apparatus. Subject. Chair calori- meter. Bed calori- meter. Respiration apparatus. Severe diabetes. Case A c.c. 4.62 4^45 4^53 4.66 5^82 5.01 c.c. 4.22 4.42 4.15 4^38 4.05 6.03 5^57 i'37 4.90 4.51 c.c. 4.08 4.27 4.23 4.19 i'M 4^54 4 65 4.23 i'24 5.34 3^67 .... Severe diabetes — Con. Case U c.c. c.c. c.c. 5.20 4.72 B v.. c Av . severe cases . . Av. all expts.with bed calorimeter and respiration apparatus Moderately severe diabetes. Case K (1909) L (1909) W D 4.85 4.66 4.41 E 4.54 F G H I J 4.06 4.53 i.ii i.ii 4.04 3^77 3.79 K (1910) L fl910) N O P X Q Av. moderately severe cases. . . Light diabetes. Case M R 4.25 4.41 3.87 S T 3.15 3.11 3 21 RESPIRATORY QUOTIENT. The relationship between the volume of carbon dioxide produced and oxygen consumed I — — ) , the so-called respiratory quotient, has peculiar sig- v O2 / nificance in interpreting the degree of severity in cases of diabetes. The accu- racy of this value depends upon the accuracy of both the determination of carbon dioxide and the determination of oxygen, and it can thus be seen that the respiratory quotient as such is a difficult matter to determine with great exactness. In the earlier report the respiratory quotient for all the cases of diabetes was considered in detail and in table 125 we have presented anew the earlier work, carefully distinguishing between the severe cases and the lighter cases. In recording the results for the respiratory quotient, it is unnecessary to consider separately those obtained with the three forms of apparatus, for there is no physical difference in the respiration in either the chair or the bed calori- meter, and obviously the character of the combustion and the material burned or metabolized will not be appreciably altered by different body positions. On the other hand, it is reasonable to suppose that the carbon-dioxide production and oxygen consumption might indicate a difference in the character of the combustion, according to whether the subject breathed freely in the calori- meter, or whether he breathed into the nosepieces or mouthpiece of the respi- ration apparatus. Accordingly, in giving the results of the earlier experiments, the values obtained with the calorimeter are compared with those obtained with the respiration apparatus. It can be seen that the respiratory quotient in the severe cases of diabetes averages 0.74 with the calorimeter and 0.73 with the respiration apparatus. The fact that there are not an equal number of experiments made with the same subject on both apparatus complicates some- DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. Ill what the comparison. Particularly is this true with subjects having light diabetes with whom an average quotient of 0.76 was obtained in the chair cal- orimeter, while apparently a quotient of 0.70 was found with the respiration apparatus. An examination of the figures shows, however, that the second value depends wholly upon a single experiment with Case K, and hence as an average value is very much to be questioned. The important thing to be emphasized here is the fact that there were no abnormal quotients found, although a single value of 0.64 was found with Case C and one of 0.66 with Case A. In general, however, none of the abnormally low quotients which have frequently been cited by earlier writers were found; at least there was no persistent evidence of an abnormal katabolism which such low quotients would indicate. Table 125.- -Average respiratory quotients in experiments with diabetics without food, 1908-1910. Subject. Calorimeter. Respiration apparatus. Respiratory quotient. Average. Respiratory quotient. Average. Severe diabetes. Case A 0.75 0.75 0.74 0.76 0.68 0.72 0.71 0.66 0.73 0.74 0.74 0.75 0.75 0.67 0.69 0.69 0.74 0.71 0.71 0.72 6!72 Q.U '.'.'.'. '.'..'. 0.74 0.73 0.75 0.79 0.81 0.72 0.76 0.76 0.72 0.75 0.76 0.78 0.75 0.75 0.78 0.70 0.78 0.78 0.72 .... 0.71 0.74 0.71 0. 73 0.74 0.73 0.77 0.74 0.75 0.71 0.70 0.71 0.68 0.73 0.76 0.70 0.75 0.70 0.64 0.71 0.68 0.67 0.69 0.71 0.71 0.66 0.70 0.69 0.74 0.75 0.72 0.69 0.74 076 B C D E.. F . G.. H I J Av. severe cases Light diabetes. 0.74 0.73 0.76 0.77 0.76 0.70 L M Av. light cases . 0.76 0.70 It should be pointed out again that the respiratory quotient is entirely independent of the total metabolism, and indicates only the character of the metabolism and not the total amount. When the body is subsisting chiefly upon carbohydrates, the respiratory quotient approximates 1. When it is subsisting chiefly upon fat, the respiratory quotient approximates 0.71. The quotients, therefore, here observed with severe diabetes indicate a combustion which is chiefly that of fat. Inasmuch as the relatively small amounts of protein burned tend to raise the quotient, we find the average values slightly above 0.71 rather than slightly below. The respiratory quotients for the new series of experiments are given in table 126. These quotients, which are classified as severe cases and moder- ately severe and light cases, indicate again a low respiratory quotient as the characteristic of severe diabetes, the average quotient found with the calori- 112 METABOLISM IN SEVERE DIABETES. meter being 0.73 and with the respiration apparatus 0.72, values not appre- ciably different from those obtained in the earlier series. As a matter of fact, the lowest individual respiratory quotient found in the new series of experi- ments was the value 0.68 obtained with Case P in one experiment. The moderately severe and light cases are too few in number for us to draw any deductions, but there is a tendency for the respiratory quotient to be somewhat higher with the light cases than with the severe, thus indicating a slightly higher combustion of carbohydrate. The low averages found with the severe cases indicate a combustion almost exclusively of fat, with a relatively small amount of protein and almost no carbohydrate combustion. This is Table 126. — Average respiratory quotients in experiments with diabetics without food, 1910-1911. Subject. Severe diabetes. Case A H I K L N O. P. Q. R. S.. T. U. V. Av. severe cases . Moderately severe and light diabetes. Case M W X Av. moderately severe and light cases Calorimeter. Respiratory quotient. Average. 0.76 0.72 0 74 0.76 0.73 0.74 0.76 0.72 0.71 0.69 .... 0 76 0.78 0.72 .... 0.71 0.75 0.73'.... 0.76 0.72 0.74 0.69 0.77 0.72 6'73 ■0.73 Respiration apparatus. 0.73 0.78 6^73 6'80 6!8i 0.78 6^78 0.78 Respiratory quotient. Average. 0.71 0.71 0.71 0.73 0.71 0.73 6!72 0.73 0.74 0.71 0.72 0.70 0.70 0.68 0.71 0.71 .... 0.72 0.70 0.73 6!73 0.76 0.71 0.74 0.71 0.732 0.75 0.72 0.75 0.74 6!73 0.73» 0.72 0.75 0.74 0.74 0.74 'The respiratory quotient for this experiment was for the periods llh 55m p.m. to lh 27m a.m. and 5h 05m to 6h 05m a.m., June 2-3, 1911. JAt 6" 45™ a.m. the subject ate a light breakfast consisting of a 2-egg omelet and a cup of coffee. The experiment began at 9h 22m a.m., the last period ending at llh 10™ a.m. fully in conformity with the very low carbohydrate supply in the bodies of dia- betics, and it is fully in accord with what theoretically would be predicted. Here again we find a complete absence of the abnormally low quotients fre- quently reported by earlier writers. In order to sum up the results of all the experiments thus far made, we have computed the respiratory quotients for each individual case both in the calorimeter and with the respiration apparatus when experiments with both apparatus had been made, and they are combined in table 127. It is seen that the average value with severe diabetes in both the calorimeter experiments and the respiration experiments was 0.73, although here again it should be pointed out that experiments on each individual were rarely performed with both apparatus. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 113 It may be concluded, therefore, that with the subject lying quietly without food the respiratory quotient in cases of severe diabetes is 0.73; as pointed out in the earlier report, respiratory quotients carefully determined that indicate values higher than this are to be considered a favorable prognostic indication, and show a rather more liberal supply of carbohydrate material in the body than is usual in severe diabetes. The difficulties incidental to determining accurately the respiratory quo- tients are only too well known to experimenters, and hence it would be entirely incorrect to lay great stress upon individual figures in this series. The general tendency of all the quotients to approximate the value 0.73 is significant, as is likewise the absence of abnormally low quotients. Table 127. — Average respiratory quotients in experiments with diabetics without food, 1908-1911. Subject. Severe diabetes Case A B C D E F G H I J K (1910) L (1910) N O P Q R S Calori- Respiration meter. apparatus. 0.71 0.71 0.74 0.72 0.71 0.69 0.74 0.73 0.74 0.73 0.77 0.76 0.73 0.75 0.77 0.72 0.73 0.74 0.72 0.69 0.70 0.77 0.72 0.73 Subject. Severe diabetes — Con. CaseT U V Av. severe cases. Moderately severe diabetes. CaseK (1909) L (1909) W X Av. moderately severe cases. . . Light diabetes. Case M Calori- meter. 0.73 0.73 0 73 0.76 0.77 6i78 0.77 0.77 Respiration apparatus. 0.73 0.73 0 73 0.70 o.ii 0.74 0.73 0.75 INDIRECT CALORIMETRY. Although, as pointed out on page 12, the direct heat measurement in this series of experiments was unsatisfactory in a large majority of the cases, it is important to record that in one-third of the experiments in which accuracy in the heat measurements is assured, the relationships between the oxygen con- sumption, carbon-dioxide production, and heat production are essentially those recorded in the earlier publication. We have, therefore, no reason to change our belief that the calorific equivalents of carbon dioxide and oxygen are essen- tially as previously outlined, namely, 3.26 calories per gram of carbon dioxide and 3.31 calories per gram of oxygen. If, then, in experiments with subjects having severe diabetes, the carbon-dioxide production is accurately deter- mined, we believe that the heat production can be computed with considerable accuracy by multiplying the total carbon-dioxide production in grams by the factor 3.26. Usually, since the carbon-dioxide production is obtained with the subject absolutely quiet, lying in bed, it can be easily seen that the results obtained by this computation will represent the minimum heat production and not the average or maximum heat production. When the subject is sitting up it has 114 METABOLISM IN SEVERE DIABETES. been shown that there is essentially an increased heat production amounting to 10 or 15 per cent.1 Walking and all muscular activity, also the partaking and the digestion of food, produce an increase in the heat production. The difference in heat production measured on the same subject in the chair calori- meter and in the bed calorimeter is further evidence of the difference in energy output. A careful record of daily routine, muscular activity, exposure to cold, etc., would be necessary for the intelligent computation of the total output of energy from the carbon-dioxide production. It is not outside the range of pos- sibilities that this factor may be of actual benefit in making a tentative compu- tation of the energy requirement in diabetes. That this carbon-dioxide pro- duction can be determined equally as well by the small respiration apparatus as with the large respiration calorimeter has, we think, been fairly demon- strated, and we may conclude from this research that, although calorimetric measurements are highly important and desirable if possible, in severe dia- betes a measurement of the carbon-dioxide production alone, or still better a measure of the oxygen consumption, will give the means for computing with great accuracy the heat production of the individual while lying quietly at rest. COMPOSITION OF THE ALVEOLAR AIR OF DIABETICS. The carbon-dioxide tension of the alveolar air has come to be regarded as an excellent index of the degree of acidosis by reason of the interesting obser- vations of Beddard, Pembrey and Spriggs2 and the confirmatory work of Porges, Leimdorfer and Markovici.3 The presence of acids in the blood causes the respiratory center to respond to a smaller tension of carbon dioxide in the blood ; as the carbon-dioxide tension in the alveolar air bears a direct relation to that in the blood, it is evident that a low alveolar carbon-dioxide tension indicates an acidosis. The alveolar carbon dioxide in normal individuals varies from about 36 to 46 mm. tension of mercury as found by the Haldane method;4 according to results obtained by the Plesch method5 it is about 10 to 15 per cent higher. The best method for determining the alveolar air has not yet been thor- oughly established. Both the Haldane and Plesch methods involve good gas analysis technique and not a little cooperation on the part of the subject. Alveolar air determinations were made on three of the subjects, N, Q, and I, and are interesting as showing the presence and degree of acidosis. The observations made with Cases N and Q were by the Haldane method; those with Case I were by the Plesch method. The results obtained with Case N are given in table 128. ■Emmes and Riche, Am. Journ. Physiol., 1911, 17, p. 406. 2Beddard, Pembrey and Spriggs, Journ. Physiol., 37, Proceedings Physiol. Soc, 190S, p. xxxix. 'Porges, Leimdorfer and Markovici, Zeitschr. f. klin. Med., 1911, 73, p. 389. 4Haldane and Priestley, Journ. Physiol., 1905, 32, p. 225. 6Plesch, Zeitschr. f. Exp. Pathol, u. Ther., 1909, 6, p. 380. The Plesch method, in fact, gives the carbon-dioxide tension of the venous blood, but we have found that this value bears a proportional relation to the alveolar air. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 115 On several occasions observations were also made with this case of the rate of respiration, and the total ventilation of the lungs, the results being included in the table. Two observations were likewise made of the blood- pressure (Riva Rocci), one at 7h 30m a. m. December 12, and the second at 7h 10m a. m. December 14; both gave a result of 90 mm. It will be seen that on December 10, when the alveolar carbon-dioxide tension was lower and pre- sumably the acidosis greater than on December 14, there was also an increased ventilation of the lungs. The respiration rate, however, did not vary with the alveolar air or with the ventilation of the lungs. Table 128 — -Determinations made on alveolar air with Case N. Date. Time. Tension of — Date. Time. Tension of carbon dioxide. Ventilation of lunj;s, time re- Respi- ration Carbon dioxide. Oxygen. quired for 10 liters.i minute. 1910. mm. mm. 1910. Dec. 1 Dec. 2 After expt., 10h 25ma.m. Before expt., 8 a.m 17.4 16.7 16.4 21.1 122.3 123.8 126.6 Dec. 10 Before expt.: 7h 20m a.m. 7 30 a.m. m m . J18.6 \18.9 sees. 73 i9 After expt., llh 15ma.m. 22.1 21.7 119.2 7 31 a.m. 76 73 19 18 Dec. 3 Before expt., 7h 15ma.m. After expt., 10h30ma.m. 25.6 25.3 27.2 26.8 118.3 After expt.: 10h 50m a.m. J18.9 \17.3 '75 22 Dec. 5 Before expt., 7h20,na,m. 22.2 24.2 122.0 117.7 11 01 a.m. 68 76 22 22 Dec. 7 After expt., 10h45ma.m. Before expt., 7h 15ma.m. 23.5 24.1 19.7 18.3 122.4 120.1 Dec. 12 Before expt.: 7h 15m a.m. 7 22 a.m. /2S.5 \26.9 ill 19 After expt., 10h 40m a.m 22.1 21.1 7 26 a.m. 119 117 18 16 After expt.: lOhSCPa.m. [28.9 \28.9 11 00 a.m. 105 22 11 01 a.m. 121 23 11 02 a.m. = 75 21 22 11 05 a.m. 19 Dec. 14 Before expt.: 7 15 a.m. 7 25 a.m. After expt.: 10h 40m a.m. 10 51 a.m. 10 54 a.m. /24.9 \25.4 (26 9 \26.1 io9 112 i20 141 264 i6 18 is 14 'At room temperature and observed barometric pressure. !Time required for 5 liters. On each of the four experimental days with Case Q, the carbon-dioxide tension of the alveolar air was determined after the respiration experiments. The results are given in table 129. On November 19 the subject had taken no breakfast previous to the experiment, but the two experiments on November 21 and 22 followed an oatmeal breakfast, while that on November 23, although the subject was without breakfast, followed two oatmeal days. It is interest- ing to note that the carbon-dioxide tension is very much lower on the 19th than it is on the 23d, indicating a greater acidosis on the former day; the experi- mental evidence also shows that the metabolism was considerably higher on 116 METABOLISM IN SEVERE DIABETES. the 19th than it was on the 23d after the two oatmeal days. Further reference will be made to these two days in the discussion of the question of the relation- ship between the acidosis and the severity of the diabetes and intensity of the metabolism. Table 129. — Determinations made on alveolar air with Case Q. Date. Diet previous to experiment. Carbo- hydrates Tension of — in diet on day pre- ceding. Time. Carbon dioxide. Oxygen. 1910. Nov. 19 Nov. 21 Nov. 22 Nov. 23 Without breakfast... Oatmeal breakfast. . . Oatmeal breakfast.. . Without breakfast, following 2 oat- meal days. gtns. 55 55 165 165 After experiment After experiment After experiment After experiment mm. (30.6 132. 9 (34.6 \29.5 (35.8 139.7 (40.3 \40.2 mm. 108.7 94.7 During the short sojourn of Case I at the hospital in February 1912, when he was in a very critical condition and coma was impending, a number of obser- vations were made on the carbon-dioxide tension of the alveolar air in which the subject breathed the same air several times in and out of a rubber bag. In these experiments the subject first inspired 600 c.c. of air, breathing it back Table 130. — Determinations made on alveolar air with Case I. Date and time. Tension of carbon Pulse per minute. Respira- tion per Remarks. dioxide. minute. mm. Feb. 14, 1912: Impending coma. llh07ma.m 29.1 11 15 a.m 25.6 18 11 30 a.m 27.1 110 11 40 a.m 27.3 After taking sodium citrate. Very little could be taken because of diarrhea resulting from it. 11 47 a.m 18 Respirations heard and counted from across room. 2 34 p.m 114 Still impending coma Had been up in a wheel chair for a few moments at noon. 2 39 p.m 24.8 2 50 p.m 19 2 53 p.m 26.5 Drew in some air around mouth while inspiring. 26.3 Between 12 noon of Feb. 14 and 7 a.m. Feb. 15, the sub- ject took 90 grams of levulose. Still conscious; was very restless during the night. Feb. 15, 1912: 8h03ma.m 19 8 10 a.m 21.0 8 20 a.m 17.5 8 35 a.m 22.4 Took some sodium citrate at 8h 30m a.m.; none previous since 2h 30"" a.m. 8 47 a.m 118 8 48 a.m 21.4 9 00 a.m |20!6 21 Dressed, ready to go home. Still breathing heavily; 5 00 p. m. about U9.5 probably no better. Had had morphine in afternoon. and forth four times in 20 seconds. The last expiration was analyzed for carbon dioxide. The values obtained are given in table 130, together with a few records of the pulse and respiration rates. This subject was characterized by an abnormally high pulse-rate running from 110 to 118; although the respiration-rate was not extraordinarily high, DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 117 averaging not far from 19 per minute, the deep breathing of impending coma was very noticeable, the respirations being easily counted from across the room with one's back to the subject. A gradual fall in the carbon-dioxide tension will be noticed during the two days on which experiments were made. Between noon of February 14 and 7 a. m. of February 15 the subject took 90 grams of levulose, but this seems to have had no effect on the carbon-dioxide tension in the alveolar air. Comparison of the Metabolism of Diabetics with that of Normal Individuals. One of the difficulties hitherto encountered in the interpretation of experi- ments on the metabolism of diabetic patients has been the lack of sufficient controls with normal individuals. In our previous report we were able in a measure to supply this deficiency, and, we believe, presented enough data regarding normal individuals to establish a satisfactory base-line for com- parison. Criticism, however, has arisen not only as to the character of the normals selected, but also as to the number. Lusk,1 whose opinion on matters of diabetes is not to be regarded lightly, maintained that the normal individuals weighed very much more than did the diabetics and hence were not comparable on the basis of per kilogram of body-weight. In the second place, Lusk laid a great deal of stress upon the fact that one of the subjects, Case I, was extremely high-strung, nervous, and apprehensive, and by no means an ideal subject. He maintained that the results with this individual played too important a role in our determination of the apparent increase in metabolism. Leaving out of consideration the heavy individuals used in the normal comparison, and omit- ting, also, the results obtained with Case I, he computed that the increase in the heat production was but 5 per cent instead of the 15 per cent that we maintained. At the time of going to press with the first diabetic publication, the num- ber of normal individuals available for comparison was somewhat limited, and it was obviously desirable to increase this as rapidly as possible. Fortunately in the intervening time we have been able to study a sufficiently large number of normal individuals so as to extend the list, and are now prepared to meet this criticism by presenting data based on (1) an enlarged number of normal subjects, and (2) a normal individual corresponding in height and weight for all of the diabetics save one. We also have normals to correspond with two dia- betics during the several stages of their disease when their weight changed. While, therefore, in the first report the comparisons were made between normal individuals collectively and diabetic individuals collectively, we shall attempt in this publication to compare each diabetic with one or more normal individuals with essentially the same body-weight and height, and finally, as before, to compare normals and diabetics collectively. Under these conditions the criticism of Professor Lusk can be much better met than it could have been two years ago, when the normal data were limited. That Professor Lusk's 'Lusk, loc. cit. 118 METABOLISM IN SEVERE DIABETES. criticism was more of a theoretical than a practical nature is demonstrated by the fact that the actual increase in metabolism noted in the new observations is somewhat higher than that noted when the earlier tests were made. The measurements of the metabolism of Case I were stated in the first report to be unsatisfactory for the reason that the subject was high-strung and nervous, and consequently by no means an ideal subject. Fortunately, some months later it was possible to secure this subject for another experiment. At this time he was weak, emaciated, and disinclined to muscular activit}'. During the experimental period he lay in the bed calorimeter extremely quiet, and prior to the experiment exhibited none of the nervousness and excitement which he had shown before the two experiments of the year previous. These later results may accordingly be taken as a measurement of the metabolism of a diabetic with severe acidosis, but with a minimum amount of extraneous muscular activity. While, therefore, in the earlier experiments with the chair calorimeter he did not appear to be an ideal subject, in his last experiment with the bed calorimeter no criticism could be raised with regard to the conduct of the experiment or to the subject himself, so that the influence of extraneous muscular activity may be disregarded. The results of the last experiment with the subject abundantly confirm those of the first two in showing a marked increase in the total metabolism. SELECTION OF CONTROLS. In this comparison of normal individuals with diabetics care has been taken to select controls that approximate as nearly as possible the exact body- weight and height of the diabetic subjects to which they are to be compared. This has been difficult in certain instances, owing to the fact that frequently the dia- betics were much emaciated and it was difficult to find a person of a correspond- ing height and weight. The evidence with regard to the disproportion between skin area and body-weight, first suggested by Magnus-Levy and considered by us in the earlier publication, has been further amplified by observations during an experiment with prolonged inanition. Although during this experiment the subject lost in weight 15 kilograms, there was no loosening of the skin. The skin contracted as the flesh disappeared and hence there was no evidence that there was a disproportion between the body-surface and the body-weight. A further precaution was taken to select normal subjects who were not on the laboratory staff, except when it was necessary in order to obtain subjects that were comparable in size and weight. Of the 20 or more subjects used for comparison, more than half did not belong to the laboratory staff; hence, on the whole, the normal subjects were more often untrained than were the diabetics with most of whom experiments were frequently made. EVIDENCE OF THE KYMOGRAPH RECORDS. The use of one or more tube pneumographs about the thighs or chest for a record of the degree of muscular activity of the subject has proved a most suc- cessful venture, but the expense incidental to reproducing kymograph records makes it impossible to present them here. A most careful scrutiny of the DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 119 large number of kymograph records obtained in connection with this research makes it evident that the normal individuals on the whole were considerably more restless than were the diabetic individuals. The diabetic patients were for the most part sick, weak, and disinclined to any extraneous muscular move- ments and remained lying quietly in bed. It may therefore be safely stated that the influence of extraneous muscular activity was infinitely less with the diabetics than with the normal individuals. Hence one would expect to find a higher metabolism with the normal individuals than with the diabetics, as the influence of even minor muscular activity upon the metabolism is surpris- ing— a fact only appreciated by one who is constantly working in the labora- tory, measuring the metabolism of a subject and comparing the simultaneous records of muscular activity. This relationship between minor muscular activ- ity and metabolism has been observed in this laboratory,1 even with infants. In an experiment designed to answer a criticism as to the soundness of using kymograph records to indicate muscular rest, it was found by actual test that the kymographs are so sensitive that even a minute muscular tremor, such as the movement incidental to slight shivering, is instantly transmitted to the tambour and recorded on the kymograph. DETAILED COMPARISON OF NORMALS AND DIABETICS. From our list of normal subjects it is possible to select for purposes of com- parison one or more to compare with each individual diabetic, with the single exception of Case N. As he was a boy, we had no normal subject who was comparable in age, weight, and height; consequently, Case N is not included in the averages. On one occasion Case A weighed 51.6 kilos., and later weighed 46.1 kilos.; a fall in body-weight of 7 kilos, was likewise noticed with Case C. Accordingly, in order to make the analogy as complete as possible, we have compared the diabetics with different normals at the stages of the disease when there was a change in their body-weights. All these comparisons have been brought together in table 131, in which are grouped first, the cases of severe diabetes and the normal individuals with whom they are compared, and second, the moderately severe and light cases, of which only three were studied. Of particular interest are the comparisons between the cases of severe diabetes and the normal individuals. The carbon-dioxide production per kilogram of body-weight with all of the cases of severe diabetes was 3.31 c.c. per kilogram per minute, and with normal individuals 3.13 c.c. per kilogram per minute. This increase, which is approxi- mately but 6 per cent, is fully in line with that noted in the earlier publication, and is obviously explained in part by the fact that the metabolism of the diabe- tics was essentially a protein-fat metabolism, while that of the normal subjects was unquestionably a protein-fat and glycogen or carbohydrate metabolism. As pointed out earlier, the difference between the carbon-dioxide produc- tion on these two groups of individuals does not measure by any means the difference in the actual metabolism. This is best shown by a comparison of the lBenedict and Talbot, Am. Journ. Diseases of Children, 1912, 3, p. 1. 120 METABOLISM IN SEVERE DIABETES. oxygen consumption. Of the 19 severe cases, the intensity of the metabolism as measured by the oxygen consumption was in each individual case higher than that of the normal individuals with whom they are compared. The single exception was Case B, the normal individual, Miss E. W., having the Table 131. — Comparison of the carbon dioxide eliminated and oxygen absorbed by diabetics and normal individuals in experiments without food. [Bed calorimeter and respiration apparatus.] SEVERE DIABETES. Diabetic. Normal. Subject. ■ 'q O tc '53 w BE a _ a o H a> . Q. o a -a .2 S -a i. o a ■° 2. o 3 . o >- 3 a> £ c , o Subject. Jj-t3 o o is "3 £-§ m 43 .a '8 n km o u m Cv ^ !§ c'E at _ o. d SI 0 H u ° 3 2 a is H Is X o kilos 51.6 46.1 41.4 62.7 55.5 48.8 67.1 52.4 40.0 52.9 59.1 55.6 63.0 66.5 31.5 52.6 40.0 51.7 55.3 58.0 51.4 39.5 60.0 cm. 171 171 158 166 166 173 178 159 176 171 180 180 183 183 146 173 173 168 181 177 180 160 173 1 1 5 6 7 3 1 7 1 1 1 3 1 1 7 3 5 2 1 1 2 5 1 c.c. 3.22 2.89 3.10 2.81 3.01 3.11 3.22 3.09 4.33 3.48 2.84 3.31 3.44 3.08 4.11 3.06 3.75 3.36 3.51 2.64 3.29 3.80 3.42 c.c. 4.22 4.08 4.29 4.12 4.35 4.19 4.38 4.05 6.03 ; 4.54 4.04 4.65 4.41 4.23 5.57 4.24 | 5.34 4.37 4.90 3.67 4.51 5.20 4.72 A. F. G kilos. 53.9 48.5 43.3 42.6 40.5 37.4 62.2 61.1 55.2 55.1 48.5 66.0 52 2 48.5 55.1 58.5 57.8 63.2 66.7 66.0 cm. 175 166 157 165 157 155 164 165 164 169 166 177 158 166 169 181 179 185 182 182 168 166 162 175 179 179 179 175 165 157 155 173 1 18 3 2 2 2 31 13 9 9 18 54 2 18 9 5 44 4 16 13 2 18 19 1 44 44 44 1 2 2 2 7 c.c. 3.30 3.25 3.30 3.24 3.78 3.26 2.89 2.96 2.89 3.14 3.25 3.12 3 31 3.25 3.14 2.62 2.86 2.71 2.92 3.04 3^09 3.25 3.66 3.30 2.86 2.86 2.86 3.30 3.24 3.78 3.26 3.19 c.c. 3.88 3.86 3.74 3.99 4.57 3.77 3.51 3.62 3.55 3.72 3.86 3.68 3.91 3.86 3.72 3 34 3.32 3 47 3.62 3.63 3'67 3.86 4.33 3.88 3.32 3.32 3.32 3.88 3 99 4.57 3.77 3.84 CaseB T. M.C Miss J CaseC Miss A. C Miss E. W Mrs. S. C H H A Case D S. A. R Dr. P. R C. H. H T. M. C M. A. M Case G CaseH Miss B Case I T. M. C Case J C. H. H Dr. S Case L H. F.T E. P. C K. H. A i J. R CaseN Case O 52.4 48.5 54.3 53.9 57.8 57.8 57.8 53.9 42.6 40.5 37.4 60.0 CaseP T. M. C Case Q V. G. Case R A.F. G H. F. T H.F.T H. F. T A. F. G Miss A. C. CaseS CaseT CaseU Case V MissE. W Mrs. S. C H.B.L A v. normal subjects. Av. severe cases •• 3 31 4.54 •• 3 13 3 75 MO DER^ LTEL1 f SE\ 'ERE AND LIGHT DIABE TES. Case M 82.1 59.5 64.6 172 161 170 3 2 1 2.42 2.75 2.82 3.14 3.77 3.79 O. F. M.. 85.8 83.0 59.4 64.0 171 169 162 171 2 3 2 6 2.44 2.40 3.03 2.89 3.12 2.88 3.79 3.72 CaseW Prof.C... Miss B. W Case X D. M Av. normal subjects. Av. moderately severe and light cases •• 2.66 3.57 .... .... •• 2.69 3.38 higher metabolism. On the other hand, the three remaining individuals with whom Case B is compared had a much lower metabolism, the average oxygen consumption for the four normal subjects being less than that of Case B. The average oxygen consumption of the cases of severe diabetes, Case N excluded, DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 121 was 4.54 c.c. per kilogram per minute, while with the normal subjects the average oxygen consumption was 3.75 c.c. This corresponds to an increase of 0.79 c.c. per minute above normal, or somewhat over 20 per cent.1 In the earlier publication it was stated that the increase in metabolism was not far from 15 to 20 per cent, and it will be seen that these figures bear out perfectly this conclusion. Furthermore, taking into consideration the inti- mate relationship between minor muscular activity and metabolism, it is evi- dent that these subjects should have been under exactly the same conditions in regard to the muscular activity. An examination of the many pneumograph curves obtained on these subjects shows that in these as in the earlier experi- ments the normal individuals were invariably somewhat more restless than were the diabetics, which would tend to increase their oxygen consumption above that of the diabetics. If the normals had shown as little muscular activity as did the diabetics, it is obvious that their oxygen consumption would have been still less than reported, and that the increase due to the diabetes woidd be even greater than here shown. While the observations on this point have to deal more particularly with the comparison between the cases of severe diabetes and normals, it is of inter- 1 Roily (Deutsch. Archiv f. klin. Med., 1912, 105, p. 494) gives the following values for his cases of severe diabetes: Subject. Age. Weight. Carbon dioxide per kilo. per minute. 0\ygen per kilo. per minute. Respiratory quotient. H yrs. 21 66 21 30 34 24 20 21 kilos. 44.5 38.8 45 3 40.5 51.5 61.2 63.5 57.5 c.c. 3.969 3.219 3.791 3.344 3.565 3.396 3.281 3.146 c.c. 5.276 4.046 5.168 4.506 4.892 4.708 4.830 4.357 0.753 .795 .734 .742 .728 .702 .680 .722 B Scho.. Bo. Schn . Kr. . . W. K U. L .... 3.464 3 13 4.723 3.75 Av. found by Benedict and Joslin for normal Leirndorfer (Biochem. Ztschr., 1912, 40, p. 326) reports the niichtern value for five severe cases as follows: Subject. Age. Weight. Height. Carbon dioxide per kilo. per minute. Oxygen per kilo. per minute. Respiratory quotient. Joh. Gr yrs. 36 28 19 29 15 kilos. 56.8 68 50 50 45 cm. 172 178 154 159 165 c.c. 2.85 2.75 3.56 3.35 3.29 c.c. 4.41 4.25 5.57 5.23 4.86 0.644 .645 .638 .641 .678 Karl Ki F. S Max G Agn. M Av. found by Benedict and Joslin for normal __ .... 3 16 3.13 4 86 3.75 The abnormally low quotients found by Leirndorfer with the Zuntz-Geppert method are strikingly at variance with those commonly found by us using the respiration apparatus designed in this laboratory and by Roily using a modified form of it. 122 METABOLISM IN SEVERE DIABETES. est to note that the relatively few light cases of diabetes show essentially the same carbon-dioxide production as the normal subjects, with a slightly greater oxygen consumption. This difference in oxygen consumption may easily be explained by the fact that the number of cases studied was altogether too few from which to draw deductions. If we compare the values for the severe cases of diabetes with those for the mild cases, we find that both the carbon-dioxide excretion and the oxygen consumption were materially less with the moderately severe and the light cases of diabetes than those with the severe cases. As pointed out earlier, however, they are in large part affected by the very low values found with Case M. Comparison of the Metabolism of Diabetics with Varying Degrees of Severity. The observations made in our earlier publication indicated that there was a tendency for the metabolism to increase pari passu with the severity of the diabetes, but this inference was based upon slight experimental data, the num- ber of cases of light diabetes being very few. Similarly, in connection with the new experiments, we find a difficulty in drawing a careful deduction on this point, owing to the fact that we still have so few observations upon cases of light diabetes. A comparison of the carbon-dioxide production and oxygen consumption per kilogram of body- weight per minute, as well as the respiratory quotient, with both severe and light cases, is, however, of interest. These com- parisons are given in table 132. Table 132. — Comparison of the metabolism of diabetics with varying degrees of severity. Degree of severity. Bed calorimeter or respiration apparatus per kilogram of body- weight per minute. All experi- ments with all forms of apparatus. Carbon dioxide eliminated. Oxygon absorbed. Respiratory quotient. Severe cases c.c. 3.33 2.82 c.c. 4.54 3.73 0.73 0.75 It is obvious that with the severe cases there was a greater intensity of metabolism as indicated by an increased carbon-dioxide production and an increased oxygen consumption. On the other hand, there was a lower respira- tory quotient, indicating a consumption of fat with a minimum consumption of carbohydrates; with the moderately severe and light cases there is a slightly increased respiratory quotient, corresponding to the slightly greater carbo- hydrate tolerance. A critical examination of these figures and the tables from which they are drawn, namely, tables 119 to 127, shows that the values for the moderately severe and light cases are enormously affected by the very low values for both carbon dioxide and oxygen found with subject M, who was dis- tinctly fat. While, therefore, the original contention may be made that in severe diabetes a somewhat higher metabolism is shown than in moderately severe or DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 123 light cases, nevertheless there is a serious objection to this form of comparison owing to the fact that we have so few light cases. If, however, we examine the figures in table 120, we see that if Case M be omitted the carbon-dioxide pro- duction is still lower with the two remaining cases than the average value for the severe cases. Similarly, if the low oxygen consumption of Case M be omitted in table 123, the average oxygen consumption with severe cases is greater than with any of the moderately severe cases; hence it seems perfectly justifiable to state that the more severe the case, the greater the intensity of the meta- bolism. Thus the experimental evidence seems to justify fully our earlier con- tention to this effect. A Comparison of the Metabolism of Fasting Diabetics under Varying Conditions as to the Intensity of the Acidosis. As was pointed out in the earlier report, there was a period in the history of Case A when he was apparently in a much more serious condition than at any other time. During this period the evidence was clear that both his meta- bolism and pulse-rate were considerably higher than at other times. This suggested a relationship between metabolism and the degree of severity of the diabetes, a suggestion that was emphasized and accentuated by the fact that the whole group of subjects with severe diabetes indicated a higher metabo- lism than did those with light diabetes, although admittedly the number of the latter was too few for us to draw any definite deductions. In the new cases here reported at least two gave indications of a markedly different severity of the disease within a very short period of time, and these fluctuations in severity occurred during the experimental period at the labora- tory. Both cases were boys. With Case N it was noted that on days fol- lowing green days the metabolism was high, there was a higher excretion of 0-oxybutyric acid, the pulse-rate was high and the alveolar carbon-dioxide tension was low. On days following oatmeal days, on the other hand, the metabolism was distinctly lower, the pulse-rate lower, and the alveolar carbon- dioxide tension was higher. The results with this case were, however, com- plicated by an uncertainty as to whether there was not a surreptitious inges- tion of food ; since the ingestion of food per se would stimulate metabolism, it is uncertain whether the high metabolism experienced on certain dates was due to the severity of the disease or to the previous ingestion of food. Nevertheless the other evidence, particularly the carbohydrate balance, is of material assist- ance in determining whether or no food was ingested prior to coming to the laboratory, and we believe that for the two days here cited there is reasonable ground for belief that the actual conditions of metabolism were not compli- cated by the previous ingestion of food. The results are given in table 133. On November 30 to December 1 the acidosis was severe; the /3-oxy butyric acid, which was fortunately determined on that day, amounted to 35 grams, with a minus carbohydrate balance of 25 grams; the oxygen consumption was 179 c.c. with a pulse-rate of 75 and a carbon-dioxide tension of 17 mm. On December 1 the subject had an oatmeal day, and on December 2 to 3, the dia- 124 METABOLISM IN SEVERE DIABETES. cetic acid reaction and the carbohydrate balance were essentially the same, but there was a fall in the ammonia-nitrogen nitrogen ratio; there was, however, a considerably lower metabolism, inasmuch as but 160 c.c. of oxygen were consumed per minute, the pulse-rate was 57, and the alveolar carbon-dioxide tension was 26 mm. Unfortunately the /3-oxybutyric acid was not determined. In examining the original table for this case (table 33) we find varying days, even when the subject was supposed to be fasting, the variations in the oxygen consumption ranging from 179 down to as low as 160. These high days can not always be sharply designated as being days on which no food was Table 133. — Comparison of the metabolism of Case N under varying conditions of acidosis. Date. Diacetic acid. /3-oxy- butyric acid. NH'-N Total N Carbo- hydrate balance. Metabolism at beginning of following day. Alveolar carbon- dioxide tension. Oxygen per kilo- gram per minute. Pulse- rate. 1910. Nov. 30- Dec. 1 +++ + + + + + gmn. 35 > p. ct. 42 36 gms. -25 -15 c.c. 179 160 75 57 mm. 17 26 Dec. 2-3 taken, as we have reason to believe that the subject took food on one or two occasions before coming to the laboratory, either through a misunderstanding or otherwise, and it was not properly reported. In any event, the relationship between the intensity of the metabolism, the diet of the previous day, and the general physical condition of the subject was such as to be of considerable significance, and seemed to indicate a rather close connection between the severity of the acidosis and the intensity of metabolism. With Case Q we are confident that the diet was properly controlled. We have accordingly selected two days with this subject in which both the degree of acidosis and the total metabolism were determined. The results are given in table 134. Under these conditions we find on November 18-19, when there was severe acidosis with a large amount of /3-oxybutyric acid and a low carbo- hydrate balance, that the metabolism and pulse-rate were considerably higher than three days later, when the /3-oxybutyric acid was two-thirds that of the first and the positive carbohydrate balance was considerable, this day being a carbohydrate oatmeal day. There was likewise an increase in the tension of the alveolar carbon dioxide. On the other hand, the whole comparison is some- what complicated by the fact that the volume of urine on the second day was but one-half that of the first day ; the total amount of nitrogen was also lower. This of course would keep up the high percentage of ammonia nitrogen, and might account for the low excretion of /3-oxybutyric acid, but need not neces- sarily affect the carbohydrate balance. It is much to be regretted that other experiments without food could not have been made with this subject, but the only other two experiments obtained with him were after definite feeding. The results of the experiments with Cases N and Q strongly suggest an intimate relationship between the severity of diabetes and high metabolism; DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 125 while this evidence from experiments with individual subjects is by no means conclusive, it supplements the general impression derived from experiments with different individuals that with severe diabetes there is a high metabolism, and with mild diabetes a lower metabolism. This last inference, however, is drawn from experiments with different individuals, while the experiments with Cases N and Q imply that with the same individual, differences in intensity of the disease may be accompanied by differences in the intensity of the metabolism as measured by the oxygen consumption, the pulse-rate, and the alteration in the carbon-dioxide tension of the alveolar air. Table 134. — Comparison of the metabolism of Case Q under varying conditions of acidosis. Date. Diacetic acid. /3-oxy- butyric acid. NHs-N Total N Carbo- hydrate balance. Metabolism at beginning of following day. Alveolar carbon- dioxide tension. Oxygen per kilo- gram per minute. Pulse- rate. 79 65 1910. Nov. 18-19 +++ ++ + + Qtns. 30 19.6 p. ct. 27.4 25.9 gms. -55 +75 c.c. 232 220 m m . 31 40 Nov. 22-23 The Influence of a Normally Induced Acidosis upon Metabolism. Since diabetics with severe acidosis showed a higher metabolism than did light cases, and since the metabolism was higher with the same individual when the diabetes was very severe than when it was milder, it seemed desirable to find out the effect of an experimentally induced acidosis upon the metabolism of normal individuals. While studying in the laboratory of Dr. Joseph Barcrof t, of Cambridge, England, Mr. H. L. Higgins, an associate in this laboratory, made some interesting observations on the relationship between the effect of a carbohydrate-free diet and the dissociation curve of the blood. While upon a carbohydrate-free diet he observed great lassitude and a general feeling of malaise. On repeating this experiment in the fall of 1911, it occurred to him that a study of the metabolism as measured by the oxygen consumption and carbon-dioxide production during this period would be of interest, and hence some observations were made of the total metabolism. Subsequently, a second experiment was made with another subject, H. H. A., a student in the Harvard Medical School. This was more carefully planned, with the special purpose of studying the effect of the carbohydrate-free diet upon the meta- bolism. In a paper recently published by Benedict and Higgins,1 discussing the effect of the amount of carbohydrates in the preceding diet upon the respira- tory quotient, it was shown that the respiratory quotient with a carbohydrate- free diet was as low as the ordinary quotients in diabetes, if not lower, and that the respiratory quotient could be elevated persistently by increasing the quan- 'Benedict and Higgins, Am. Journ. Physiol., 1912, 30, p. 217. 126 METABOLISM IN SEVERE DIABETES. tity of carbohydrates in the diet. Inasmuch as this paper dealt especially with the character and not with the amount of the metabolism, practically no reference was made to the significant fact that apparently the lower the amount of carbohydrates in the diet, the higher the metabolism. It is the purpose of the following section of this discussion to state the details of these experiments and to discuss the results. EXPERIMENTS WITH H. L. H. The study made with this subject included four experiments, all with the respiration apparatus. Three of these were made with the carbohydrate-free diet; the fourth followed normal diet. The special diet was begun on Sep- tember 6, 1911, but the plan to study the respiratory exchange was not devel- oped until the next day, so that the first respiration experiment was made on September 7, 1911. The experiment on normal diet was therefore delayed until the second day after the discontinuance of the carbohydrate-free diet. The vital statistics for this subject are as follows: Date of birth, March 26, 1887; height, 172 centimeters; body-weight with- out clothing during experiments, 60.2 kilos. STATISTICS OF EXPERIMENTS WITH H. L. H. Respiration Experiment No. 1. Date, September 7, 1911. Body-weight without clothing, 60.2 kilos. The last meal preceding the beginning of the carbohydrate-free diet was taken at 12h 30m p. m., September 5, and consisted of beef stew with vegetables and bread and butter. The subject fasted the remainder of the day. On the day preceding the first experiment he took for his breakfast eggs and beef tea; for dinner, sardines and cheese; and for supper, pork chops. Samples of the alveolar air were taken at 2h 56m and 3h 52m p. m. on this day. On the experimental day the subject came to the laboratory fasting; the experiment began at 8h 50m a. m., continued for three 15-minute periods, with intermissions of 19 and 11 minutes respectively, and ended at 9h 55m a. m. The pulse-rate ranged from 80 to 88. The results of the experiment are given in table 135. After the experiment was over the subject ate for his breakfast at 10 a. m. soft-boiled eggs with butter; also took pepsin gum. For his dinner, at 3h 30m p. m., he again took soft-boiled eggs with butter, while for his supper he ate fried ham with a little butter. Respiration Experiment No. 2. Date, September 8, 1911. Body-weight without clothing, 60.2 kilos, (assumed). At 8 a. m. on the experimental day the subject took a few sips of coffee, a piece of pepsin gum, and a little lemon juice. The experiment began at 9h 25m a. m., continued for three 15-minute periods with intermissions of 11 and 9 minutes each, and ended at 10h 30m a. m. The pulse-rate ranged from 72 to 80. The food taken by the subject throughout the day consisted of a break- fast of lamb chops at 10h 30m a. m., a dinner of sardines at 2h 30m p. m., and a supper of beefsteak at 8 p. m.. Samples of the alveolar air were taken on this day. The results of the experiment are given in table 135. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 127 Respiration Experiment No. 3. Date, September 9, 1911. Body- weight without clothing, 60.2 kilos, (assumed). This experiment began at 9h 53m a. m. with the subject fasting, was con- tinued for two 15-minute periods, and ended at 10h 31m a. m. The pulse-rate ranged from 64 to 78. The carbohydrate-free diet was discontinued beginning with this day, no record being made of the food eaten on this and succeeding days. The results of the experiment may be found in table 135. Respiration2Experiment No. 4. Date, September 11, 1911. Body-weight without clothing, 60.2 kilos, (assumed). On the second day after the discontinuance of the carbohydrate-free diet, another respiration experiment was made with the subject after a 12-hour fast. The experiment began at 8h 22m a. m., continued for three 15-minute periods, and ended at 9h 37m a. m. The pulse-rate ranged from 66 to 72. The results of the experiment are given in table 135. Table 135 — -Results of respiration experiments Nos. 1 to 4 with H. L . H., without food. Experi- ment No. Date. Diet and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration- rate. 1 2 3 4 1911. Sept. 7 . . Sept. 8 . . Sept. 9 . . Sept. 11 . Carbohydrate free.1 8h 50m a.m 9 14 a.m 9 40 a.m Average 9Q 25m a.m 9 51 a.m 10 15 a.m 9h 53m a.m 10 16 a.m Average Normal.2 8h 22m a.m 8 50 a.m 9 21 a.m Average min. sec. 15 4 15 7 15 10 15 7 15 4 15 6 15 9 15 4 15 24 15 40 15 18 c.c. 206 197 198 200 209 196 189 198 198 191 195 212 207 211 210 c.c. 305 292 301 299 281 279 280 280 276 268 272 248 233 248 243 0.68 .67 .66 .67 .75 .70 .68 .71 .72 .71 .72 .86 .89 .85 .87 85 83 84 84 76 75 74 75 70 74 72 69 67 71 69 16 15 16 16 16 17 16 16 16 16 16 16 17 15 16 ■Subject began the carbohydrate-free diet after the noon meal of Sept. 5, 1911. 2 Subject resumed his normal diet on the morning of Sept. 9, 1911. RESULTS OF EXPERIMENTS WITH H. L. H. It is obvious from the data given in table 135 for the oxygen consumption that the metabolism was much higher during the carbohydrate-free diet than during the normal diet. This is further substantiated by the fact that the pulse-rate was higher, particularly on the first day on which measurements were secured. Table 136. — Statistics of urine — Subject H. L. H. Date. Period. Volume of urine. Acetone. 0-oxy- butyric acid. Nitrogen. Ammonia. Total. NH3-N. Total N 1911. Sept. 6-71.. 7-8... 8-9... 8h 45m a.m. to 8h 25m a.m c.c. 1130 1120 1300 gms. 1.548 1.726 2.792 gms. 4.247 8.028 gms. 21.92 18.05 18.93 gms. 1.58 2.46 4.07 p. ct. 5.9 11.2 17.7 8 25 a.m. 7 50 a.m 7 50 a.m. 9 35 a.m ■The subject subsisted on a carbohydrate-free diet after the noon meal of Sept. 5, 1911. 128 METABOLISM IN SEVERE DIABETES. Urine analyses. — To study the degree of acidosis, the subject made a care- ful urine analysis on three days of the study. The results of these analyses are reported in table 136. Unfortunately, the value for /3-oxybutyric acid on Sep- tember 7-8 is questionable and is therefore not included. It will be seen that there was a measurable amount of acetone and /3-oxybutyric acid appearing in the urine; there was also an increase in the amount of ammonia which rose on the last day to about 4 grams with approximately 18 per cent of the total nitrogen in the form of ammonia-nitrogen. These commonly accepted indices of an acidosis are particularly well shown in this experiment. Composition of the alveolar air. — This subject had been particularly interested in studying the composition of alveolar air and so made a number of observations upon himself prior to and during the experiment, the results of which are given in table 137. Of special interest is the carbon- dioxide tension, which falls below the normal immediately after the beginning of the carbohydrate-free diet, the average on September 8 being some 7 mm. below the normal. The oxygen consumption shows a corresponding increase. Table 137. — Determinations made on alveolar air with H. L. H. 1 Carbon- ' ^ Date and time. dioxide i ten's;on Diet, tension. 1911. July 21-22, average. . . . Sept. 6: 2h56m p.m 3 52 p.m Sept. 8'2 mm. 36 5 m m . 111.1 Normal. Carbohydrate-free.1 Carbohydrate-free. 35.5 33 9 103.8 29.9 28.6 30 3 120.4 29 6 120.4 'Subiect began the carbohvdrate-free diet after the noon meal of Sept. 5, 1911. He ate food at 12h 20m p.m. Sept. 6. 2 Probably after food. EXPERIMENTS WITH H. H. A. The important point observed in connection with the study with H. L. H., namely, an increased metabolism incidental to the ingestion of a carbohydrate- free diet, justified a second carefully-planned study on another subject. The subject of this second study was placed in the New England Deaconess Hos- pital, so that the diet was under rigid control throughout the entire period. Being a medical student and a man of unusual intellectual keenness in the problems involved, he cooperated most heartily with us in all these tests. A series of nine experiments was made with this subject, including a pre- liminary experiment with a normal diet, five experiments with a carbohydrate- free diet, one experiment during which oatmeal was ingested, one experiment with cane sugar, and a final experiment following a normal diet. The vital statistics of the subject were as follows: Date of birth, August 10, 1890; height, 164 cm.; range in body-weight during experiments, 60.9 to 63.5 kilos. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 129 STATISTICS OF EXPERIMENTS WITH H. H. A. Respiration Experiment No. 1. Date, December 27, 1911. Body-weight without clothing, 63.5 kilos. The diet on the day preceding the study was a mixed diet. Breakfast: coffee, with sugar, fried potatoes, and bread. Dinner: barley soup, potatoes, bread, apple pie, coffee, hard candy. Supper: fried potatoes, tea with sugar, bread, and a few dates. On the experimental day the subject came to the laboratory without breakfast and lay down upon the couch at 8 a. m. The experiment began at 8h 50m a. m., continued for four 15-minute periods with intervals of 8 to 10 minutes, and ended at 10h 18m a. m. The pulse-rate ranged from 74 to 82. The subject urinated before the experiment at 7 a. m., and after it was over, at 10h 25m a. m. A sample of the blood was taken at llh 10m a. m. The results of the experiment may be found in table 138. Respiration Experiment No. 2. Date, December 27, 1911. Body-weight without clothing, 63.5 kilos. This experiment was made on the afternoon of the day of the preceding experiment, being the first with a carbohydrate-free diet. At 12 o'clock noon the subject took for his dinner steak and butter, with a cupful of beef tea. The experiment, which consisted of two 15-minute periods, began at 4h 38m p. m. and ended at 5h 19m p. m. The pulse-rate ranged from 94 to 104. After the experiment the subject ate for his supper, at 6 p.m., scrambled eggs, butter, and tea without milk or sugar. The results of the experiment are given in table 138. Respiration Experiment No. 3. Date, December 28, 1911. Weight without clothing, 61.9 kilos. The subject came to the laboratory without breakfast, lay down upon the couch at 7h 45m a. m., and a blood sample was taken about 8h 12m a. m. The experiment began at 9 a. m., continued for three 16-minute periods, and ended at 10h 03m a. m. The pulse-rate ranged from 78 to 88. The subject urinated at 10h 35m a. m. The diet for this day consisted of eggs, butter, and coffee at 12 o'clock; cheese, fried eggs, bacon, and beef tea at 3 p. m., and lean pork chops and tea at 7h 30m p. m. The results of the experiment may be found in table 138. Respiration Experiment No. 4. Date, December 29, 1911. Body-weight without clothing, 61.3 kilos. Previous to the experiment, the subject said he felt very well, fully equal to taking a long walk. He came to the laboratory without breakfast. The experiment began at 8h 12m a. m. and continued for five periods of 15 to 16 minutes each. The subject urinated at 7 and llh 25m a. m. On this day he ate, at 12h 35m p. m., eggs and fried ham, with weak coffee; at 3 p. m., boiled scrod with butter, and beef tea ; and at 7 p.m., fried lamb chops and tea. The results of the experiment are given in table 138. Respiration Experiment No. 5. Date, December 30, 1911. Body-weight without clothing, 61 kilos. No breakfast was taken by the subject on the day of the experiment. The respiration experiment began at 10h 46m a. m. and continued for one 8-minute and two 15-minute periods, ending at 12h 12m p. m. The pulse-rate during the experiment ranged from 67 to 78. The subject urinated at 7 a. m. and 12h 30m p. m. He took food during the day as follows: lh 10m p. m., scrambled eggs, 130 METABOLISM IN SEVERE DIABETES. butter, cheese, and beef tea; 3h 30m p.m., beefsteak and butter; 7h 30m p. m., boiled chicken, butter, and eggs. The results of the experiment are included in table 138. Respiration Experiment No. 6. Date, December 31, 1911. Body-weight without clothing, 61 kilos. As usual, the subject fasted for 12 or more hours previous to the experi- ment. He lay down upon the couch at 8h 04m a. m., the experiment beginning at 9h 01m a. m. The measurements were made in three 15-minute periods, ending at 10h 30m a. m. The pulse-rate during the experiment ranged from 75 to 83. During the day the subject ate as follows: At 1 p. m., boiled eggs, includ- ing a little of the whites, butter, and cream (32 per cent fat) with soda; at 3h 30ra p. m., eggs (yolks only), bacon, and beef tea; at 7h 30m p. m., eggs (yolks), olive oil, cream with soda, and tea. He said subsequently that he felt very thirsty on this day, and drank considerable water, but this did not affect the volume of the urine. Table 138 gives the results of the experiment. Respiration Experiment No. 7. Date, January 1, 1912. Body-weight without clothing, 60.9 kilos. The experiment was divided into two sections with an interval of some 3 hours; in the first part the subject fasted for three periods; shortly before the second part of the experiment began he ate a considerable amount of oatmeal and eight periods followed, an additional portion of oatmeal being taken before the last two periods. The subject lay down upon the couch at 7h 45m a. m., and the experiment began at 8h 22m a. m. The fasting periods ended at 9h 51m a. m. At 12h 12m p. m., the subject took 582.8 grams of cooked oatmeal, 83.6 grams of butter, and 400 c.c. of water. The following six 15-minute periods began at 12h 41m p. m. and ended at 4h 18m p. m. At 4h 35ra p. m. the subject ate a second por- tion of oatmeal (350.7 grams) and butter (65.1 grams) and drank 400 c.c. of water. The two last periods of the experiment began at 5h 23m p. m., and ended at 6 p. m. In the first period after food, the subject probably went to sleep for a moment or so. In the final period he coughed during the last minute of the experiment. The times of urinating were 7 a. m., 10h 15m a. m., llh 55m a. m., 3h 05m p. m., and 6h 15m p. m. The pulse-rate during the fast- ing periods ranged from 76 to 84, while during the periods following the inges- tion of food it ranged from 75 to 93. The measurements of the metabolism are given in table 138. Respiration Experiment No. 8. Date, January 2, 1912. Body-weight without clothing, 61.2 kilos. This experiment was divided into two sections, the first three periods being fasting, and the last six periods following the ingestion of cane sugar. For supper the night preceding the experiment the subject took coffee with sugar, and bread. The fasting periods began at 7h 42m a. m. and ended at 8h 45m a. m. At 9h 12m a. m., the subject took 100 grams of cane sugar in 400 c.c. of water and lemon juice. The following periods began at 9h 22ra a. m., ending at 12h 57m p. m. During the fasting periods the pulse-rate ranged from 64 to 68; in the periods following the taking of the cane sugar it ranged from 73 to 86. The subject urinated at 10h 30m a. m., also urinated and defecated between the eighth and ninth periods, resting afterwards for about 15 minutes. The results of the experiment are to be found in table 138. DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 131 Respiration Experiment No. 9. Date, January 3, 1912. Body-weight without clothing, 62.5 kilos. After leaving the laboratory at 1 p. m., January 2, the subject drank, at lh30m p. m., two cupfuls of coffee with sugar and ate an egg sandwich. At 6 p. m. he took beef stew with potatoes, bread, coffee, rice pudding, and apple pie. Table 138. — Results of respiration experiments Nos. 1 to 9 with H. H. A. Experi- ment No. Date. Diet and time. Duration. Carbon dioxide eliminated per minute. Oxygen absorbed per minute. Respiratory quotient. Average pulse-rate. Average respiration- rate. Normal. 1911. Without food: min. sec. c.c. c.c. 1 Dec. 27.. SbStr^a.m.... 14 23 208 225 0.93 76 12 9 13 a.m.... 14 19 208 223 .93 77 11 9 37 a.m.... 14 16 193 228 .85 78 12 10 02 a.m.... 15 30 195 221 .88 79 13 Average 201 224 .90 78 12 Carbohydrate-free. With food:1 2 Dec. 27.. 4h38mp.m.... 14 54 205 289 .71 98 14 5 04 p.m.. . . 14 46 209 290 .72 102 12 Without food: 3 Dec. 28.. 9h00ma.m.... 15 55 189 263 .72 83 11 9 22 a.m.... 15 52 187 250 .75 81 14 9 47 a.m.... 15 51 195 262 .74 84 12 Average 190 258 .74 83 12 4 Dec. 29.. 8h 12raa.m.... i5 28 176 262 .67 73 12 8 38 a.m.... 15 52 176 273 .65 74 11 9 05 a.m.... 15 48 177 247 .72 73 10 9 59 a.m.... 15 37 183 264 .69 74 10 10 48 a.m.... 15 05 184 246 .75 74 12 Average 179 258 70 74 11 5 Dec. 30.. 10h46ma.m.... "l 44 185 250 .74 69 11 11 03 a.m.... 14 58 171 237 .72 70 10 11 57 a.m 15 05 177 235 .75 72 9 Average 178 241 74 70 10 6 Dec. 31.. 9h01ma.m.... ii 35 169 242 .70 79 14 9 35 a.m.... 14 39 175 238 .73 80 14 10 16 a.m.... 14 22 175 246 .71 77 13 1912. Average 173 242 .71 79 14 7 Jan. 1 8h22ma.m.... 14 40 162 240 .67 81 14 9 07 a.m.... 14 49 160 233 .69 77 14 9 36 a.m.... 15 05 169 243 .70 79 13 Average 164 239 .69 79 14 Oatmeal and butter With food: 12h41mp.m.2.. 14 52 180 267 .67 84 16 1 08 p.m.... 15 07 192 275 .70 86 16 1 41 p.m.... 15 12 199 275 .72 82 15 2 08 p.m.... 15 39 204 274 .74 92 16 3 33 p.m.... 15 13 207 283 .73 85 11 4 04 p.m.... 14 12 186 254 .73 77 13 5 23 p.m.3. . 15 02 208 284 .73 82 13 5 45 p.m.. 14 42 211 291 .72 84 14 Without food: 8 Jan. 2 7h42ma.m.... 14 27 158 223 .71 67 11 8 05 a.m... 15 16 146 208 .70 65 13 8 29 a.m... 15 41 156 215 .73 67 11 Average 153 215 .71 66 12 Cane sugar. With food:4 9h22ma.m... 14 01 209 241 .87 73 11 9 45 a.m... 14 09 242 232 1.04 79 15 10 14 a.m... 14 28 238 245 .97 76 15 11 05 a.m... 15 08 229 247 .93 80 15 11 34 a.m... 14 32 201 241 .83 85 14 12 41 p.m... 14 30 173 230 .75 80 12 Normal. Without food: 9 Jan. 3... . 7h55ma.m... 16 04 172 216 .79 74 10 8 24 a.m... 15 05 169 212 .80 73 8 Average 171 214 .80 74 9 1 Subject ate 169 gms. beefsteak, 14.5 gms. butter, and 1 cup beef tea at 12 noon. 'Subject ate 582.8 gms. cooked oatmeal and 83.6 gms. butter at 12h 12m p.m. 'Subject ate 350.7 gms. cooked oatmeal and 65.1 gms. butter at 4h 35m p.m. 4 Subject took 100 gms. cane sugar in 400 c.c. of water with juice ot lemon at 9 12 a.m. 132 METABOLISM IN SEVERE DIABETES. On the experimental day the subject came to the laboratory fasting, and the experiment began at 7h 55m a. m., continuing for two periods of approxi- mately 15 minutes each and ending at 8h 39m a. m. During the experiment the pulse-rate ranged from 72 to 75. The measurements of the metabolism are given in table 138. RESULTS OF EXPERIMENTS WITH H. H. A. The measurements of the total metabolism of the subject for the whole series of experiments are given in table 138. Previous to the first experiment the subject had been on a normal diet, but fasted for some 12 hours before com- ing to the laboratory. Under these conditions he absorbed about 225 c.c. of oxygen per minute and had an average pulse-rate of approximately 78. On the morning following the carbohydrate-free diet, the oxygen absorption was increased to approximately 255 c.c. per minute, and the pulse-rate to 83. On the next four days of the carbohydrate-free diet, the metabolism remained high, although there was a tendency for it to approximate more nearly the normal level as the experiment progressed. Singularly enough, notwithstand- ing the high metabolism, the pulse-rate on the first two days was considerably below that on the normal day. Unfortunately simultaneous observations with regard to the blood-pressure were not obtained. Table 139.- —Statistics of urine —Subject H. H .A. Date. a '£ 3 *o a s "o > >> '> a u > 43 3 J2 >> X O a a 61 O S3 Ammonia. 4^ "3 >JS .2 d So £ m ■ < Diet. "ca 43 o Eh S3 1 S3 "3 43 o H 1911. Dec. 25-26. Dec. 26-27. Dec. 27-28. Dec. 28-29. Dec. 29-30. Dec. 30-31. Dec. 31-1 Jan. 1 /•■ 1912. Jan. 1- 2. Jan. 2- 3. Jan. 3- 4. c.c. 1245 1974 1667 985 1304 928 880 991 818 648 1.0155 1.013 1.018 1.0285 1.026 1.0265 1.026 1.016 1.0165 1.023 Pale Acid. gms. gms. 10.22 9.39 11.82 16.45 21.28 17.52 14.63 8.72 6.62 7.18 gms. 0.88 .87 .56 1.0 1.27 1.62 1.93 1.75 1.29 p.ct. 7.1 7.6 3.9 5.0 4.9 7.6 10.9 16.5 16.0 gms. 11.6 20.9 14.0 8.6 6.3 7.1 5.8 174.3 197.4 100.0 384.1 326.0 352.6 423.6 297.0 237.2 194.1 Normal. Do. Carbohydrate-free Do. Do. Do. Do. Oatmeal.2 Cane sugar.5 Normal. Slightly pale. Normal Normal Pale Acid. Acid. Acid. Acid. Acid. 0 0 Normal Pale Acid Acid. Acid. 0 0 0 4.8 Pale 'Sugar and albumen tested for each day and uniformly absent. Subject ate 582.8 gms. cooked oatmeal and 83.6 gms. butter at 12.12 p.m.; also 350.7 gms. cooked oatmeal and 65.1 gms. butter at 4.35 p.m. See statistics of experiment No. 7. 'Subject took 100 gms. cane sugar in 400 c.c. of water with juice of lemon at 9.12 a.m. For diet rest of day see sta- tistics of experiments Nos. 8 and 9. Urine analyses. — The urine was collected in 24-hour periods from Decem- ber 25 to January 4, although on certain days the determinations were made in periods corresponding to the experimental periods. The results of the urine analyses are given in table 139. Only one determination of the /3-oxybutyric acid was made, i. e., on the fifth day of the carbohydrate-free diet, and 4.8 grams of /3-oxybutyric acid were found. There was no diacetic-acid reaction, but the percentage of ammonia-nitrogen to total nitrogen was somewhat higher than normal, if not excessively high. On the oatmeal and cane-sugar days following the carbohydrate-free diet, the percentage of ammonia-nitrogen in DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 133 the proportion of total nitrogen increased considerably, this being largely due to the fact that there was a decided decrease in the total nitrogen. Sugar and albumen were tested for each day and were uniformly absent. The general picture of the urine analyses with this subject does not by any means indicate as striking an acidosis as was found with subject H. L. H. On the other hand, it is reasonably clear from the presence of /3-oxybutyric acid that there was an acidosis, and that this was due to the carbohydrate-free diet. The absence of the determinations of /3-oxybutyric acid on the other days is much to be regretted. The alkali retention by the kidney, which, taken together with the ammonia excretion, makes up the protective mechanism of the body against acidosis, shows an increase during the days of carbohydrate-free diet and a return toward normal with the addition of carbohydrates to the food, fol- lowing closely the ammonia curve.1 Table 140. — Determinations made on alveolar air with H. H. A. Date. Carbon dioxide. Remarks. Date. Carbon dioxide. Remarks. Per cent. Tension. Per cent. Tension. 1911. Dec. 26... Av.... Dec. 28... Av... Dec. 29. . . Av.... Dec. 30. . . Av.... 5.62 5.43 5 46 5.68 5.94 5.60 m m . At about 3 p.m.; prob- ably food taken about noon. About 10h45m a.m.: be- fore eating About llh45m a.m.; be- fore eating. Aboutl2h15mp.m.; be- fore eating. 1911. Dec. 31. . Av .... 1912. Jan. 1 Av... Jan. 1 Av... Jan. 1 Av.... 4.70 4.64 4.53 4.69 mm. About 11 p.m.; before eating. About 10 a.m.; before eating. At 2h 30™ p.m.; after oatmeal and butter at 12h 12m p.m. At 6h 15m p.m. after oatmeal and butter at 4h 35m p.m. 4.64 33.2 5 . 62 40 1 4.34 4.53 4.39 4.75 4.56 4.76 4.70 5.11 5.04 5.00 5.05 35.6 4.81 4.67 4.66 4 85 4.58 32.6 5.27 5.18 4 75 33.9 5 23 37.2 4.54 4.85 4.79 4.87 5.10 5.02 5.03 4.76 34.4 5.05 36.0 Composition of the alveolar air. — Determinations of the alveolar air, with particular reference to the carbon-dioxide percentage and tension, were made on a number of days throughout this test. The results are presented in table 140. The normal value found when the subject began the carbohydrate-free diet was 5.62 per cent of carbon dioxide, corresponding to about 40.1 mm. ten- sion. With the carbohydrate-free diet this tension dropped almost immedi- ately, and reached its minimum on the fifth day, 32.6 mm. On the resumption of a normal diet with oatmeal there was an immediate response and an increase JH. M. Adler and G. Blake, Archives of Internal Medicine, 1911, 7, p. 479. 134 METABOLISM IN SEVERE DIABETES. in the carbon-dioxide tension to 37.2 mm. The correlation, therefore, between the carbon-dioxide tension, the alveolar air, the total metabolism and the acidosis is clearly shown. Blood examination. — The blood was examined daily and the results are reported in table 141. Table 141. — Results of blood examinations1 — Subject H. H. A. Date and time. Time after last meal. Hemo- elobin (Fleischl). White blood- corpuscles. Red blood- corpuscles. Dec. 27, 1911: 4h 00" p.m Dec. 28, 1911: 8h 12m a.m 4 00 p.m Dec. 29, 1911: 4h 00m p.m Dec. 30, 1911: 4h 00m p.m hrs. min. 4 0 14 0 1 0 1 0 30 p. cl. 95 96 95 96 17,300 10,600 11,100 11,700 8,000 5,860,000 5,676,000 5,864.000 fi.128,000 •On Dec. 28 a stained specimen of the blood was examined microscopically with the following result: Differ- ential count of 200 white blood-corpuscles showed polynuclear leucocytes 82.5 per cent, lymphocytes 15.5 per cent, transitionals 1 per cent.eosinophiles 1 percent. The red blood-corpuscles showed nothing abnormal. It will be seen that the hemoglobin was constant for the four days; the number of red blood- corpuscles was also essentially constant. We are unable to explain the increase in the number of white blood-corpuscles on the first afternoon after the first carbohydrate-free meal. The slight decrease in the white blood-corpuscles found for the following successive days does not warrant conclusions, particularly without support from similar experiments. The differential count of the white blood-corpuscles shows nothing abnormal. RELATIONS BETWEEN A NORMALLY INDUCED ACIDOSIS AND THE OBSERVED INCREASE IN THE METABOLISM IN SEVERE DIABETES. With both of these subjects there was a noticeable increase in the total metabolism as measured by the oxygen consumption, coincident with the use of a carbohydrate-free diet. With one case at least there was a corresponding increase in the pulse-rate, while with the other there was a temporary increase in the pulse-rate, followed by a decline. Since it is probable that an intimate relationship exists between the blood-pressure and the pulse-rate, we have every reason to believe that if all the data had been available this seeming discrep- ancy between the results with the two subjects could be readily explained. If the presence of the small amount of /3-oxybutyric acid found with these subjects was sufficient to stimulate the metabolism so that the metabolic activity of the body itself as a whole was increased by the amount here found, it is not at all surprising that in severe diabetes the same processes which involved the formation and circulation of /3-oxybutyric acid molecules would likewise tend to stimulate the body activity of the diabetic. On the other hand, the constant presence of /3-oxybutyric acid throughout a long period of time during the course of the disease might easily lead to an acquired tolerance for the presence of /3-oxybutyric acid which would involve the necessity for the DISCUSSION OF RESULTS AND GENERAL CONCLUSIONS. 135 presence of a very much larger amount of the acid in order to produce a given stimulating effect. In a recently concluded experiment with a fasting man in this laboratory, after 31 days of fasting it was found that the amount of /3-oxybutyric acid in the urine was not materially greater than that found with these two subjects when they were subsisting upon a carbohydrate-free diet. There was, how- ever, no measurable increase in the metabolism noted with this subject; on the contrary there was a marked decline in total metabolism as the fast progressed. While, therefore, it would appear possible to explain the increased metabolism noted with diabetics upon the ground that the severity of the acidosis caused an increased metabolism, we can at present only state the fact that coincidental with the severe acidosis there was found an increased metabolism. Whether the presence of /3-oxybutyric acid molecules passing through the blood stimu- lates the cell activity, or whether the decrease in the alkalescence of the blood produces a similar effect, we can not at present state. Whatever the effect, the body probably to a certain extent may accustom itself to this stimulus and thus react less as time goes on. The fact that there may be 55 grams or more of /3-oxybutyric acid excreted per day with diabetics, with no greater increase in the metabolism above normal than the increase found with a normal individual subsisting on a carbohydrate-free diet, who had but 4 or 5 grams of /3-oxy- butyric acid, would imply that as the disease progressed from day to day, the body became accustomed to the specific stimulus (probably the presence of acid) and responded less and less.1 Clinical experience with diabetic patients suggests that an acid intoxica- tion of moderate severity suddenly produced by the withdrawal of carbo- hydrates is more dangerous than a much more severe acidosis produced by a gradual withdrawal of carbohydrates. Thus the sudden withdrawal of carbo- hydrates from diabetic patients upon entrance to hospitals may result in the acute onset of coma. It is often a surprise to find that in the urines of such patients the quantity of acid is so small. In contrast, cases of severe diabetes subjected to marked restriction of carbohydrates for a long period may present an acidosis of severe degree amounting to even 50 grams of (8-oxybutyric acid daily, and yet show no inconvenience therefrom. In these cases the acidosis apparently greatly exceeds for weeks at a time the acidosis of the former group of cases. 1Rolly (loc. cit.), noting that the high oxygen consumption observed when patients first came to the hospital was frequently lowered by dietetic treatment, infers that this can not be explained alone by the reduction in protein ingestion, but that the previous high oxygen consumption must be due to improper diet, exercise, consumption of food, or other causes as yet unknown. Leimdorfer (loc. cit.) maintains that the increased metabolism of severe diabetes is caused for the greater part by an increase in the intermediary metabolic processes, such as the formation of sugar and acetone bodies from protein and fat. A small part is due to the increased work of respiration. As the page proof of this publication leaves our hands, we note that Grafe and Wolf (Deutsch. Archiv f. klin. Med., 1912, 107, p. 227) probably have evidence in regard to the increased metabolism in severe diabetes as a later communication is promised. Publications of the Nutrition Laboratory. Publications will be sent post-paid at the prices indicated. Orders should be accompanied by a remittance payable to the Carnegie Institution of Washington, Washington, D. C. No. 42. Atwater, W. O., and F. G. Benedict. A Respiration Calorimeter with Appliances for the Direct Determination of Oxygen. Octavo, 193 pages, 49 figures. Pub- lished 1905. Price $1.25. No. 77. Benedict, F. G. The Influence of Inanition on Metabolism, Octavo, vn+542 pages, 2 text figures. Published 1907. Price $2.75. No. 123. Benedict, Francis G., and T. M. Carpenter. Respiration Calorimeters for Studying the Respiratory Exchange and Energy Transformations of Man. Octavo, vn + 102 pages, 32 figures. Published 1910. Price $0.75. No. 126. Benedict, Francis G., and T. M. Carpenter. The Metabolism and Energy Transformations of Healthy Man during Rest. Octavo viii+255 pages. Published 1910. Price $1.75. No. 136. Benedict, Francis G., and Elliott P. Joslin. Metabolism in Diabetes Mellitus. Octavo, vi +234 pages, 2 plates. Published 1910. Price $2.00. No. 155. Benedict, Francis G , and Edgar P. Slack. A Comparative Study of Tem- perature Fluctuations in Different Parts of the Human Body. Octavo, v+73 pages, 38 figures. Published 1911. Price $0.50. No. 166. Benedict, Francis G. The Composition of the Atmosphere with Special Reference to its Oxygen Content. Octavo, 115 pages, 1 plate, 1 text figure. 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Pub- lished 1909. Price $9.00. No. 173. Reichert, Edward T. The Differentiation and Specificity of Starches in Relation to Species, Genera, etc.: A Contribution to the Application of Stereochemistry to Protoplasmic Processes. Quarto. In press. Mill. WHOl LIBRARY IfiK L D a^ r