COLUMBIA LIBRARIES OFFSITE HEALTH SCIENCES STANDARD iiiiiiiiiiiiii ^„^ HX641 47789 RC660 .J784 1915 Carbohydrate utiliza RECAP CoUege of ^tjpgiciansf mh burgeons! Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons http://www.archive.org/details/carbohydrateutilOOjosl CARBOHYDRATE UTILIZATION IN DIABETES Based on Studies of the Respiration, Urine and Blood ELLIOTT P. JOS LIN, M. D. BOSTON Reprinted from the Archives nf Internal Medicine November, 1915, Vol. xvi, />/>. 693.-732 CHICACO American Medical Association Five Hundred and Thirty-Five North Dearborn Street 1915 RCUo 1315 CARBOHYDRATE UTILIZATION IN DIABETES BASED ON STUDIES OF THE RESPIRATION, URINE AND BLOOD * ELLIOTT p. JOSLIN, M.D. BOSTON In the classical work of Naunyn^ on diabetes mellitus occurs the following passage : "In general, even in severe diabetes, at least in man, the carbohydrates ingested are not completely excreted in the urine again as sugar. A portion of the starch, as well as of the dex- trose, will be burned in the organism." This view was also shared by Kulz. Naunyn, however, refers to a case in which von Mering records an excretion of all the sugar ingested, and attention is called in the report of the cases of Kulz to four instances in which apparently a similar condition existed. Von Noorden^ defines diabetes as "a disease in which the capability of the organism adequately to burn grape sugar is pathologically lowered," and in another place^ he says : "One cannot help thinking that, in man, even when death has resulted from coma, the diabetes has not always been 'quite complete' — that is to say, the pathological processes which produce diabetes have not developed so far, and the factors which favor the storing up of glycogen have not been so com- pletely destroyed as is the case in a dog whose pancreas has been entirely ablated." Notwithstanding all the work on diabetes, this question of the utili- zation of carbohydrates in human diabetes has not been settled. In diabetic dogs evidence has accumulated pointing to the complete loss of this power to utilize carbohydrate, and the work of Alurlin and * From the Nutrition Laboratory of the Carnegie Institution of Washington, Boston. * I wish to acknowledge my grateful appreciation of the help received from Mr. Emmes, Miss Babcock, Miss Tompkins, Miss Corson and Miss Sandiford of the Nutrition Laboratory, as also my indebtedness to Mr. Higgins, who con- trolled several of the experiments with the Tissot apparatus, and to my secre- tary, Miss Helen Leonard, for cheerful work on long computations and puzzling charts. L Naunyn: Der Diabetes Melitus, 1906, p. 173. 2. Von Noorden : Zuckerkrankheit, Ed. 6, 1912. p. 2. 3. Von Noorden : Metabolism and Practical Medicine, 1907, iii, 542. Cramer* has given definite results on this point, although so recent a writer as Landsberg,^ working from a different point of view with other animals, comes to the opposite conclusion. The present paper is concerned with diabetes in man and I wish to call attention to certain observations bearing on this problem which are related to the body weight, the urine, the storage of carbohydrate in the body, the respira- tory metabolism of diabetics both fasting and following the administra- tion of food and the remarkable disappearance of acidosis in diabetics with prolonged fasting, which is associated with a rise in their respira- tory quotient. I. THE INFLUENCE OF WEIGHT ON THE DETERMINATION OF THE UTILIZATION OF CARBOHYDRATES IN DIABETES The changes in weight which occur in a normal individual, fol- lowing a slight increase of the carbohydrate in the diet, are so striking that one might hastily conclude that a study of the weights of a diabetic patient would give some idea as to his utilization of starch and sugar. A closer scrutiny of the problem, however, reveals many difficulties. In the first place, the diet employed in most cases of dia- betes and all severe cases, is low in carbohydrates, and seldom reaches 10 per cent, of that of normal individuals. In other words, it amounts to less than 50 gm. carbohydrate — 200 calories — per day. The effect of 200 calories on the weight is possible of determination theoretically, but practically such an experiment is difficult because the protein, fat and carbohydrate must be kept at uniform levels for a long period. But in a severe case of diabetes some of even this small amount is lost in the urine, which renders the available carbohydrate for increasing the weight still less. There are other complications. In a severe case of diabetes, the patient with 50 gm. of carbohydrate in the diet, usually excretes more than 50 gm. of sugar in the urine, and it is difficult to assign in proper proportion this excess of urinary sugar between the carbohydrate ingested and the carbohydrate already stored in the body on the one hand, and the protein simultaneou.sly ingested and the body protein on the other. Remarkable changes in the weight of normal as well as of diabetic patients will also occur, although the caloric value of the diet remains constant, if the proportion of fat to carbohydrate is altered. A diet rich in carbohydrate brings about an increase in weight, whereas a diet of exactly the same number of calories, although chiefly made up of fat, lowers the weight. These changes undoubtedly are due simply 4. Murlin and Cramer : Jour. Biol. Chem., 1913, xv, 365. 5. Landsberg: Deutsch. Arch. f. klin. Med., 1914, cxv, 465. to the retention of water by the tissues on a carbohydrate diet, and loss of water on a fat diet. Such changes appear reasonable because the storage of 1 gni. of carbohydrate in the body demands the retention of 3 gm. of water, 1 gm. of protein requires the storage of 0.75 gm. of water, and 1 gm. of fat requires only 0.1 gm. of water. These changes are well illustrated" by Table 1. TABLE 1. -Changes in Weight Under Fat and Carbohydrate Diets Carbohydrate Diet Food and Drink Body Weight kilos Gain (-f) Date Solid Matter gm. Water gm. Total gm. or Loss ( — ) gm. 4/lfi/04 4/16-17/04 4/17-18/04 4/18-19/04 970 966 966 3.577 3.5S3 3,491 V.547 4.519 4,457 75.086 75.443 75.414 75.269 +"357 — 29 — 143 Fat Diet 4/19-20/04 4/20-21/04 4/21-22/04 750 745 747 3,108 4.150 4,152 3,859 4,896 4,899 74.319 73.480 72.5.28 — 950 — 839 — 952 Average gain per day, carbohydrate diet, + 61 gm. Average loss per day, fat diet, — 914 gm. Water stored per day, carbohydrate period, + 165 gm. Water lost per day, fat period, — 906 gm. It is important for the clinician to bear this in mind, because it explains the rapid change in weight which often follows the initial diminution of the carbohydrate in the diet of diabetic patients and its replacement with fat. An increase in weight following a marked increase of carbohydrate in the diet is strikingly illustrated in severe diabetic patients under the oatmeal treatment.'^ Under these conditions the weight may rise 4.5 kg. in one or twp days. Undoubtedly you all have seen edema during the course of an oatmeal cure. It is significant that some of these cases show little or no carbohydrate in the urine. I cannot give proof that patients showing this increase in weight fail to give evidence of burning more than a trifling amount of carbohydrate, but from other similar cases I suspect this often to be the case. This point deserves further study. I think, however, that there will be general agreement that the gain in weight following the sudden introduction of large quantities of carbohydrate is accounted for by the storage — tempo- rarily, perhaps — of carbohydrate in the body. That this storage or delay of excretion is accentuated in the presence of diseased kidneys 6. Benedict and Joslin : A Study of Metabolisin in Severe Diabetes, Carnegie Institute of Washington, 1912, Pub. No. 176, p. 93. 7. Mirowsky: Deutsch. med. Wchnschr., 1912, xxxviii, 459. is common knowledge. Barrenscheen^ showed that milk sugar excre- tion was delayed on the day following an oatmeal cure. .The administration of sodium bicarbonate is frequently followed by a gain in weight. Thus,^ in Case 220, the changes in weight during the administration of sodium bicarbonate were as shown in Table 2. TABLE 2. — Changes in Weight During the Administration of Sodium Bicarbonate Date Sodium Bicarbonate gm. Body Weight kilos. Date Sodium Bicarbonate gm. Body Weight kilos. 11/2 11/3 11/4 11/S 11/6 20 48.1 48.6 49.0 48.6 49.3 11/ 7 11/ 8 11/ 9 11/10 11/11 20 20 20 20 20 S0.7 51.5 52.4 53.3 53.3 In order to show that this gain in weight was not directly due to the alkali, but rather to retention of salt, the weights of another dia- betic patient. Case 135, were taken while on a salt-free diet^° (Table 3). TABLE 3. — Changes in Weight on a Salt-Free Diet Intake Urine Date, 1908 NaHCOs Gm. Carb., Gm. Pro- tein, Gm. Fat, Gm. Alco- hol, Gm. Liquids c.c. Vol., c.c. N, Gm. NHs, Gm. Acetone and Diacetic Acid.,Gm. Beta- oxy. Acid, Gm. P2O5, Gm. 01., Gm. Sugar, Gm. W LI L/26 135 110 185 3,500 3,720 21.8 4.2 7.9 29 4.4 8.2 160 8€ L/27 135 UO 185 3,500 3,940 19. 0' 4.3 7.8 29 4.5 6.3 165 8S L/28 135 110 185 3,500 3,210 20.5 4.4 7.3 24 4.6 5.9 160 86 L/29 135 90 155 3,500 3,210 19.2 4.1 7.3 26 4.2 4.8 163 8S L/30 25 135 70 185 3,500 3,190 16.3 3.5 8.7 33 4.1 1.6 146 85 L/31 25 120 60 95 23 5,370 4,600 19.1 4-.3 12.6 51 5.1 2.3 146 8S !/l 37 130 100 130 45 5,250 4,050 18.7 3.3 10.7 39 4.3 2.0 137 82 !/2 52 70 60 95 45 5,370 3,510 16.0 3.5 10.2 37 3.9 2.1 121 81 !/3 •• 15 15 30 45 800 260 15.0 ... 86 It will be seen that while on the salt-free diet the weight steadily fell, and despite the administration of sodium bicarbonate later, no increase in weight occurred. This observation has been elsewhere con- firmed. I might here make the clinical observation that a salt-free diet in diabetes is inadvisable. It is also interesting that I have never 8. Barrenscheen : Biochem. Ztschr., 1912, xxxix, 232. 9. Benedict and Joslin : Loc. cit. (Note 6) p. 94. 10. Joslin and Goodall: Jour. Am. Med. Assn., 1908, li, 727. seen the death from diabetic coma of a diabetic patient who had dropsy, nor have I encountered such in the literature. The simple enumeration of these various facts affecting the weight shows how complicated is the determination of the utilization of car- bohydrate from it alone. Changes in weight, however, do afford, when combined with other methods of clinical investigation, new fields for work. The changes in weight which a healthy fasting man undergoes at the beginning of a fast are known. The fasting man at the Nutrition Laboratory lost 2,850 gm. in three days, and consumed during these three days body substance equivalent to 161 gm. of protein, 149 gm. of carbohydrate and 407 gm. of fat. It is possible that from a series of observations on diabetic patients similarly fasted, conclusions of value as to the storage of carbohydrate in the body might be secured. Ten of m)'- patients who were available for this purpose showed on an initial fast a loss of weight considerably less, and occasionally a gain in weight was recorded. Following the termination of the fast, although very little food was given, an increase in weight out of proportion to the amount of food given was almost invariably observed. In one case no mineral waters or alkalies were taken, and yet gain in weight occurred during fasting. It is not unexpected that the gain in weight was often coincident with a fall in the excretion of urine. A gain in weight during fasting raises the question as to whether new carbohydrate has not been formed in the body, and as a result of its formation water retained. This line of investigation deserves atten- tion. It will be referred to later in the discussion of severe cases of diabetes treated by prolonged fasting, the method which Dr. F. M. Allen" has had the courage to introduce and has so accurately defined that it is safe for any practitioner to employ. II. THE UTILIZATION OF CARBOHYDRATES BASED ON INTAKE IN DIET AND OUTGO IN URINE The comparison between the carbohydrate ingested and the sugar excreted in the urine is the common method of determining the utiliza- tion of carbohydrates. It would appear to be a simple procedure, but, as a matter of fact, the problem is far more difificult than has heretofore been considered. Your attention is first directed to the possibilities of error in reckoning the carbohydrate in the diet. Most severe diabetics under careful observation live on diets low in carbohydrate, seldom in excess of 50 em. Therefore errors of 5 gm. in the estimation of 11. Allen: Jour. Am. Med. Assn., 1914, Ixiii, 939; Boston Med. and Surg. Jour., 1915, clxxv, 241. carbohydrates, though actually small, are proportionately large. It is seldom that the actual quantity of carbohydrate in the diet has been analyzed. In many of the cases food has not even been carefully weighed, and approximate portions of food have been supposed to contain definite quantities of carbohydrate. Take, for ex^taple, cream: The quantity of carbohydrate contained in half a pint may vary 5 gm., making an error of 10 per cent., if the total carbohydrate for the day amounted to 50 gm., or 20 per cent, if limited to 25 grams. Vegetables constitute a considerable proportion of the diet of these patients with severe diabetes. Often in the literature — and I plead guilty to the charge — the quantity of carbohydrate in the mixture of vegetables chosen from those containing less than 10 per cent, carbo- h3'drate for the day, has been roughly estimated. Recently I have taken more careful account of the amount of vegatables eaten, and it has come out that the quantity of vegetables prescribed and eaten frequently varies from 300 gm. to 1,000 gm. Any accurate computa- tion, therefore, of a carbohydrate balance must be based not alone on the total quantity of vegetables eaten in the day, but on the actual quantity of each vegetable, even in these low carbohydrate groups. Furthermore, varieties of the same vegetable vary in percentage of carbohydrate. It makes a difference of 5 gm. in a day whether 500 gm. vegetables contain 1 per cent, more or less of carbohydrate. But this is not all. Analyses of carbohydrate in vegetables include the cellulose contained in them as well as the starch and sugar. How much shall we subtract from our total carbohydrate intake on account of this undigested cellulose which is lost in the feces? The other foods commonly used in the study of the metabolism of diabetic patients are potato, oatmeal, bread, fruit. The potato, oat- meal and bread are usually carefully weighed, and the analyses of these foods are fairly constant, but the percentage of carbohydrate is so large that I should not dare to be positive about the quantity of carbohydrate which my patient received unless standard varieties of these foods were employed. With fruit frequent errors exist, because usually an orange or grapefruit is allowed and seldom the actual weights of the portions eaten are determined. A further error occurs in that the intake of carbohydrate is reckoned indifferently as starch or sugar. As a matter of fact, 100 gm. of starch when converted to sugar amount to 105 gm. Errors of 5 and 10 gm. a day in computing the carbohydrate intake may easily occur and in a period of a week form notable amounts, from 35 to 70 gm. Physiologists and physicians must not take too seriously clinical statements about the carbohydrate in the diet, and greater accuracy must be employed in the future. We need, first, a standard test diabetic diet, and, second, we need to employ it for at least five days. Unfortunately, even at the end of this time the results may be unsatisfactory, because the condition of the patient's tolerance may have changed in this period either for better or worse. The estimation of sugar in the urine is far more accurate than that of the carbohydrate in the diet, provided the analysis is made in one of our best laboratories, but I would hesitate to accept as final in accurate computations many routine analyses made in private practice or in hospitals. Too often the method employed in the estimation of the sugar is not mentioned, and I suspect many results are obtained with the polariscope which may involve an error of 20 gm. or more, owing to the presence of levorotary bodies. Urinary analyses, how- ever, are usually far and away ahead in accuracy of that observed in the collection and measurement of the urines of diabetic patients. The admirable methods adopted in the ward of the Russell Sage Institute at Bellevue Hospital and at the Rockefeller Hospital have been seldom followed by experimenters in the past. I pass over errors of forgetful- ness or design on the part of the patients, as regards both diet and collection of urine. Dogs may not be any more honest, but we do not expose them to temptation or trust their memory. How often a patient states that a trifling amount of urine has been lost at stool! I realize this is trite, but a good share of the arguments based on the utilization of carbohydrate rests on data which are not above reproach. The variability of excretion of urine and urinary constituents from day to day is another source of error. If the diet is not constant the variation may be great. In one of our tests designed to determine the utilization of levulose, during seven days prior to the administration of levulose the average volume of urine was 1,079 c.c. On the day the levulose was given the volume of urine was 966 c.c, the next day 390 c.c, and on the following day it amounted to 1,175 c.c; it then returned to near the average quantity. Yet the habits of this patient's daily life were nearly constant, and except for the one levulose day changes in the diet were not extreme. Such marked variations in the volume of the urine on successive days must be reckoned with, because with such great changes in volumes of urine, the quantities of the constituents of the urine change too, though to a much less extent. In this same case, the average daily excretion of nitrogen for the fifty-five days which included this period was 7 .Z gm., but on the day when 81 gm. levulose were given with very little other food, it fell to 6.53 gm. and on the next day to 4.34 gm. This low point was never reached by this same patient on a fasting day, and the quantity of levulose is considerably less than would be supposed to exert so strong a positive action, particularly when delayed or diminished oxidation 8 is taken into consideration. Consult Table 4 and also chart of varia- tions in excretion of urine and sugar of a severe diabetic on a constant diet, shown further on. TABLE 4. — Effect of Levulose Case 785. Male, aged 17. Weight, 42 Kilos. Output Intake Vol., cc Diae. Acid Sugar, Gm. Nitrogen, , Gm. Ammo- nia, Gm. Garb., Gm. Prot., Gm. Pat, Gm. Alcohol, Gm. Calo- ries 1,079* + ll.lt 7.83 .... 17 58 127 9 1,506 966 + 7 6.53 0.69 90t 21 30± 3 735 390 ++ 5 4.34 0.35 20 63 110 9 1,385 1,175 + 3 8.35 0.74 20± 63 110± 9 1,385± * Average for previous seven days. t None on six days. X Levulose, 81 gm. Garb, in Diet 9 gm. in the form of vegetables. Experiments designed to test the utilization of carbohydrate should be conducted on patients who are in equilibrium both as regards weight and urinary excretion. III. THE IMPORTANCE AS V/ELL AS THE INFLUENCE OF CARBO- HYDRATE STORED IN THE BODY ON TFIE UTIILIZATION OF CARBOHYDRATE INGESTED It is well known that following a period of fasting large quantities of carbohydrate can be administered without subsequently appearing in the urine. The best illustration of this is von Noorden's oatmeal treatment. Thus Case R. of the Benedict and Joslin series^^ showed a positive carbohydrate balance of 520 gm. during an oatmeal cure, although he never after this cure became sugar-free save for occasional days, despite rigorous dieting. A more spectacular demonstration is the severe diabetic of Klemperer,^^ who took 100 gm. of glucose in divided portions during twenty-four hours without more than a few grams appearing in the urine. Almost as striking is that of a boy of 17 (Case 785) who came to me in the twentieth month of the disease. By consulting Table 4 it will be seen that only 7 gm. of sugar appeared in the urine following an intake at one time of 81 gm. levulose, although by observations before and after the tolerance was known to be low. A summary of his metabolism is given in Table 5. 12. Benedict and Joslin: Loc. cit. (Note 6) p. 57. 13. Klemperer: Therap. d. Gegenw., 1911, lii, 447. TABLE 5. — Summary of Metabolism in Cask Shown in Tablk 4* Case 785. Severe diabetes. Weight, 42 kilos. Male. Age at onset, 15. Duration since onset twenty months. Nitrogen Balance Carbohydrate Balance Period Urine and Feces Diet Urine Diet 55 days Daily average 440. 8.0 407. 7.0 190. 3.5 919. 16.7 8.9 .Sugar present in urine 20 days • Daily average 7.8 8.8 15.4 7.5 Sugar absent from urine 32 days Daily average 6.4 0.0 15.1 ' Nitrogen in feces estimated at 10 per cent, of nitrogen in diet. During the fifty-five days lie was under my observation the average daily nitrogen in the diet was estimated at 7.0 gm., and in the urine and feces 8.0 gm. The carbohydrate in the diet was 16.7 gm. and in the urine 3.5 gm. During thirty-two of the fifty-five days, sugar was absent from the urine and on twenty days it was present, although the average daily carbohydrate in the diet was the same. A study of Table 5 would suggest this being due to the slightly lower nitrogen intake on the sugar-free days. This is not quite justifiable, because another factor enters in — namely, starvation — for on several of the thirty-two days the patient received no food at all. These starvation days evi- dently played an important role. How very important is shown by the test already recorded in Table 4, where 81 gm. of levulose were administered and only 7 gm. carbohydrate appeared in the urine. Is it possible for the body to store so large a quantity of carbo- hydrate as 520 or even more grams ? Furthermore in what form may it be retained in diabetic patients? Nearly all experiments on the utilization of carbohydrates in the past have been based on the difference between the carbohydrate intake and the carbohydrate excreted. Unless the amount of the carbo- hydrate stored in the body is known, it is unjustifiable to say that the carbohydrate excreted represents a part of that ingested during the same twenty-four hours. All data in reference to the D : N ratio are confused by the possibility of stored carbohydrate. The impor- tance of the storage of carbohydrate thus becomes evident. The influence of carbohydrate so stored in the body is also great. Whatever virtue the oatmeal cure possesses, all agree that it depends 10 in major part on preceding starvation, which has tended to exhaust the carbohydrate depots of the body. Glycogen. — Carbohydrate is stored in the body in various ways but most of it is supposed to be in the form of glycogen, and this is about equally divided between the liver and the muscles. An old estimate of Bunge that the body had 400 gm. is roughly approximated by experi- ments on fasting men and professional athletes doing severe work without food. This figure may be taken as a fair average, but there are enormous variations. This statement is based on glycogen which has been shown to be burned; it does not exclude the possibility of some glycogen still remaining in the body, and in fact Benedict says : "It would appear that the estimate of 400 gm. of glycogen for the content of the body is if anything too small rather than too large." Experiments on fasting men show that they may burn from 93 to 232 gm. in the first three days.^*' ^^ In diabetic patients the quantity of glycogen is universally considered to be far below this amount, but Frerichs^^ found, on puncturing the liver of two diabetics, a small amount of glycogen in one and a considerable amount in the other, and Kulz^'^ found from 10 to 12 gm. glycogen in the liver of a diabetic who had been for a long time on a diabetic diet. Examinations of the tissue removed from the livers of living diabetic patients show appre- ciable quantities of glycogen, and it is the experience of pathologists that the organs of diabetic patients contain more than traces of glyco- gen. It is most unfortunate that no data exist which enable us to determine what this minimum is. It is quite conceivable that although it might be extremely small at any one moment, a small quantity might be frequently formed and destroyed, and the sum of these small quantities reach a substantial amount in twenty-four hours. The recent work of Helly^® throws new light on the problem. He points out the striking contrast between the constant presence of gly- cogen in the liver of human diabetes and the very small quantity which is found in the severe diabetes of depancreatized dogs, yet even in the latter the power of the liver to form or deposit glycogen is shown when levulose is administered. If a milder form of diabetes is pro- duced in the dog more glycogen remains in the body and there is a closer resemblance to human diabetes ; whereas with total removal of the pancreas there was only 0.065 per cent, of glycogen in the liver. 14. Benedict: The Influence of Inanition on Metabolism, Carnegie Institute of Washington, 1907, Pub. 77, p. 464. 15. Benedict : A Study of Prolonged Fasting, Carnegie Institute of Washing- ton, 1915, Pub. 203, p. 251. 16. Frerichs : Ueber den Diabetes, p. 272 ; cited by Nehring and Schmoll (Note 34). - 17. Kulz: Arch. f. d. ges. Physiol. (Pfliiger's), 1876, xiii, 267. 18. Helly: Ztschr. f. exper. Path. u. Therap., 1914, xv, 464. 11 • On the other hand, with partial removal, even though there be 8 to 10 per cent, of sugar in the urine, there v^as 0.3 per cent, of glycogen. By microscopic examination . so considerable a quantity as this appeared small. Blood Sugar. — Sugar is also stored in the body in the form of blood sugar. The normal quantity of sugar in the blood of healthy indi- viduals varies between 0.07 and 0.11 per cent, and for convenience in calculations may be considered 0.1 per cent. This rises quickly after a meal rich in carbohydrates, but soon falls to its former level. In fifty- five observations on fifteen of our diabetic patients the percentage of blood sugar varied from 0.12 to 0.36 per cent. But the blood of these diabetic patients does not behave like that of normal individuals fol- lowing the ingestion of food. It is true that the percentage of sugar rapidly increases following a carbohydrate meal, but it does not as rapidly fall, and in my own experience most diabetic patients, even after prolonged fasting, show values for blood sugar which are far above normal. Certain types of diabetic patients — namely, those with disease of the kidneys — are especially prone to maintain high per- centages of sugar in the blood for many days after their urines have become sugar-free. It is impracticable to consider that the percentage of blood sugar is maintained independently of the other tissues in the body — first, because the percentage is so unstable ; second, because there is no constant relation between the sugar in the blood serum and the sugar in the total blood, and third, because the capacity of the blood for storage of sugar is so slight. If we assume an individual of 70 kilos body weight and consider that 7 per cent, of the weight is made up of blood, we have 4.9 kilos of blood with a normal sugar content of 0.1 per cent. This would amount to 4.9 gm., even taking the highest for the normal individual, and should we take the highest figures we have encountered even after the administration of food with our diabetic patients, namely 0.36 per cent., the total quantity of sugar stored in the blood would not be far from 18 gm. — a trifle more than a half ounce. Falta^'' has called attention to the slow return of the blood of dia- betic patients to its former sugar level, and emphasizes this point as of fundamental importance in diabetes. He points out that the dis- turbance of blood sugar utilization is not the same as the disturbance of glycogen formation for the blood sugar regulation may be inter- fered with when the glycogen formation is not. Kleiner and Meltzer-° have also beautifully shown this same dif- ference in depancreatized dogs. Whereas, following the injection of 19. Falta: Med. Klin., 1914, x, 9. 20. Kleiner and Meltzer : Proc. Soc. for Exper. Biol, and Med., 1914. xii, 58. 12 4 gm. dextrose per kilo weight, the sugar in the blood of normal dogs increases fourfold — namely, from 0.20 per cent., to 0.79 per cent. — and that of depancreatized dogs threefold — from 0.38 per cent, before to 1.19 per cent, after the injection — the blood sugar of the former returned nearly to normal at the end of an hour and a half,\vhile the diabetic dogs even then showed 0.86. It is significant that in these experiments the quantities of sugar excreted in the urine were prac- tically the same. Interesting as these figures are from this point of view, from another they are still more interesting. It is impossible to account for all the sugar ingested by adding together the sugar found in the blood and that in the urine. Where did the sugar go ? You may say it was burned, and this possibility, though not probability, must be admitted in the normal animal, but no one would contend this to be wholly the case in the depancreatized animal. At the Nutrition Laboratory we have been able to carry these experiments to their logical conclusion, for we have had the oppor- tunity to determine the respiratory quotient following the administra- tion of levulose to severe diabetics. In Table 20 will be found a report of the effect of levulose when administered to severe diabetic patients in amounts to 2.51 gm., 2.42 gm. and 1.95 gm. per kilogram body weight. In the first and third cases there was no increase in the respiratory quotient. A considerable portion of the levulose was probably excreted in the first case, but in the third little or none. The explanation of this difference in behavior in the storage of levulose is probably that the first patient had not fasted beforehand and that the third had been on a low carbohydrate diet for a long time ; this is con- firmed by the second case, in which also little of the levulose was excreted when administered following a period of strict dieting. An increase in the respiratory quotient occurred in this case, but it was so slight as to preclude any considerable quantity of the sugar having been burned. It should also be recorded that in all the cases the levulose was given at one time and not spread out through the twenty- four hours, as in Klemperer's test. This gives added emphasis to the possibility of the presence of an empty storehouse for carbohydrate in the body. I also have evidence that the gradual administration of carbohydrates is of little value, provided the body is not prepared to retain it. Following etherization a patient (Case 808), while fasting for the first twenty-four hours was sugar-free, but on the next day, although only 2 gm. carbohydrate per hour were administered, he excreted practically all of it, although formerly his tolerance amounted to 50 gm. carbohydrate. The small amount of glycogen and the still smaller quantity of blood sugar represent an amount of carbohydrate far too low to 13 account for the phenomena above described in diabetes. Other sources for storage of sugar in the body must be sought, as has been empha- sized by Ivar Bang. If we should assume tliat the percentage of sugar in the blood was the same for all the fluid in the body, certain amounts of sugar might be stored in this manner. While such an assumption is not wholly justifiable, it has some basis, for we know that sugar exists in the spinal fluid of diabetics, as well as in other fluids. In normals Dr. Jacobson tells me that he has not found it so closely to follow the blood, but the opposite was true in his cases of diabetes mellitus. It gets into the blood and cannot seem to get out. Notable percentages of sugar, not very different from those in the blood, have been found in pleuritic and ascitic fluids, and Husband found even 0.7 per cent, in the amniotic fluid. There is some doubt about its presence in sweat, but we do have a record of sweet tears. Yet granted that the assumption is correct, we cannot increase our storage capacity very much that way. For example, assuming the total quantity of fluid in the body as 60 per cent, of the body weight of 70 kg., we have 42 kg. of body fluid, from which we must deduct 4.9 kg. already reckoned as blood. This leaves us a remainder of 37.1 kg. of fluid in the body, and using the highest figure^O.36 per cent. — for blood sugar which we have encountered, the quantity of sugar in this mass of fluid would be only 133 gm. This is not enough relatively to explain Kleiner's and Meltzer's experiment. Another source for the formation, although perhaps not for the storage of carbohydrate in the body, has long been recognized in pro- tein. The close connection which is maintained between protein and carbohydrate in diabetes would make a clinician with modest chemical knowledge seek for some combination of carbohydrate in the protein molecule — some arrangement by which a portion of the sugar molecule could be stored in protein or given up as occasion arises, just as water is squeezed out of a sponge. Good chemists, and I have asked many, assure me that even with glucoproteins sugar can be extracted from the protein molecule only when the molecule itself is disintegrated. The large quantity of movable protein and fat in the body suggests a large carbohydrate reservoir, too. Few realize how large this quantity of movable protein is. It has been shown by Albert Miiller-^ that by overfeeding, 210 gm. of nitrogen, the equivalent of 1260 gm. of body protein, in turn the equivalent of 6.3 kilos of muscle tissue, can be retained by the body, and conversely, it has been shown by Benedict^^ that even more — 277 gm.— can be removed. This movable protein amounts to about one-third of the total body protein. The readiness 21. Miiller: Zenlralbl. f. d. Ges. Phvsiol. u. Path. d. Stoffswechs., 1911, vi. 617. 14 with which fat can be increased and decreased in the body is univer- sally recognized. Although we are not allowed to say that carbohydrate can be extracted from the protein molecule, leaving it intact, we do know that in severe diabetes sugar can be formed out of protein. Professor Lusk-^ has demonstrated this in completely depancreatized dogs and in his now famous diabetic patient, 3.65 gm. dextrose appeared in the urine for each gram of nitrogen therein contained. This represents approximately 60 gm. dextrose for each 100 gm. protein. If we should assume that in diabetic patients there were 1,200 gm. movable protein, this would furnish a possible source of 720 gm. more of car- bohydrate. Unfortunately one cannot be sure that in the disintegration of the protein molecule the nitrogen and carbohydrate leave the body hand in hand. As a rule, the nitrogen loiters behind, greatly to our annoyance in estimating the source of the sugar in the urine. Mendel and Lewis^^ have recently shown that this delay was increased if either indigestible substances or cotton seed oil form a prominent part of the diet — just the sort of foods which our diabetic patients eat. Con- sequently if an attempt to determine the quantity of carbohydrate from protein (dextrose nitrogen ratio D: N) is made, this irregularity in the excretion of nitrogen must be considered. When one adds to this difficulty that of determining what share the quantity of residual carbohydrate in the body bears to the total sugar excreted, and when one considers that even under an absolutely uniform diet of 1,000 gm. meat and 1,750 c.c. fluid intake for fifteen days Naunyn^* found variation of sugar excretion from 12 gm. to 43 gm., and frequently of 100 per cent., I feel very modest about asserting that my patients are producing any given quantity of sugar for each gram of nitrogen excreted. Naunyn says that these spontaneous variations may reach even 70 gm. Kulz has emphasized this same point. If under ideal con- ditions for fifteen days such variations exist, it behooves one to accept with caution reported D : N ratios for a period of a few days as being of value or to base arguments, as is sometimes done, on the D : N ratio of single isolated days selected from a series. In the tables of Rumpf, Allard, Hesse, and some of Liithje's, D: N ratios are recorded which Professor Lusk and I would feel indicated a far larger per cent, of carbohydrate coming from protein than is actually the case. It is arbitrary selection to pick from these tables all ratios above 3.65 : 1 and say they are wrong and to class the remainder as correct. It is 22. Mandel and Lusk: Deutsch. Arch. f. klin. Med., 1904, Ixxxi, 472. 23. Mendel and Lewis: Jour. Biol. Chem., 1913-14, xvi, pp. 19, 37. 24. Naunyn: Des Diabetes Melitus, 1906, p. 183. 15 furthermore remarkable that with fasting all IJ : N ratios cease to exist. It is also hard to understood how a patient one day fails to burn the protein of an ox, but the next day burns his own body protein with ease. Fasting diabetics will afford unusual opportunities to study this point. As a rule, the high D : N ratios are found when the nitrogen excretion is high, and it may be tiiat to produce these high ratios large quantities of protein may be required. VoluTue Sugar Nove-mber Dece-mber I e.e. em. 23 24 25 26 Z7 Z8 29 1 50 1 2 3 4 5 6 1 1 2 150 zioo 2050 2000 1950 1900 1850 1800 17 50 1700 1650 1600 1550 1500 14 50 1400 1350 1300 1250 1200 1150 MOO 1050 lOQO 42 40 38 36 34 32 30 28 26 24 22 ; 20 18 16 14 12 10 I \ \ / \ N / \ 1 / \ / 1 \ / \ / \ 1^ \ I ll V j \ 1 \ ' 1' 1 ll 1 1 1/ 1' T L 1 / \ i i^ V, 1 11 f V \ f \ \ / < / 1, 1 > >.. J r J 1/ \ 1 1 R / > \' / j \ / ^ / 1 If Y / 1 1 / '\ / 1 \ 1 1 _ __ Chart illustrating variations in excretions of urine and sugar of a severe diabetic on a constant diet (from Naunyn). Diet constant 1,000 gm. meat, 1,750 c.c. fluid. Line composed of dots and dashes indicates c.c. urine in twenty- four hours ; continuous line, gm. sugar in twenty-four hours. The small part which the blood plays in the storage of carbo- hydrate has been pointed out. This is peculiarly unfortunate because one would hope from the percentage of sugar in the blood to derive some knowledge of the course of metabolism in dis.betes. As if to emphasize the independence of the metabolism to the content of sugar in the body, I submit at this point Table 6, which gives the respira- tory quotients obtained upon individuals whose blood sugar was deter- 16 mined at the time of the test, reserving discussion of the same to a later portion of the paper. TABLE 6. — The Blood Sugar and Respiratory Quotient in Severe Diabetes ^ Case No. 806 806 786 806 765 810 806 765 765 714 786 765 773 773 746 746 786 Condition Fasting Fasting Fasting After potato (60 gm. carb.) I'asting Fasting After one egg and 200 gm. vegetables Fasting Fasting Fasting After oatmeal (60 gm. carb.) After oatmeal (10 gm. carb.) and potato (48 gm carb.). Fasting After oatmeal (80 gm. carb.) Fasting After oatmeal (40-60 gm. carb.) After oatmeal (120 ± gm. carb.) Per cent, of Sugar in Blood 0.12 0.14 0.17 0.18 0.18 0.19 0.19 0.23 0.24 0.25 0.25 0.26 0.27 0.30 0.30 0.36 0.36 R. Q. 0.71 0.68 0.69 0.69 0.74 0.72 0.72 0.76 0.73 0.78 0.74 0.74 0.70 0.70 0.70 0.74 0.83 IV. THE RESPIRATORY METABOLISM AND ITS RELATION TO THE UTILIZATION OF CARBOHYDRATE An examination of the composition of the carbohydrate molecule will show that it contains sufficient oxygen to unite with all the hydro- gen present. Consequently, for each volume of oxygen used in the oxidation of carbohydrate a volume of carbon dioxid will be produced. The relation which the volume of carbon dioxid produced bears to the oxygen required for the oxidation of a food constitutes its respiratory quotient. It is obvious, therefore, that the respiratory quotient of such a carbohydrate as glucose (CeHjoOe) is 1. It matters not whether the oxidation takes place rapidly outside of the body in a flame, or less obtrusively in the body during twenty-four hours. Pro- tein, on the other hand, does not contain sufficient oxygen for the hydrogen atoms contained in its molecule. As a result, in the burning of protein, oxygen must be used not only for the carbon in the mole- cule, but for the hydrogen as well. The denominator of the fraction is thus increased, and the respiratory quotient of protein must be less than 1, and is 0.81. The protein molecule is made up of many component parts and while the respiratory quotients of these parts vary greatly, yet for protein as a whole the foregoing quotient, 0.81, holds. With fat a similar condition exists to that in protein, only there is still more hydrogen present to require oxygen, so that the amount of oxygen necessary for the combustion of fat is still greater, and as a result the respiratory quotient falls to 0.70. The respiratory quotient of alcohol is still lower, namely, 0.67. Beta-oxybutyric acid, which can be taken 17 as the chief one of the group of acid bodies formed in diabetes, has a respiratory quotient of 0.89, diacetic acid has a respiratory quotient of 1.00, and acetone of 0.75, so that one will not go far astray to take 0.89 as a common respiratory quotient for these three acid bodies. The respiratory quotient of an individual can be determined by measurement of the quantity of carbon dioxid exhaled and the oxygen absorbed. When this is done, information is obtained concerning the character and total amount of the combustion taking place in the body. Since the urinary nitrogen gives us a definite idea of the quantity of protein metabolized, if we calculate what this represents and subtract it from the total material burned, we have left the combustion derived simply from fat and carbohydrate. When the respiratory quotient of fat and carbohydrate, as well as that of the individual, is known, it is possible, by computation, to determine the share which these two variables have taken in the total metabolism. TABLE 7. — The Respiratory Quotient (R. Q.) of a Food is Obtained BY Dividing the Volume of Carbon Dioxid Produced During Its Oxidization by the Volume of Oxygen Absorbed Volume of Oxygen Absorbed Carbohydrate: CoHiaOe + 6 O2 = 6 CO2 +6 H2O Oxygen is required for oxidation of carbon alone 6 CO2 produced 6 O2 I'.bsorhed Fat: CsiHioiOg Oxygen required for carbon and a large quantity of hydrogen. Protein : Occupies an intermediate position Alcohol: CoHeO B eta-0 xybiityric acid : C4H8O3 Diacetic acid: C^HeOs Acetone: CaHeO R. Q. 1.00 0.71 0.81 0.67 0.89 1.00 0.75 The Technic of the Determination of the Exchange of Carbon Dioxid and Oxygen in Man. — Two types of apparatus are employed to learn the exchange of carbon dioxid and oxygen in man ; the calorime- ter and respiration apparatus. In the closed chamber of the calorime- ter the oxygen admitted and the carbon dioxid withdrawn can be accurately determined in periods usually of one hour's duration, but it is better to take the average of the results obtained in three succes- sive periods. Occasionally each period may be shortened to three- quarters of an hour, exceptionally to half an hour, but tlie large size of the calorimeter increases the chances for error. The calorimeter is cumbersome, expensive to construct and to maintain, and the length of the experiment is not only disagreeable to the patient, but disad- vantageous in studying the results of rapid changes in the metabolism, which are desirable in a study of the utilization of foods. On the other hand, the respiratory apparatus is advantageous because the exchange 18 of gases can be determined during short periods of fifteen minutes. It is disadvantageous, however, because, the periods being so short, errors at the beginning and end of the periods are magnified and because the individual must breathe through a nosepiece or mouthpiece, and this introduces an abnormal state. Unfortunately, in each form of apparatus, the error of a leak falls chiefly on the oxygen, because the patient and the apparatus constitute a closed circuit, and any diminution in gas in this circuit must be offset by the addition of oxygen. A more troublesome source of error and one difficult to avoid arises from the possibility of the patient exhaling carbon dioxid, which has previously accumulated in the body, at a more rapid rate than corresponds with the oxygen inhaled. The patient is said to "pump out" carbon dioxid. There is also another error due to carbon dioxid which is lost by cutaneous respiration, and it has been calcu- lated that this would lower the 'quotient 0.01 to 0.15. Many pitfalls, therefore, lurk in the determination of the respira- tory exchange of an individual. The carbon dioxid is the more easily estimated of the two gases and in early experiments on metabolism investigators attempted this alone. The determination of oxygen is far more difficult. Hence, in dealing with the respiratory quotient, which depends on the relation of these two determinations to each other, one treads on very dangerous ground, and all statements regard- ing the respiratory quotient of individuals must be accepted with caution. The general picture of the respiratory quotient in an individual is far more valuable as a guide to his true metabolism if based on several experiments than is the result of a single experiment. Similarly, it is probably safer to average the results of a series of cases than to attach too much importance to figures obtained in one. -The Respiratory Quotient of the Normal Individual. — The respira- tory quotient of the normal individual is best determined at least twelve hours after a meal. It has been shown that if this rule is not followed the composition of the meal will have a marked influence on the result. Under these circumstances the respiratory quotient of normal individuals does not greatly vary. Benedict, Emmes, Roth and Smith^^ working at the Nutrition Laboratory of the Carnegie Insti- tution, have studied the basal gaseous metabolism for 89 men and 68 women and their average results are shown in Table 8. I would call attention to the slight difference existing between the respiratory quotient of men and women — 0.83 and 0.81. I have also incorporated the heat production, calculated from the oxygen intake, which was approximately 25 calories per kilogram per twenty-four hours. This latter figure is lower than we are apt to consider, but it 25. Benedict, Emmes, Roth and Smith: Jour. Biol. Chem, 1914, 18, 139. 19 should be remembered that it is based on fasting periods when the patient is purposely endeavoring to be quiet. It would be absolutely wrong, from such determinations covering periods of fifteen minutes, or even a few hours, to draw conclusions on the total heat production for the day. In illustration of the method and at the same time of the difficulties of determining the respiratory quotient of normal individuals I give the figures in my own case (Table 9). TABLE 8. — Respiratory Quotient and Total Metabolism of Normal Individuals at Rest at Least Twelve Hours After the Last Meal Individuals R. Q. Calories per Kilo per 24 Hours 89 men 68 women Average = 0.83 Average = 0.81 2S.S 24.9 TABLE 9. — Respiratory Quotient of a Normal Person Normal individual (E. P. J.) fasting experiment. December 23, 1914. Weight, 64.9 l 10 60+ 6 66 1 3 0.68 •i 0.71 * 48 gm. carb. as potato 1 10 gm. carb. as oatmeal [ 63 gm. Later in day, 22 gm. carb. as potato and vegetables 5 gm. carb. as cream J - Also 1 egg and 30 gm. butter. t 60 gm. carb. as potato. Later in day, 1 egg, butter, 6 gm. carb. as vegetables. there was an increase of three points in the respiratory quotient, indi- cating a slight utilization of the levulose and there was no excretion of levulose of account. It was possible to determine the effect of the administration of potato in two cases. In the first case the experiment was complicated in that the patient was given a small quantity of oatmeal at the start, which, however, was stopped on account of her dislike to it, and potato was substituted. In this case. No. 765, no change in the respiratory quotient took place, but in the second. Case 806, a slight increase was noted, and apparently rather more than would be accounted for by the limits of error. Eleven experiments have been carried out on cases of severe dia- betes with oatmeal. These were arranged in some cases to determine the immediate effect of the administration of oatmeal, and in other cases to determine the effect of the prolonged administration of 35 TABLE 22. — Effect of Potato on thk Respiratory Quotient of a Severe Case of Diabetes Case 806. Male. Weight 62 kilos. Date 12/22/14 Condition 002 per Oi per Min., Min., c.c. c.c. R. Q. Cals. Blood per Kilo Sugar per 24 Hrs. Per Cent. 25 I 54 22 45 55 59 22 55 00 26 54 45 Fasting. Potato = 60 gm. carb. 166 150 155 181 168 172 170 157 166 223 224 228 257 252 250 233 227 231 0.70] O.67I0.6S 0.681 24 1 24 24 27J 261 25 [25 25J 0.18 TABLE 23. — Effect of Oatmeal on the Respiratory Quotient of a Severe Diabetic Case nz. Female. Weight 40 kilos. Date Condition CO2 per Min., c.c. O2 per Min., c.c. E. Q. Cals. per Kilo per 24 Hrs. Blood Sugar Per Cent. 10/10/14 8:00 11:00 Fasting Oatmeal = 42 gm. carb. 146 178 212 , 9.49 0.69 ^.72 36 43 10/13/14 8.00 11:00 Fasting 138 189 0.73 S3 0.32 0.27 0.27 0.30 0.34 10/19/14 9:00 12:00 Fasting Oatmeal =: 80 gm. carb. 135 167 195 •'37 0.70 0.70 34 40 10/20/14 After breakfast Diet contained 15 gm. carb. October 9 and October 18. TABLE 24. — Effect of Oatmeal on the Respiratory Quotient of Severe Diabetics Duration Date Carbohydrates Ignited Respiratory Quotient Sugar in Urine, Gm. Carb. Intake, Carb. Bal- ance, Gm. « Onset to Coma, Months Month of Test No. Day Preced- ing, Gm. Before Test Gm. Fast- ing After Oat- meal 194 •34 31 9/22 15 0.74 42 15 —27 9/23 ' 15 100-)- 0.71 0.71 50 165 -ms 9/24 165 ... 0.72* .... 19 15 —4 246 15 11 8/ 9 50 40 0.71 0.67 124 ? ? 13 10/29 65 60 0.68 0.70 100 125 -f25 10/30 10/25-31 125 71 ... 0.71* 0.69 .... 93 102 65 72 —28 —30 281 19 17 12/ 1 15 0.75 69 135 +66 12/2 135 29 .... 0.76* 58 45 —13 12/ 3 45 0.76 38 I 30 —8 332 28 13 24 5/19 5/26 4/2 100 96 ? 25± 52 0.73 0.74 ' 0.73 0.74 15 in 3 brs. 3 in 3 hrs. 97 26 6/ 2 ? 48 71 0.69 36 336 132 127 5/18 20 0.73 .... 26 45 -H9 5/21 45 25 0.75 SI 45 +14 441 11 9 9/29 15 75 0.70 0.71 65 165 +100 10 10/ 9 15 73 0.69 ?■ 79 ' 561 33 23 2/ 7 60 ... 0.75. 31.1 60 +30 2/ 8 60 116 0.71 0.74 128.4 185 +57 2/ 9 185 200 0.72* 0.72* 209.3 205 —4 2/10 200 ... 0.76t .... 101.86 60 -42 591 50 44 4/10 V ... 0.74 63 30 —33 4/11 30 0.73 37 15 —22 4/12 15 80 0.70 0.70 85 165 +80 4/13 165 80 0.73* 0.69* 77 165 +88 4/15 40 0.69 29 ■I 773 20 18 10/ 8 115 70 0.70 175.6 165 —10 10/10 15 47 0.69 0.72 95.4 130 +35 10/13 50 ... 0.73 83.97 50 —34 10/19 15 80 0.70 0.70 96.50 115 +18 746 ■ 22t 18 10/ 7 65 28 .... 0.73 93.11 65 —28 10/ 9 15 50 0.73 0.71 86.69 163 +76 10/10 165 0.72* .... 34.88 25 —10 10/15 165 80 0.74t 96.28 165 +69 786 171 14 11/12 15 . 60 0.69 0.73 62 +62 * R. Q. taken following an oatmeal day. t R. Q. taken subsequent to two oatmeal t Prior to March, 1915. days. 37 oatmeal. It will be seen from a study of the tables that as a rule the respiratory quotient remained stationary or fell ; in one case it rose 4 points, and in two other cases it rose one point. It will be noted further that the respiratory quotient, when taken fasting on the morn- ing following an' oatmeal day, amounted in three cases to 0.73, 0.72 and 0.73 respectively, and that on the morning following a second oatmeal day it was 0.69 and 0.76. The respiratory quotient was also deter- mined in three experiments after the administration of carbohydrate and on the second day it was 0.72. If one looks at the table as a whole, it will be seen that little change in the respiratory quotient took place: in fact, none of any account except on the morning following the second oatmeal day. The sum total of the results following the feeding of levulose, potato and oatmeal to severe diabetics affords little evidence, from the respiratory quotient, that the carbohydrate was burned, save in the case of one of the experiments with levulose, one with potato, and one with oatmeal. There results correspond closely with what has been recorded in the literature. Personally, I believe that before a final decision on this point can be reached from this particular line of study, further experiments must be performed. Unfortunately in the experiments recorded no stated agreement was noted between changes in respiratory quotient and variations in the quantity of blood sugar. From Table 6 it is evident that there is a general tendency for the respiratory quotient to rise with an increase in blood sugar, but this may be accidental. Studies now in progress will soon throw light on this phase of the question. ■V. ACIDOSIS AS A MEASURE OF THE UTILIZATION OF CARBOHYDRATES It has been generally accepted that acidosis will appear when carbo- hydrate food is either withdrawn from the diet or excreted in the urine. It has been unquestionably the universal clinical experience that the patient who excretes quantities of sugar in the urine equal to or in excess of that in the diet exhibits acidosis, and that patients do not show acidosis who are able to utilize approximately 70 gm. of carbohydrate, or large quantities of protein from which carbohydrate may be formed. This statement cannot be so unqualifiedly made, because I have under observation a woman who in her sixth month of pregnancy showed over 6 per cent, of sugar, and later under a careful diet became sugar-free, acquired a tolerance for approximately 100 gm. of carbohydrate, and yet a slight acidosis persisted. Neverthe- less, the general mass of evidence points to the disappearance of acid- osis when carbohydrates are burned, and on this general concept arguments have been based for and against the utilization of carbo- hydrate in severe diabetes. 38 During von Noorden's oatmeal treatment a considerable quantity of carboh3'drate ingested is usually retained or burned in the body, and the decrease of acidosis at the same time is usually considered evidence of the latter supposition being correct, but occasionally the acidosis persists although the carbohydrates are not excreted. I doubt if we are in a position to accurately explain the disappearance or non- disappearance of acidosis under these conditions. Oatmeal and other carbohydrates are better retained in the body following starvation, and it is quite possible that a mechanical retention of acid bodies goes hand in hand with the retention of carbohydrate. Magnus-Levy pointed out long ago that these were seldom excreted in concentration of more than 1.5 per cent., and that the fall in acidosis during an oatmeal cure may be simply apparent, because the volume of urine excreted has diminished. The influence of preceding fasting is also important, because this undoubtedly regulates to some extent the storage of car- bohydrate. Despite these possibilities, which lessen any argument for combustion of carbohydrate based on the decrease of acidosis follow- ing the ingestion of carbohydrate, the slight amount of acidosis which is usually found when diabetic patients are on a full carbohydrate diet points strongly to the view that some carbohydrate is burned. The increase in respiratory quotient 'on the last days of an oatmeal cure, which Falta observed and we also have noted, is conformatory to this position. Various writers have observed that the acidosis in diabetics decreases on a vegetable day or fasting day, but it remained for Allen to demonstrate conclusively the remarkable fact that acidosis vanished in practically all severe cases of diabetes under these conditions, and that in the remainder, if carbohydrates to a moderate extent are allowed temporarily the acidosis wholly clears up. If a normal indi- vidual fasts, it has been the universal experience of observers that acidosis appears. In other words, the normal fasting individual cor- responds with the concept that when carbohydrates are withdrawn from the diet (and this implies carbohydrates which might be formed from protein) acidosis appears. Thus, in the fasting man at the Nutrition Laboratory, acidosis appeared on the second day and con- tinued until the fast was terminated. How can we reconcile the appar- ent contradiction in the fact that fasting, which dissipates acidosis in diabetes, produces it in normal individuals ? Must the prevalent concep- tion be given up that carbohydrate oxidation and acidosis are unrelated and must we acknowledge that here is an instance where the absence of the burning of carbohydrates does not lead to acidosis? Such a con- clusion appeared unavoidable until observations at the Nutrition Labo- ratory on severe diabetics during prolonged fasting began to accumu- 39 late, showing that whereas at the beginning of the fast the respiratory quotient was the ordinary respiratory quotient of severe diabetes, 0.72, with a continuance of the fast this had a tendency to rise several points, occasionally even to the neighborhood of 0.80. Later experi- ments, as yet unpublished, at the Russell Sage Laboratory made under the direction of Dr. DuBois and Professor Lusk on one of Dr. Allen's patients suggested a similar condition. In other words, whereas the normal individual showing acidosis exhibits a respiratory quotient based on the combustion of protein and fat alone, the severely affected diabetic during fasting shows a respiratory quotient which could be accounted for only by the combustion of notable quantities of material other than fat and protein. That this material was not protein was evident, because the amounts of nitrogen in the urine excreted during these periods were not abnormal. This increase in the respiratory quotient furnishes the explanation of the fact that the severely afTected diabetic in contradistinction to the normal individual, shows no acidosis during a fast. Several explanations for this increase in the respiratory quotient of fasting diabetics are available. During fasting the diabetic may be able to draw on sources of carbohydrate in the body which the norm.al individual cannot. Furthermore, the diabetic has in the body undoubt- edly more carbohydrate stored than we have hitherto supposed, and the supposition must be entertained that the diabetic really may actu- ally have more carbohydrate in some form in the body than exists in the normal individual. A third supposition for the increase in the respiratory quotient is that considerable quantities of acid bodies have accumulated and that with the improvement of the condition of the patient during fasting these are burned. It will be remembered that beta-oxybutyric acid, diacetic acid and acetone all have relatively high respiratory quotients, namely, 0.89, 1.00 and 0.75 respectively, and therefore the oxidation of a small quantity of these substances would markedly raise the respiratory quotient. Which of these suppositions is correct will be eventually known because of the improved methods of estimating carbohydrate and acid bodies in the blood, fluids and tissues of the body,^** and also by the help which is afforded from the estimation of the carbon dioxid tension of the blood. I should like to point out this further possibility : During prolonged fasting, acidosis tends to disappear, in part because the sources of the acid bodies, save for body fat and protein, have been eliminated. So soon as acidosis begins to decrease, there is, as we and others have found, a lessening of the total metabolism, and with this lessening of total metabolism an improvement in the combustion of carbohydrate 39. Marriott : Jour. Am. Med. Assn., 1914, Ixiii, 397. 40 takes place. This in turn favors the combustion of acid bodies. It might well be that the first step to take in the treatment of a case of diabetes is to abolish acidosis completely. All may be ready to concede that all diabetic patients under fasting conditions are burning carbohydrates, but some may say t'hat the character of the disease has changed, and instead of being a severe type of diabetes the case has become one of moderate severity. Such a criticism is hard to answer. It presupposes, however, that an indi- vidual can readily change in the space of a few hours from a state in which death is imminent to one of safety, and that so fundamental a function as the loss of power to utilize carbohydrates can be quickly regained. This would be a remarkable phenomenon. Against this explanation also is the fact that many who have employed fasting treatment with severe cases of diabetes have regretfully acknowledged that either very slight or no increase of tolerance for carbohydrates has been produced in these patients. This would make it still more unlikely that the diabetic patient by fasting altered his nature. It would rather point to the view that the diabetic condition remained unchanged, but that during fasting the diabetic was able to secure and burn material which under other conditions he could not reach, and which the normal individual could not secure. In conclusion it is gratifying to be able to record that the recent experimental evidence confirms the old clinical view that the severe diabetic still retains power to utilize a portion of the carbohydrate of his diet, small though it may be and that herein lies renewed hope for the success of treatment. 81 Bay State Road. COLUMBIA UNIVERSITY LIBRARIES This book is due on the date indicated below, or at the expiration of a definite period after the date of borrowing, as provided by the rules of the Library or by special arrange- ment with the Librarian in charge. DATE BORROWED DATE DUE DATE BORROWED DATE DUE ,_.' £Q .^ 1, l5--c 1 C2e(tl4l)M100 ^oslin RC660 J 784 1915 diabetsf^'^ ''tiU^ation i„