Type 1 Diabetes

American pathologist Eugene Opie of John Hopkins University in Baltimore establishes a connection between the failure of the islets of Langerhans in the pancreas and the occurrence of diabetes.

Frederick Allen—one of the first to appreciate that diabetes involves total metabolism rather than carbohydrate metabolism alone—developed this model to show that complete removal of the organ resulted in uncontrolled diabetes and death, whereas dogs who retained more than 20% of their pancreas never developed diabetes. The fate of those with 80–90% pancreatectomy depended upon what they ate. ‘On an Eskimo diet they may be found to live in health’, said Allen, but ‘on a Hindu diet they soon go down to fatal diabetes’ [8]. Carbohydrate loading produced progressive glycosuria and hydropic degeneration of the islets, leading Allen to conclude that the as yet unknown pancreatic factor that prevented diabetes had been exhausted. Glucose toxicity had found its first advocate. Physiology also has its cycles, and investigators discovered in 1988 that glucose infusion precipitated pancreatic islet failure in dogs with subtotal pancreatectomy, little suspecting that they had reproduced one of the classic experiments in diabetes 75 years later [9].

Allen concluded that people with diabetes should be given just enough food to keep body and soul together, with as little carbohydrate as possible, and the starvation regimen was born [8]. The physician in charge of this diet has been described as a yachtsman sailing as close as possible to the wind [10]. Too many calories, and symptomatic hyperglycaemia would result; too few, and the patient would die of starvation (as some did). Naunyn had taught that ‘fat burns in the fire of the carbohydrates’, and carbohydrate was needed for the proper combustion of dietary fat, which might otherwise precipitate ketoacidosis. One risk having thus been balanced against another, a man weighing 60 kg and able to tolerate 100 g of carbohydrate might end up on 60 g of protein, 130 g of fat and 25 g of carbohydrate. His daily ration of the latter might consist of 7 oz (198 g) of thrice boiled cabbage, or 5 oz (142 g) of similarly treated spinach or two and a half bran biscuits [10]. The bran was needed to counteract the constipation induced by the rest of the diet.

Adults did relatively well on this regimen, but children hovered miserably between death from diabetes and death from starvation. One 12-year-old boy, already blind from diabetes, was reduced to eating toothpaste mixed with birdseed stolen from his pet canary. ‘These facts were obtained by confession after long and plausible denials’, remarked the pitiless Allen. The unfortunate child died of starvation. A few physicians hailed the treatment as a means of prolonging life, but Carl von Noorden shuddered and turned away when Joslin showed him one of his cases. The controversy concerning the value of extra months or years purchased at the cost of so much misery was very bitter, and Allen was banned from the diabetic clinic at the Rockefeller Institute in 1918 [11].

CASE NO . 1 . Female, unmarried, age 28 yrs. American; no occupation . Admitted Feb. 24 , 1914 . Family History . — Grandparents lived to healthy old age. Father living , aged 58 , has arterial hypertension , neuralgia , and tendency to melancholia. Mother died at birth of this patient . An uncle died of tuberculosis . One full brother of patient died at 16 of appendicitis . One half-sister aged 22 has nephritis , consequent upon scarlatina . 

Past History . — No childhood diseases except measles and one dysenteric attack . Normal menstruation began at 13. Patient graduated from university at 20. She has had a nervous, overactive life with late hours and irregular eating. Was considered remarkable among her family and friends for the amount of candy and sweets she consumed. Normal weight 115 to 120 pounds. July, 1912, patient's fiancé died of accidental poisoning . Patient became melancholic and kept more to herself , while eating still more candy than usual. She and her parents were inclined to attribute onset of diabetes to grief. 

Present Illness . - In Jan. , 1913 , abnormal thirst was first noted . In Mar. , pruritus vulvæ . In May , menstruation stopped and remained absent. Hair fell out and is still thin . July , 1913 , diagnosis of diabetes was made and routine diet prescribed, which was taken in huge quantities owing to polyphagia . Symptoms persisted and increased till Jan. 4 , 1914 , when she began treatment at a well known diabetic sanitarium . Qualitative and quantitative restriction of the diet, oat cures, vegetable days , etc. , failed to clear up the condition . She was then transferred to this hospital , and arrived tired but not dangerously exhausted after a journey of 32 hours . 

Physical Examination . - Height 165.6 cm . Weight 40.1 kg . Marked emacia tion , face flushed and slightly puffy , drowsy and slightly alcoholic expression . No enlargement of tonsils or lymph glands . Blood pressure 103 systolic , 80 diastolic . Examination otherwise negative . 

Treatment . This was the first patient for the proposed treatment , and she was closer to coma than was desired for a first trial . Accordingly the attempt was made to be conservative . She was put to bed and a light supper ordered of two eggs , a slice of toast , and a cup of milk - cocoa . Breakfast the next morning in . cluded oatmeal ; the rest of the diet was light and included vegetables and potato in limited quantities . Notice should be taken that the blank food space in the graphic chart for Feb. 24 to 25 does not represent fasting , but exact reckoning of the diet was impossible because cooking and other arrangements were not in readiness . At the same time liquids were forced to 6 or 7 liters per day , and alkali was given as stated under acidosis below. As coma was imminent , there was no choice but to take the chance of beginning the proposed treatment. Therefore Feb. 27 was a vegetable day with 45 gm . carbohydrate and 530 calories . Feb. 28 was a fast-day with nothing but 200 calories of whisky. Marked improvement was evident in the urine, which became alkaline , but there was a large bicarbonate edema as illustrated by the weight curve , and weakness and drowsiness continued . Then , in order to guard against any supposed dangers of fasting , 20 gm . oatmeal were permitted on Mar. 1 , increased to 52.5 gm . on Mar. 2. By this time glycosuria and coma symptoms were entirely cleared up , and alkali was diminished . On Mar. 3 the diet consisted of soy beans and green vegetables . On Mar. 4 the diet was greatly reduced , consisting only of 90 gm . banana , 20 gm . oat meal , 10 gm . potato , and 10 gm . cream . The patient was extremely weak , therefore the attempt was made to build her up by a routine diabetic diet , in the hope that she might be strengthened for later undernutrition treatment . No gain of weight or strength was achieved , but glycosuria returned and the persisting acido sis was greatly increased , as shown in the graphic record . It was again reduced by undernutrition , and brought to a minimum by a fast - day on Mar. 23. A carbohydrate period was then instituted to clear up the tendency to acidosis if possible , and the opportunity was taken to compare the assimilation of oatmeal and pure starch . On Mar. 24 , 40 gm . Kahlbaum's soluble starch were the only nourishment given , and 80 gm . on each of the succeeding days , in ten doses of 8 gm . each . On Mar. 29 a change was made to oatmeal , reducing the quantity of carbohydrate slightly as an allowance for the oat protein . Nevertheless a glycosuria of 1.39 gm . appeared on Mar. 31 , proving the absence of any superiority of assimilation of the oatmeal over the soluble starch . The resulting traces of glycosuria were cleared up by a fast-day on Apr. 1. Acidosis now being entirely absent , another attempt was made to overcome the persistent weakness by as high a diet as possible without glycosuria. Though the attempt was made to balance protein, fat, and carbohydrate to this end, the graphic record shows that acidosis returned promptly, and glycosuria resulted on Apr. 12. This was cleared up by a fast-day on Apr. 14. The attempt was then made to build up strength by still higher diet and to diminish acidosis by increasing carbohydrate, even at the cost of glycosuria , with the idea that glycosuria could later be checked by brief fasting. Acidosis was not controlled , and weight and strength were not gained , and on Apr. 25 this attempt was abandoned . From this date to May 1 , pure protein-fat diet was attempted , but both glycosuria and acidosis were present . At this time a more rigid program of undernutrition was begun . It will be seen that the calories during May averaged less than 1000 daily , a maximum of carbohydrate was introduced , and frequent fast-days were employed . The weight diminished very slightly . The complaints of weakness were about the same . 

Most of this period from May 1 to the end of July was vegetarian , chiefly nuts and green vegetables , of which the patient was fond. On June 30 an enormous fat intake was permitted experimentally , as mentioned under acidosis . No special virtue of the vegetarian régime was perceptible . Glycosuria and acidosis were practically absent during the undernutrition of the month of May ; both returned with the higher caloric diet of June and July . This period was terminated because of the increasing weakness of the patient , due particularly to the low protein. In the period July 10 to 14 a test was made with raw pancreas feeding as described in Chapter IV .

Most of the month of Aug. was occupied with pure protein-fat diet of between 1000 and 1100 calories , and about 30 gm. protein . The patient was relieved of the fast-days , of which she had been complaining bitterly. Glycosuria was mostly absent , but acidosis was persistent . In Sept. the calories were increased , partly by use of alcohol , and a few fast-days mitigated by vegetables or alcohol were employed . Weight and strength were not thereby improved , and both glycosuria and acidosis were troublesome . Oct. was a period of marked undernutrition , the calories being mostly about 900 daily , carbohydrate-free , except for two tests in which respectively 60 and 58.8 gm.carbohydrate resulted in glycosuria , when added to this caloric intake . In Nov. and Dec. the carbohydrate-free diet was pushed to the upper limit of tolerance , so that traces of glycosuria and ketonuria kept recurring and were checked by occasional fast - days . The attempt thus to build up weight and strength failed as usual. The patient was dismissed on Feb. 26. Each day the patient took 2.4 gm . potassium citrate , small quantities of light magnesia , and calcium carbonate in quantities equal to the so dium bicarbonate . It was thus hoped to provide a balance of salts , and perhaps also to neutralize some acid with a non - irritating substance such as chalk . The sodium bicarbonate dosage was as follows : Feb. 25 , 20 gm .; Feb. 26 , 32 gm .; Feb. 27 , 72 gm .; Feb. 28 , 48 gm .; Mar. 1 to 7 , 40 gm . daily ; Mar. 8 to 20 , 20 gm . daily. All alkali was stopped at this time . No effect upon the carbohydrate tolerance was evident . As mentioned, acidosis was brought under control by the initial undernutri tion period. With the high diets ( Mar. 10 to 15 ) it returned very markedly , the ammonia nitrogen rising slightly above 1 gm. notwithstanding the alkali dosage , and the ketonuria reaching 28.7 gm . ( as B - oxybutyric ) on Mar. 15. With a single fast - day ( Mar. 16 ) the ammonia nitrogen fell to 0.63 gm . and the acetone bodies to 9.57 gm . With reduced diet the acidosis diminished further , and was entirely abolished by the carbohydrate period , Mar. 24 to 31 , the ammonia and acetone figures falling to normal , and the ferric chloride reaction turning entirely negative . Milder acidosis returned with the beginning of mixed diet after Apr. 2 , and it was proved that carbohydrate , even to the point of causing glycosuria , could not keep acidosis absent . Especially in the period Apr. 19 to 24 the carbohydrate was gradually increased to 90 gm . , with a total diet as high as 2800 calories ( over 75 calories per kg . on 37 kg . weight ) . The highest glycosuria resulting was 7.26 gm . on Apr. 24. This program was adopted on the principle frequently stated in the literature , that 90 gm . carbohydrate intake is worth a glycosuria of 7 gm . The attempt was to build up weight and strength with the high diet , while keep ing acidosis in check by a favorable carbohydrate balance. Acidosis , however , remained present as stated , and the peculiar weakness and malaise characteristic of severely diabetic patients with even moderate acidosis persisted likewise . Carbohydrate had to be discontinued in order to check the steady increase of gly cosuria . Thus the diets of Apr. 29 to 30 consisted of 61 gm . protein and 200 gm . fat . Both protein and fat were then diminished , until on May 1 the diet was 53 gm . protein and 177 gm . fat . This would correspond to an orthodox diabetic diet of about 1.5 gm . protein and 37 calories per kg . Nevertheless slight glycosuria and heavy ferric chloride reactions persisted , and the ammonia nitrogen by May 1 was up to 1.2 gm . May 2 was a fast - day with 34 gm . butter , this quantity of fat being almost negligible for either good or ill . The glycosuria ceased before the close of the 24 hours , the ferric chloride reaction diminished to a trace , and the ammonia nitrogen fell to 0.6 gm . Thus 1 day of undernutrition accomplished what had been impossible on full diets either rich or poor in carbohydrate . 

For the next 3 months a vegetarian régime was tried , as described under " . weight and nutrition ” below . Because of the low protein and fat , a relatively high car bohydrate tolerance was exhibited , which was also assisted by the very frequent fast - days . In this way both glycosuria and acidosis were almost continuously absent for a month . The hope of a gain in tolerance was disappointed , however , as demonstrated by the prompt return of both glycosuria and ketonuria when a moderate increase of diet was attempted in June and July . On June 30 an enormous fat intake was allowed experimentally for a single day , followed by a series of lower diets , as shown in Table II .

The relation between combustion of food fat and body fat is here illustrated . The huge ration of June 30 did not produce any explosive increase of acidosis . The acetone bodies showed a rise on the same day , but a more marked one the follow ing day , while the ammonia nitrogen did not reach its summit until July 3. It is evident that what happened was not the conversion of any large proportion of the fat on June 30 into acetone bodies , but rather an injury of fat assimilation pro duced by this excess and continued by reason of the fat rations ( lower but still excessive ) of July 1 to 3. On the fast - day of July 5 , storage or depot fat was necessarily burned , yet the ammonia nitrogen was approximately the same as on June 30. On July 6 , with a limited fat intake , the effect of carbohydrate was evident in producing a lower ammonia nitrogen excretion than on the fast - day . The entire observation is against the idea of a difference between food fat and body fat in combustion , and indicates rather an overtaxing of fat metabolism by excessive intake and improvement of assimilation by relief from the strain . On the carbohydrate - free diet beginning in Aug. , strong ferric chloride reactions and unduly high ammonia excretion were the rule . Temporary control of both glycosuria and acidosis was achieved with the low diets ( about 900 calories ) in early Oct. Thereafter it will be noted that the ferric chloride reactions were some times negative and never more than slight , even on carbohydrate - free diet , the gen eral diabetic condition being now under better control . The continuance of slight acidosis , however , throughout so much of the period of treatment represents one of the serious mistakes in the management of this case . 

Weight and Nutrition . - Weight at admission 40.1 kg . , at discharge 35.2 kg .; i.e. , a loss of 4.9 kg . The initial gain in weight , up to 43.5 kg . on Feb. 28 , repre sented a marked bicarbonate edema , simultaneous with the turning alkaline of the urine . Slighter edema was present on certain occasions later , notably Aug. 15 and Nov. 7 , being due apparently to sodium chloride and removed by diminish ing the salt intake. 

On Mar. 21 the large fluid intake began to be restricted . The patient had been accustomed to large quantities of water for some months past and com plained of thirst when the allowance was diminished by order ; within a few days this complaint disappeared and the thirst remained normal thereafter. 

Vegetarian diet was tried for a period of nearly 3 months, chiefly because of the claims in some quarters concerning differences in the glycosuric effect of different proteins , and the bare possibility that meat protein might at least stimulate a greater flow of gastric juice and correspondingly of pancreatic juice , and thus perhaps depress the internal function of the pancreas by stimulating its external function . Undernutrition was employed at the same time to create the most favorable conditions, and acidosis was kept absent by such quantities of carbohydrate as seemed within the tolerance. Butter was regularly allowed , eggs rather frequently , and a little bacon and bacon fat sometimes, but for much of the time the ration was vegetarian in the strictest sense , composed entirely of vegetables , fruits , nuts , soy beans , and occasional gluten preparations . There was no gain of tolerance , and no advantages of a vegetarian diet or evidence of specific differences between proteins were observed. 

Neither food nor feces was analyzed. The former was calculated as usual from the Atwater - Benedict tables. On this basis the following reckoning can be made for the period from Mar. 16 to Nov. 30 , for which the records of both food and urine are complete. Also, the total period of 260 days is divisible into two nearly equal portions , namely , 136 days up to July 31 , during which the diet was largely and sometimes wholly vegetarian and contained considerable carbohydrate , and 124 days after July 31 , in which the protein was of animal origin and the diet was almost continuously carbohydrate-free . The results for the various periods may be compared as shown in Table III.

The patient lost 5 kg . weight in 9 months . If it be assumed that 90 per cent of a weight change is ascribable to fat , in this instance the loss of nitrogenous " tissue ” would not exceed 500 gm . Using Voit's figure of 3.4 per cent N , the possible loss of body nitrogen would then be 17 gm . If it be urged that in an emaciated person the wasting of “ tissue ” in proportion to fat is higher , the above comparison of intake and output shows that the patient must have been nearly in equilibrium . At worst , the nitrogen deficit must have been small , and it may be assumed that the diet fulfilled the purpose of protecting body protein from any extreme loss while maintaining prolonged undernutrition . 

Two deductions seem justified. 

( 1 ) Digestion and absorption of protein were , as would be expected , distinctly better during the " animal ” period , but the utilization of vegetable proteins , including the times when the diet was exclu sively vegetable , was reasonably satisfactory . 

( 2 ) Though the nitrogen intake was lower in the " vegetable ” period , it must be called low also in the “ animal ” period , and it is evident that there is no serious obstacle to maintaining equilib rium on strict carbohydrate - free diet with a low protein ration . It is to be borne in mind that the energy intake is a question not of food ingested but of food ab sorbed . If it be permissible to assume that the same proportion of total calories as of nitrogen was lost in the feces , viz . 11.29 per cent , subtraction of this num ber from the 33 calories ingested daily would leave an average of between 29 and 30 calories absorbed daily per kg . of body weight . Accordingly , it would appear that this patient lived for 260 days on an average of 0.173 gm . N and 30 calories Work and exposure to cold were both far less than in ordinary individuals . On the other hand , the rather tall , very emaciated figure presented a dispropor tionate surface . Losses in sugar and acetone bodies were slight . On the whole , the figures obtained correspond satisfactorily to the known laws of metabolism in normal persons . 

Subsequent History . - On Jan. 14 , 1915 , the patient reported by telephone that she was feeling well and had cleared up occasional traces of glycosuria by fast days . On Jan. 20 she reported increasing difficulty in remaining sugar - free , and was instructed to return to the hospital if difficulty continued . Nothing more was heard until Apr. 1 , when a letter stated that she had returned to her home in Indiana . On Apr. 26 a response to a letter of inquiry showed that the cause of her silence and removal was her adoption of Christian Science. Occasional later reports showed that she was eating everything at will , including much candy, and gradually losing strength . Death occurred from simple weakness the first of Oct. 1915 , the terminal collapse being brought on by taking a dose of Epsom salts . 

Remarks . The patient , when received , was undoubtedly close to coma . She appeared then as having diabetes of extreme severity . The results obtained seemed highly favorable . In the light of later experience this treatment was per kg . very bad . 

Part of the fault lay with the patient , who had always eaten injudiciously and was the most unruly of the entire series for dietary control . The high diets , the persistence of glycosuria and ketonuria through considerable periods , and the changes in program from time to time were in some measure forced by the necessity of appeasing the patient's demands and meeting her psychic needs . She insisted not only upon nourishment but also taste and satiety , and slight privations brought on hysterical tears and melancholy which seemed serious as a possible influence upon the diabetes , though , as a matter of fact , no particular influence of psychic upsets upon the food tolerance was observed . She was given unusual leeway as being the first patient . The cause of the final disaster was also instructive . It is noteworthy that although a very careful limitation of diet both quantitatively and qualitatively had resulted in threatened coma at the time of admission , subsequently on absolutely unrestricted diet no symptoms of acidosis were described , evidently because the patient lived so largely on carbohydrate , and the polyuria aided in the elimination of acetone bodies . Although the patient was young and the kind that typically dies in coma , death occurred from simple wasting and asthenia . The chief difficulty consisted in inexperience with the treatment . The cautious manner of beginning treatment , and the partial , irregular , and inadequate character of the measures employed belonged to this stage of uncertainty and orientation . It showed the viciousness of some of the accepted methods in the management of diabetes . The same patient admitted at a later time could have been treated far better ; and the case , though severe , was mild in comparison with some of the later ones . A bold initial fast , followed by testing of the tolerance for different classes of food and arrangement of a diet accordingly , would have brought far quicker and better results . 

The actual accomplishment was that the patient was kept alive in the hospital from Feb. 24 to Dec. 20, with a loss of 5 kg. ( one-eighth of her weight at entrance ), and about a corresponding diminution of strength. Glycosuria and acidosis were kept entirely absent at certain times , and were controlled within small quantities at all times. Actual food tolerance was slightly less at the end than in the earlier part of treatment, and the progress was slowly but distinctly downward. The bungling and inadequate treatment furnished abundant reason for this slight downward progress in 10 months, and no “spontaneous” cause need be assumed. Methods and results of this sort have been common with a large proportion of practitioners who have undertaken to apply the fasting therapy. The record of this patient stands as a useful example of how a case should not be treated.

THE TREATMENT OF DIABETES MELLITUS 

BY ELLIOTT P. JOSLIN, M.D. 

Boston 

RATHER more success is achieved by surgeons in the treatment of general peritonitis than is attained by physicians in the treatment of diabetic coma. In neither condition are the statistics flattering to the profession; but the successes obtained by our surgical colleagues in the prevention of general peritonitis make the failure to prevent coma as a cause of two out of every three diabetic deaths mortifying to say the least. We physicians should begin to regard diabetic coma in the same light as your British brother, Mr. Moynihan, has taught the medical fraternity to look upon the late stages of a neglected gastric ulcer-namely, as an emergency which should not have been allowed to arise. With this issue of the prevention of diabetic coma plainly to the fore as the cardinal point in the treatment of diabetes, it is pertinent to inquire what diabetic patients are most susceptible to coma? And your own experience will enable you to anticipate that the answer, which an analysis of my own fatal cases shows, will be children. Of the sixty-two diabetic children under the age of fifteen who have died under my care, coma was the cause of death in all, and the significance of this melancholy fact is this: that where diabetes appears in its most severe type, as in children, coma is its expression. The propositions are simpler to state than to execute -first, that the best way to avoid coma is to prevent the progress of a case of diabetes from the mild into the severe type, and second, to protect the patient from all those agencies such as infections, anesthetics like chloroform and ether, undue exertion (mental or physical), which tend toward intensifying the severity of the disease. For if the diabetes is kept mild or moderate the coma need not be feared. Next to the children in the frequency of death from coma, strange as it may appear, were those of my cases who succumbed during the first year of the disease. The cause of death in 87 per cent. of these was coma. But diabetes is a chronic disease and the first year of its course should be mild rather than severe, and in mild diabetes coma should find no place.

Diabetes should be sought in the families of diabetic patients and in order to allay anxiety from urinary examinations, it is a good plan to have these made with such frequency that they will become simply a matter of routine. Such individuals should be taught to regulate the quantity of food eaten by the body weight, and never to indulge in unusual quantities of carbohydrate.

Alternate feeding and fasting are adopted when it is found that the glycosuria persists after a preliminary four days' fast. The method which I have found most successful has been to allow, following the first fasting period, 20 to 40 grams carbohydrate not far from half a gram per kilogram body weight-and about one gram of protein per kilogram for two days

"Alternate feeding and fasting are adopted when it is found that the glycosuria persists after a preliminary four days' fast. The method which I have found most successful has been to allow, following the first fasting period, 20 to 40 grams carbohydrate not far from half a gram per kilogram body weight-and about one gram of protein per kilogram for two days.This can be avoided by still further restricting the carbohydrate, either temporarily or permanently. It is always necessary to bear in mind that one food which the diabetic patient cannot do without is protein, and to it everything else must be subservient. While testing the protein tolerance, a small quantity of fat is included in the eggs and meat given."