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Week8_Banting1 - THE CANADIAN MEDICAL ASSOCIATION JOURNAL l...

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Unformatted text preview: THE CANADIAN MEDICAL ASSOCIATION JOURNAL . l PANCREATIC EXTRACTS IN THE TREATMENT OF DIABETES MELLITUS PRELIMINARY REPORT BY F. G. BANTING AND C. H. BEST, Dept. of Physiology J. B. COLLIP, Dept. of Path. Chemistry W. R. CAMPBELL AND A. A. FLETCHER, Dept. of Medicine, University of Toronto, and Toronto General Hospital INCE the year 1889, when von Mering and Minkowski (1) produced severe and fatal diabetes by total removal of the pancreas in dogs, many investigators have endeavoured to obtain some beneficial effect in diabetes mellitus, either by feeding pancreas, or by administration of pancreatic extracts. Minkowski, Sandmeyer (2), 'Pfluger (3) and others found that feeding pancreas was followed by negative or even harmful results. More re- cently, Murlin (4), Kleiner (5) and Paulesco (6) have tried the effects of aqueous extracts of the pancreas intravenously, on depancreatized ani- mals and have found transitory reduction in the percentage of blood sugar and in the sugar ex- creted in the urine. In 1907, Rennie and Fraser (7), recognizing the possibility that pancreatic enzymes might have harmful efiects on the internal secretions, secured islet tissue from teleosteal fishes, where it exists separatelyfrom the rest of the pancreas, and fed it to human diabetics. Their studies demonstrated no beneficial influence on the con- dition of the patient. E. L. Scott (8) in 1912 sought to eliminate the influence of proteolytic enzymes by using alcoholic extracts of the pan- creu. He did not find, however, that such ex- tracts caused as marked a reduction in the uri- nary sugar or in the G-N. ratio as when extracts were made with acidulated water. The whole question has been reviewed recently by Allen: (9), by him, and, indeed, by the ma- jority of recent writers, it is usually stated that pancreatic extracts have no clinical value what- soever. During the past ten months, two of us (F. G. B. and C. H. B.), working in the Depart- ment of Physiology of the University of Toronto, have reinvestigated the problem. Certain of the results obtained have already been published, (10) others are now in press. , These may be briefly reviewed here. Believing that extracts of the pancreas, as usually prepared, did not satisfactorily demon- strate the presence of an internal secretion act- ing on carbohydrate metabolism, because the active principle was destroyed by the digestive enzymes also present in such extracts, attempts were made to eliminate these enzymes. In the first experiments, this was done by taking ad- vantage of the fact that the acinous tissue (from which the digestive enzymes are derived) but not the insular tissue of the pancreas de- generates in seven to ten weeks after ligation of the pancreatic ducts. Extracts were therefore made with ice-cold Ringer’s solution, of degenerat- ed pancreatic tissue removed ten weeks after the ligation of the ducts. The extract obtained by this procedure, when injected intravenously or subcutaneously into diabetic dogs, invariably caused a marked reduction in blood sugar and in the amount of sugar excreted in the urine. It also enabled a diabetic dog to retain a much higher percentage of injected sugar than it other,- wise would. Extracts of liver or spleen, pre- paredinthesamemannerastheextractsof degenerated pancreas, were found to have neither of these effects. The active principle of the ex- tract of degenerated pancreas was destroyed by boiling in neutralor acid solution or'byincubat; ing for two hours at body temperature with pan-' creatic juice. In later experiments, it was found that the pancreas of foetal calves of under five months development did not contain proteolytic en- zymes, thus confirming the observations of Ib- rahim (11). By extracting such foetal pancreatic tissue, a highly potent and readily procurable preparation was obtained. Besides affording a much more practicable method for securing larg- er quantities of extracts, this result demonstrated that the active principle is «sentially the same from whatever animal it is prepared. A method *- 142 was finally evolved by which an active extract, which would retain its potency for at least one month, could be obtained from normal adult ox pancreas. Daily injections of pancreatic ex- tract (foetal calf or adult beef pancreas) pro- longed life of a completely diabetic dog to seventy days, at the end of which time the animal was chloroformed. Allen states that in his experi— ence completely diabetic dogs do not live more than fourteen days. The first results of a study of the respiratory exchange in completely dia- betic dogs, before and after administration of extract, showed that the extract confers on the diabetic animal the power to burn carbohydrates. Thus, in a diabetic dog, on starvation or lean meat diet, the respiratory quotient was found to be in the neighborhood of 0.7. The ingestion of carbohydrate caused no rise in the 9%: ratio, but when preceded by an injection of extract gave a value which approached 1.0., indicat- ing that carbohydrate was being burned. Be- sides the above, it should be recorded that the administration of extract very quickly caused striking improvement in the various symptoms known to be characteristic of complete pan- createctemy. As the results obtained by Banting and Best led us to expect that potent extracts, suitable' for administration to the human diabetic sub- ject, could be prepared, one'nfus (J. B. C.) took up the problem of the isolation of the active prin- ciple of the gland. As a result of this latter in- vestigation, an extract has been prepared from the whole gland, which is sterile and highly po— tent, and which can be administered subcutane- ously to the human subject. such an extract made possible at once the study of its effects upon the human diabetic, the pre- liminary results of which study are herein re- ported. The extract containing the active prin- ciple is being further purified and concentrated. A detailed report of the method of extraction, purification and concentration will be published at an early date. For the investigation of the clinical applica- tion of these extracts in the treatment of human diabetes, Professor Graham has placed at the disposal of two of us (W. R. C. and A. A. F.) the cases of diabetes mellitus in the wards of the Medical Service of the Toronto General Hos- pital. Patients were placed on a constant diet, vary- ing with the severity of each individual case, and their reaction to‘ such treatment studied for The preparation of - THE CANADIAN MEDICAL ASSOCIATIONJOURNAL a period of a week, after which various samples of extract were administered and the efiects ob- served. The ordinary routine clinical examina- tions were carried through. Blood sugar was estimated at intervals by the revised Folin-Wu method, urinary sugar by Benedict's methods, the acetone bodies by Van Slyke’s methods, and the respiratory quotient by the Tissot-Hal- dane and Douglas-Haldane methods. Up to the present time, February 22nd, 1922, the effects of these preparations have been ob- ‘ served in seven cases of diabetes mellitus and it is now evident that certain definite results can be obtained by their administration. The efiects -observed in depancreatiwd animals have been paralleled in man. The fall in blood sugar occurs and in two cases, repeatedly examined, a rise in the respiratory quotient, indicating carbohy- drate utilisation, occurs more or less coincidently with the attainment of a normal blood sugar level. Patients report a complete relief from the subjective symptoms of the disease. The sugar excretion shows marked decrease or, if dosage be adequate, disappears. Ketonuria is abolished, thus confirming a similar observation by Col- lip in diabetic animals, (results as yet unpub- lished). These results taken together have been such as to leave no doubt that in these extracts we have a therapeutic measure of unquestionable value in the treatment of certain phases of the disease in man. In agreement with observations of other investigators on laboratory animals, it has been found that without careful control se- vere toxic reactions may be encountered and this will undoubtedly be a factor in the evaluation of the ultimate therapeutic utility of the method. The following case report illustrates these ob- Servations: ‘ N amen—L. T. (Boy), Aged-14 Admitted to the Medical Wards, Toronto Gen- eral Hospital, December 2nd, 1921. Present I amass—About December 1919, he was taken to his family physician becaun he had been wetting the bed at nights, and also be- cause his ankles became swollen occasionally. One month later, sugar was' found in the urine. He states that at this time he was in good health, his appetite was somewhat excessive, but no in- creased thirst was complained of. Careful die— tetic regulation was prescribed and he states that be adhered to this diet fairly well. This his family physician will not confirm. Fasting was also tried apparently without success. The gly- cosuria persisted, he began to lose weight, fre- THE CANADIAN MEDICAL ASSOCIATION JOURNAL 143 II—IIIII I I I I I I IIIII III IIIIIIIII ‘Ill-IIAIIIIIIF'IIIIIIIE III IIII III'AIIIII I I I I II I IIIIIIIIIIIIIIIII IIIII‘IVAIVAIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IonnxauxsuxnanmzxnzsauunuunuI23 0 lounuuuux'lnnlo Jumur; "brill, CHART I.--Efl'ect of attract an glycosuria IIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIII IIIHIIIIIIIIIIIIIII IIIIIHIIIIIIIIIIIII IIIIIHIIIIIIIIIIIII IIflIIHIIIIIIIIIIIII I IIIHIIIIIIIIIIIII IIIIIHIIIIIIIIIIIII IIIEIHIIIIIIIIIIIII :mIIIIImIIIIIIIIIIIII IIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIII 5IIIIIIIIIIIIIIIIIII Bur: Cairns—Showing “causatioankemun'afollowina MWOIW IELIIE‘JIII IIIIIIII ‘ I-IIIIII I IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII .IIIIII’AJIII I IIIIIAIIUIII IIIIIIIII‘III IIIIIIIIIHIII IIIIIIIIIIIII IIIIIIIIIIII IIIIIIIIIIIII ==III III-IN a .3 ' - . Jud! 3. 13-2'f. 2‘}. 24—25. CHART IV.—Cunaof glucose mam-inc malad- minuh-atbn. Large data indicate blood sugar mumnmm’fin: mm CHART Ill—Eject of one injection of extract on Blood Sugar (mgs. per academh per cent) .2 144~ quency of micturition, both day and night, in- cremed up to the time when his physician recom- mended admission to hospital. Past I ”ma—Always healthy up until two and one half years ago, with the exception of an at- tack of chicken-pox at the age of ten and, of discharging ear for two years as a baby. Personal History—Born in Canada, went regu- larly to school, able to work well up to time of onset of present illness. Has always been fond of sweet food and previous to the onset of this condition ate freely _of candy. . 1"me Histam—Mothér and father, one bro- ther and two sisters, all in good health: No dia- betes or other familial diseases known. Emmimrtion.—On admission he was poorly nourished, pale, weight 65 pounds, hair falling out, odour of acetone on the breath, tonsils and teeth in good condition, abdomen large and tympanitic. Blood pressure 100—70. He ap- peared dull, talked rather slowly, quite willing to lie about all day. Hands show marked xan- thochromia. No findings of note in examina- tion of cardio-vascular, respiratory, abdominal systems or of the blood. The urine at the time of admission was strongly acid, specific gravity 10.30 to 10.40. The test for sugar strongly positive. Rothera and ferric chloride tests for ketones strongly positive. 24 hours amount of urine, 3—5 litres. Blood sugar"’5.8 mg. per c.c. Treatment—He was put to bed and was Quite content to remain there most of the time. How- ever, when he wished to do so, he was allowed to get up and wander about the ward, which he did very little during the first month. His diet was as follows :— Dec. 2nd.——5, 10 and 15% vegetables as much as desired. Dec. 11th—60 grams lean meat daily added to diet. Dec. 15th.—4 bran cakes daily added to diet. Jan. 4th.—Daily ration to consist of 50 grams lean meat, 5 and 10% vegetables, and fruits and bran cakes 'to make up exactly 100 grams of car- bohydrates per day. Clear broth, cocoa, tea and cofiee in moderation. Total intake about 450 calories. No further change in diet was made. This case was one of severe juvenile diabetes with ketosis. Previous to admission, he had been starved without evident benefit. During the first month of his stay in hospital, careful dietetic regulation failed to influence the course of the disease and by January 11th his clinical condi- THE CANADIAN MEDICAL ASSOCIATION JOURNAL tion made it evident that he was becoming de~ finitely worse. The extracts given on January 11th were not as concentrated as those used at a later date, and, other than a slightly lowered sugar excre- tion and a 25% fall in the blood sugar level, no clinical benefit was evidenced. Daily injections of the extract were made from January 23rd to February 4th (excepting January 25th and 26th). This resulted in immediate im- provement. The excretion of sugar as shown in Chart I became much less. On days of treat- ment, this varied from 7.5 gins. to 45.1 gms. compared with a previous amount well over 100 gms. daily. The acetone bodies disappeared from the urine. The boy became brighter, more active, looked better and said he felt stronger. No extract was given from February 5th to Feb- ruary 15th. During this time sugar again ap- peared in the urine in large amounts along with traces of acetone. Administration of extract in smaller doses after February 16th again resulted in lowered sugar excretion and disappearance of acetone from the urine. Chart II shows the fall in the total acetone bodies of the urine during the. periods of treatment after January 23rd. Chart III gives a four hour record of the blood sugar following the administration of a single dose of 6 c.c. extract on February 17th. Chart IV shows the influence of extract on the amount of glucose excreted in each two hourly period when extract was being used. Table I records the volume of urine and amount of sugar excreted each day and blood sugar determinations. The qualitative test for the daily excretion of acetone bodies in the urine and the amount of extract given is also tabulated. Although the other six patients treated by these extracts were all favourably influenced by its administration, particular reference might be made to one—a severe case who had been ex- creting 20 gms. of glucose on a diet containing 10 gms. carbohydrate and 24 hundred calories per day. Following injection of the extract his urine became sugar free, and he obtained com- plete relief from severe depression and extreme lassitude. Repiratory quotients in this same case showed a definite rise after injection of the ex- tract, confirming the increased utilization of car. bohydrate. All patients were improved clinically. It is difficult to put in words what is meant by clinical improvement. Those who have been treating diabetes will have recognized as early signs of a.» ‘W’ .~ w' , .3; THE CANADIAN MEDICAL'ASSOCIATION JOURNAL 145 Improvement a certain change in the skin, the appearance of the eyes, the behaviour of the patient, his mental and psychic activity, and the physical evidences, as well as his testimony, of increased vigor and desire to use his muscles. Under present day treatment, such improvement occurs in diabetics free from acetone but is un- doubtedly more striking in patients recovering from a ketosis. This is the nature of the improve- ment seen clinically as a result of the admini- stration of these extracts, and, while it is of a temporary nature, we believe that it justifies the hope of more permanent results following more adequate and carefully regulated dosage. TABLE I. Total Subcutaneous 24 hr 24 hr ‘ -' Blood Sugaz acetone injection of Date amount excretion in mg. per Rothera bodies pancreatic o-f urine 0f. glucose c.c. Test in mgs. extract in c c 1“ °-c- 1“ Ems- per litre A.M. PM. 5.8 plus plus 4.5 plus plus 5.2 plus ‘plus 5.2 plus plus 4500 187.8 . . . plus plus 4020 126.2 plus plus . . . . 3650 137.2 . . . . plus plus 72 3690 126. 7 6. 2 plus 540 6870 114.0 plus plus . 3625 915 3.2-4.4 plus plus 188 15 c.c. 4060 84 4.9 plus plus 69 . . . . 3950 125.5 plus 3780 123 . 5 plus plus 3900 114 . 7 plus plus 3910 148.0 . . . . plus plus 3960 197 . 3 6 . 7 plus plus 4300 144.6 . . . . plus plus 3770 120 . 6 plus plus 3840 121.9 plus plus . . . . 4580 107 3 plus plus 137 .4540 148.5 plus plus 167 4210 71.1 5.2 plus plus 282 5 c.c. 20 c.c. 4120- 8.7 1.2—3.0 plus 30 10 c.c. 10 c.c. 3880 80.5 . . . . 0 0 . . . . 5070 130.3 0 0 3040 42.2 plus 4 4 c.c. 4 c.c. 5125 16.7 trace 0 2 c.c. 4 c.c. 3275 42.5 0 0 4 c.c. 2715 11.5 trace 0 4 c.c. . 4 c.c. 4415 7.5 0 0 4 c.c. 4c.c. 3145 21.8 ... 0 0 4! c. c. 4 3.0. 2700 9.1 0 0 5c.c. 40.0. 4150 18.2 ' 0 0 5 c.c. 4 c.c. 3740 4.5.1 0 0 5 c.c. 4 c.c. 3475 53.3 . . . . 0 0 3900 101.5 . . . . 0 0 3700 110.1 . . . . 0 0 4910 167.1 . . . . trace 0 ‘- 4940 101.7 . . . . 0 0 4710 86.9 . . . . trace 0 4510 129.9 trace 0 3170 117.7 4.87 trace 0 2595 106.7 4.9 trace 0 4670 158.5 . . . . trace 0 3275 151.4 . . . . trace 0 4611 185.0 4.73 neg. 0 5 c.c. 3930 60:4 0.85—5.2 neg. 0 6 c.c. 4790 182.3 2.0—4.5 neg. . 0 3105 39.6 neg. 0 4 c.c. 3985 92.0 neg. 0 SUMMARY its relatively low tomcrty, we are presentmg a Following the production of what appears to be a concentrated internal secretion of the pan- creas and the demonstration of its physiological activity in animals, and, under careful control, preliminary report on the pharmacological ac- tivity of this extract in human diabetes mellitus. Clinical observations at this juncture would 33-. pear to justify the followmg conclusions. —- ‘1‘ . 136 THE CANADIAN MEDICAL ASSOCIATION JOURNAL (1) Blood sugar can be markedly reduced even Duncan Graham of the Department of Medicine to the normal values. (2) Glycosuria can be abolished. (3) The acetone bodies can be made to disap. pear from the urine. (4) The respiratory quotient shows evidence of increased utilization of carbohydrates. (5) A definite improvement is observed in the general condition of these patients and in addi- tion the patients themselves report a subjective sense of well being and increased vigor for a period following the administration of these pre- parations. . For their hearty co-operation and kindly assis- tance and advice, we have great pleasure in pre- senting our best thanks to Professor J. J. R. Mac— Load of the Department of Physiology, to Pro- fessor V. E. Henderson of the Department of Pharmacology, to Professor J. G. Fitzgerald of the Department of Hygiene, and to Professor of the University of Toronto. Ramnsncas (l) VON Msnmo AND MINxowst—Arch. f. ‘arp. Path. 14. Pharmakol, 1889, XXVI, 371. ‘ (2) Ssnnnran, W.-—lechr. f. Biol., 31, 1895, 12-85. (3) Prwonn—Pflugers Arch, 118, 1907, 265-321. (4) MURLIN—Jour. Biol. Chem, 1913, XV, 365. (5) Khulna—Jaw. Biol. Chem, 1919, XL, 153. (6) PAULEsoo—Comp. rend. dc Sac. do biol., July 1921 (7) Rams AND Fauna—8mm. Joan, Vol. I, 1907 ,~ .(8) Sean, B. L.—Am. Jour. Phy., Vol.'XXIX, Jan. 1912, 3. - (9) ALLEN, F. M.—Glycosuria and Diabetes, Cam- bridge, 1913. (9) ALLEN, F. M.—Gl ' and Diabetes, Cam- bridge, 1913. ALLEN, F. ., SrranAN, E. ANDFi-rz,R.— Mum h No. II, Rockefeller Institute for Medical Re- search, ew York, 1919. (10) BANTING AND Bss'r—Jour. Lab. and Clin. Med., February 1922. (ll) InnAnIM—Biochem Zeilsch, 1909, XXII, pp. 24-35 New Opium Laws in Great Britain.— In compliance with the agreement at the Hague International Opium Convention in 1912, Great Britain in 1920 adopted a law for the regulation of traffic in narcotic drugs. This bill would doubtless have been adopted lung before, had t not been for the war. The regulations under the act went into effect September 1. “As origin- ally drafted by the Home Office,” says the British Medical Journal editorially, “they were open to much legitimate criticism; but after emendations by a departmental committee, in accordance with the recommendations of the...
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