maniy cases in which lhevulose was administered in only three was (From the Laboratory of the Royal College of Physicians, Edinburgh.

Transcription

1 ON THE NATURE OF ADRENALIN GLYCOSURIA. BY D. NOEL PATON. (From the Laboratory of the Royal College of Physicians, Edinburgh.) IN October 1901 Blum' announced the discovery that the subcutaneous administration of extracts of the suiprarenal bodies produces diabetes in rabbits and dogs. He found that such extracts given by the mouth had no influence upon the proteid metabolism as indicated by the excretion of nitrogen in the urine and that neitber sugarnor albumin appeared in the urine. He concludes from a series of 22 experiments that given subcuitaneously, suprarenal extract causes marked glycosuria not only on a diet free of carbohydrates but also after a fast so proloniged that all the glycogen has disappeared from the liver. He states, but without giving experimental data, that, in the few experiments in which the excretion of nitrogen was observed, no abnormal increase was noticed. He further states that acetone and diacetic acid were not present and that oxy-butyric acid was therefore not tested for. In a more recent paper2 he records some further experiments upon adrenalin diabetes which confirm his previous observations and show that even after repeated administration an additional dose will produce glycosuria. Zuelzer3 confirms Blum in all particullars and finds an increase of sugar in the blood. He argues that, since B1 u m has shown that the condition is not a toxic glycosuria duie to increased conversion of glycogen, and since his own observationis prove that it is not renal in origin like phloridzin glycosuria, it must be a true diabetes. Out of maniy cases in which lhevulose was administered in only three was levolusuria observed. He states that he noticed pigmentation of the mucous membranes of two cats injected for four weeks. M etzger' gives a series of observations on dogs and rabbits showing that the glycosuria is due to an increase in the glucose of the blood. 1 Deutsch. Arch. f. klin. Med. LXXI. p Pfluiger's Arch. xc. p Berlin. klin. Wochen. p Muinch. med. Wochenschr. p

2 ADRENALIN GL YCOSURIA. Herter and Richards' record a series of experiments on the intra-peritoneal injection of the adrenalin chloride of Takamine in dogs. They found that sugar appeared in the urine even after fasting, and that the animals manifested symptoms of excitement, that they vomited, and that in several cases they died in the couirse of twelve hours. In these cases they describe "destructive lesions of the gastro-enteric tract and pancreas" and a granular degeneration of the cells of the islands of Langerhans. In a footnote they further describe the effect of painting adrenalin on the surface of the pancreas. This caused a blanching followed by a congestion simultaneous with the appearance of glucose in the urine. In a more recent paper2 Herter and Wakeman record the results of further experiments, which do not fully corroborate all the previous conclusions. They found that the glycositria produced by adrenalin in a dog fasted and then treated with phloridzin was very slight. While repeated injections in some cases did not induce glycosuria, this appeared to them to be due to malnutrition and not to the establishment of any tolerance of the substance. They confirmed the previous observation that adrenalin painted on the pancreas produces glycosuria and they further discovered that the application of many reducing or toxic substances acted in the same way. The observations on the changes in the islands of Langerhans described in their previous paper are not confirmed. Throughout my own experiments the preparation used was the adrenalin chloride 1 in 1000 of Takamine supplied by Parke, Davis & Co. 1. A true glycosuria is produced. My observations fully confirm the statement of Blum as to the production of a glycosuria by the subcutaneous itnjection of adrenalin in dogs and rabbits. The nature of the reducing substance in the urine was repeatedly tested by fermentation and by the phenyl-hydrazin test and in every case it was found to be dextrose. 2. A glyccemia is produced. The observations of Metzger and Zuelzer are confirmed by the following observations. 1 New York Medical News, p Virchow's Arch. cixx2x. p

3 288 D. N. PA TON. Exp. I. Two rabbits were well fed on the night of the 12th. At 9 A.M. on the -13th each had 2 c.c. adreualin. A weighed 1540 grins., B weighed 1065 grms. A was killed at 12 noon. It had passed a little urine which gave a very strong reduction. B was killed glucose. at It had passed 60c.c. urine containing 3-120/0 The blood was collected into a measured quantity of methylated spirit by severing the caiotids; repeatedly extracted and rubbed up with alcohol; decolorised with animal charcoal; taken up in a definite volume of water, and titrated with Fehling's solution. Blood of A-40c.c. in 120c.c. spirit.,, ), B-30,. 9,.. The watery extracts made up, A to 100 c.c., B to 80 c.c. Titrated on 1 c.c. Fehling's solution they gave, A /0 glucose in blood. B /0,. Exp. II. Two rabbits, A and B of Exp. VII. which had been receiving daily doses of from 1 to 5 c.c. of adrenalin chloride for more than a month had their last dose of 3 c.c. at 12 noon on the 5th. At 12 on the 6th, they were killed, the thorax rapidly opened and the blood caught in methylated spirit and treated as described above. Blood of A contained /0 glucose B,, 0205 /0/ The urine in the bladder of each contained A /0 glucose B. 11 0/0 Exp. III. In the two rabbits used in Exp. IV. the blood contained A. 0X21 0/0 of glucose B. 0 25,S,, See also Exp. V. 3. The extent of the glycosuria is dependent on the amount carbohydrates in the body. of Exp. IV. Two large rabbits were put in cages for the collection of urine on Dec. 8th. A weighed 1650 grms. and was fed on small quantities of cabbage leaves and water. B weighed 1950 grms. and was fed on turnips in large quantities.

4 ADRENALIN GLYCOSURIA. 289 Next day the urine of A gave no reduction, while the urine of B gave a doubtful reduction. A got 2 1 c.c. adrenalin chloride and B got 25 c.c. A TABLE I. Sugar in urine Sugar in urine Weight Adrenalin at Weight - Adrenalin at Day at end of day Per cent. Total in grms. beginning of day at end of day Per cent. Total in grms. beginning of day ' '1 1X ) )_ ( ' Here the effect of adrenalin was to cause a much more copious excretion of sugar in the animal liberally fed on turnips in which an accumnulation of glycogen in the liver had occurred. The animals were killed at the end of the 4th day and the glucose of the blood determined: A. 0*21 to B e/0. The liver of A still contained 1 28 per cent. of carbohydrates expressed as glucose. 4. The glycosuria and glycceania are not due to a mere increase in the conversion of glycogen to glucose. The method of experiment was to keep the animal on a diet of a material from which glycogen could not be formed, and to clear out the carbohydrates stored in the body with phloridzin and then to administer adrenalin. Exp. V. A rabbit weighed 1690 grins. on Dec. 8th and it was fed on spongin and water and 025 grmns. of phloridzin were administered hypodermically. Next day very little urine was procured, and it gave a strong reduction. The urine passed next day gave no reduction, and the animal got 2 c.c. adrenalin. On the following day the urine gave a strong reduction, and 2 c.c. adrenalin were again given at 1 and the animal was killed at Urine in bladder gave a strong reduction and a marked fermentation. Blood contained /0 glucose. Liver contained less than 0 2 0/0 of carbohydrates as glucose. Exp. VI. A white rabbit got 025 grm. of phloridzin on the 13th and on the 14th the urine gave a strong reduction. Another 0'3 grm. of phloridzin was administered and the animal got spongin and water as food. On the 15th and 16th the urine gave a marked reduction. On the 18th the urine gave no reduction. B

5 N. PA TON. 2-2 c.c. of adrenalin chloride were injected at 3.30 p.m. The animal was found dead at 7 p.m., about 50 c.c. of urine having been passed. This gave a slight reduction. The urine in the bladder also gave a slight reduction. The clotted blood from the heart and great vessels to the amount of 7'8 c.c. was collected in alcohol and repeatedly extracted and treated as described. It showed the presence of /0 of glucose. 5. The repeated administration of adrenalin is not always followed by glycosuria. This is shown in the case of the dog in Exp. XII. and in the case of rabbits by Exp. VII. Exp. VII. Adrenalin was administered daily to three rabbits A, B and C. The following tables show the number of c.c. given on each day and the presence + or absence 0 of reducing substances in the urine. The animals were fed on cabbage leaves, unless otherwise indicated. A. Adrenalin Sugar t The weight on the 1st day was 1280 grms., on the 14th, on which day it died, 1090 grms. B. Adrenalin Sugar Adrenalin Sugar The weight on the 1st day was 1740 grms., on the last (36th) day, when it was killed, 1580 grms. C. Adrenalin. Sugar , Adrenalin. Sugar The weight on the 1st day was 1715 grms., on the last (36th) day, when it was killed, 1400 grms. 6. A certain tolerance for adrenalin is established by repeated doses. The rabbits in Exp. VII. bore without inconveniences doses of 1 c.c. per 300 grins. of body weight, or grm. of adrenalin chloride per kilo. In Exp. VIII. two small iabbits of 470 and 455 grms. had respectively the following doses on successive days. Dose in c.c. 1, 1-6, 2'0, 2'5, 0, 0, 0, 2-0, 2 5, 4*0, 4 0. On the last day they weighed 490 and 465 grms. and thus a dose of 1 c.c. per 122 and per 116 grms. was tolerated. 1 Albumin in urine. 2 Fed on grass.

6 ADRENALIN GLYCOSURIA. As a general rule a dose of 1 c.c. per 300 or 400 grms. of rabbit is rapidly fatal. 7. In my experiments upon dogs I have not detected the presence of diacetic acid or of acetone in the urine. The urine of hutch rabbits fed on cabbage was fouind almost invariably to give the reaction with ferric chloride both when under the influence of adrenalin and without the drug. A very constant reaction of the urine both in rabbits and in dogs is the development of a dark red ring when nitric acid is poured below the urine in testing for albumin. The nature of the pigment and of the chromogen yielding it has not been investigated. 8. The proteid metabolism under the administration of adrenalin undergoes the changes which are characteristic of a true diabetes. One of the most characteristic features of true diabetes is the inicrease in the ammonia of the urine. This, von Noorden' maintains, is due to the increased production of phosplhoric and sulphuric acid from the increased disintegration of proteids and the formation of lactic, diacetic, oxybutyric and other orgarnic acids. It was therefore deemed desirable to investigate somewhat in detail the influence of adrenalin on the proteid inetabolism. The experiments were made upon rabbits and upon dogs, and the analytic methods employed were those described in our various papers upon the changes in proteid metabolism already published in this Jaurnal. Throughout the observations Merck's phosphotungstic acid, which completely precipitates the ammonia salts, was used. A. Rabbits. Exp. IX. Rabbit, weight 1990 grms.: 600 grms. of cabbage-leaves daily. On days marked + had 2 c.c. adrenalin chloride hypodermically. On the 9th day the rabbit was found dead. There were 23 c.c. of urine in the collecting bottle which contained a distinct trace of hmnmoglobin and of coagulable proteids and which gave a strong reduction. The few drops of urine in the bladder also gave a strong reduction and a distinct coagulum on boiling. The animal weighed 2050 grms. No serous exudation in any of the cavities. The pancreas, liver and lungs seemed congested. 1 Pathologie des Stoffwechsels. 291

7 292 D. N. PA TON. TABLE II. Nitrogen of urine Glucose per day in grm. Day Total in grm. Urea N. in grm. Per cent. of urea N. 1 1ill * *54 * P '90 * *70 * P Reduction +8 1P65 1P The daily excretion of urine and of nitrogen was irregular but the average nitrogen excretion was as follows: Before first injection... 1'02 Day of injection '994 Next day '70 Two last days of injection 1'67 The single injection of 2 c.c. although it caused an excretion of no less than 20 grms. of glucose produced no marked change in the excretion of nitrogen, but the second administration was accompanied by a very marked increase. The urea nitrogen before the first injection averaged 91 e/o On the day of injection it was On the next day ,, On the two last days of injection it was, 1st day 79,, 2nd day 69 Proteids were not detected in the urine till after the death of the rabbit, and the ammonia nitrogen was not estimated. These points are specially studied in the next experiment. Exp. X. Rabbit, weight 1630grms.; had 500grms. of cabbage-leaves daily. On the third day it was found that all the cabbage was not being eaten and 400 grms. were given on subsequent days. On the days marked + it had 2 c.c. adrenalin chloride hypodermically, and on the days marked (D 3 c.c. To prevent decomposition of the urine 20 c.c. of a 10 e/, solution of hydrochloric acid was put in the collecting bottle and this served to keep the urine nearly neutral. On the 14th day the rabbit was found dead, weight 1500 grms. There was some serous fluid in the pleura and pericardium. The bladder contained 24 c.c. of urine which gave a faint cloud with cold HNO. and, in

8 ADRENALIN GLYCOSURIA. 293 Esbach's tube, gave a precipitate equivalent to /0 of proteids. Proteids were not found in the urine during the life of the animal. The suprarenals were very large. TABLE III. Day f otai in grms. 2'10 2'07 1' '37 2' '61 0' ' '38 0'40 Urea N. Urea N. in grms 2' '00 1'26 2'03 1'31 1'47 0'60 0' '26 Nitrogen of urine Per cent. of urea N NHS, N. in grms. Per cent of NH8, N. '014 0'6 '032 1'5 '019 '033 '015 '039 '047 '170 '065 '028 '042 The daily excretion of urine and of nitrogen was more regular than in the last experiment. The average nitrogen excretion was as follows: Four days before injection 1'72 grms. Three days of injection... 1'22, Three days after injection 1'46,, First day of second injection... 1'38,, The first injection caused an excretion of 10O35 grms. of glucose on the same day, but no sugar appeared after the two succeeding injections; the excretion of nitrogen was not increased. Proteids were not present in the urine, but the distribution of nitrogen was markedly altered. The second series of injections was accompanied by the excretion of 3'57 grms. of glucose on the first day and by the presence of glucose on the second day as well. PH. XXIX. Four days before injection First day of injection Second,... Third,. is First day following Second,, Third,, First day of second injection Second,. it. 1'3 1' '9 13' '0 10'0 Urea N. Ammonia N. 94 1'4 96 1'1 91 2'4 85 6' '9 86 4'5 91 2'0 10'0 Glucose in grms 1'72 10' reduction 19

9 294 D. N. PA TON. In this experiment the excretion of sugar was comparatively small and the decomposition of proteids as indicated by the nitrogen eliminated was not increased, but the modification of the nitrogenous metabolism was profoundly altered, the proportion of ammonia nitrogen and of nitrogen not in ammonia or urea being steadily increased for five days in the first series of injections, and on the second day with the second series. B. Dogs. Exp. XI. This was really the Srst experiment performed. The weather was warm at the time and on the fifth, sixth, seventh, and eighth days the urine was distinctly alkaline and appeared to bave undergone ammoniacal decomposition. Since in a previous experiment with the administration of extracts of suprarenal sickness had been produced, an attempt was first made to compare the metabolism on a day of fasting with the metabolism on a day of fasting with the administration of adrenalin. The dose given was small- 4'2 c.c. or 0'28 c.c. per kilo, and no result was produced. In the latter part of the experiment a larger dose, 10 c.c. or 0 7 c.c. per kilo, was administered without fastinig the animal. The experiment was conicluded with the administration of phloridzin. The dog used was a setter bitch weighing 14'9 kilos. It was kept upon a fixed diet of oatmeal as porridge and milk. TABLE IV. Day Inj ect. Fast Fast & 4'2 C.c. 10 c.c. 1-3 phl. Sugar Total in grms. 5A ' ' '29 33 grms. 6' '96 45 grms. 6'13 4'67 Nitrogen of urine Urea N. Per cent. NH8, N. in grms. of urea N. in grms. 4'50 84 *310 5' '92 84 ' '58 80 *748 5'20 81 '574 3'72 81 ' ' * '684 4'00 85 *316 Per cent. of NH3, N

10 ADRENALIN GLYCOSURIA. Leaving out of account the fourth day on which the dog fasted, the excretion of nitrogen per diem averaged as follows: First six days grins. Day of injection and three succeeding days , Day of phloridzin injection and following day Although the excretion of glucose was considerable-30 grms. on the day of injection-the excretion of nitrogen was not increased, and it was found that the dog, which was on a very liberal diet, had increased in weight at the end of the experiment. The distribution of nitrogen was however materially altered. Per cent. of total N. Urea N. Ammonia N. Other N. Before injection Day of injection following X go Day after phloridzin 85 6'8 8'2 295 This shows a disturbance in the nitrogenous metabolism in the dog similar to that found in the rabbit, except that in the dog the decrease in the proportion of uirea nitrogen is entirely due to an increase in the ammonia nitrogen. Since special precaution was not taken to prevent ammoniacal decomposition it was considered advisable to make another series of observations in which the urine was caught in a solution of hydrochloric acid. Exp. XII. An Irish terrier bitch. Weight kilos. Diet. Oatmeal 150 grm. Milk 500 c.c. Water 600 c.c. On the days indicated the dog got 5 c.c. of adrenalin chloride. On the first day the glucose was only 2 3 grm., on the second day it was practically absent, and on the third day it was something over 5 grm. On this day there was a slight cloud with cold HNO3 indicating the presence of a trace of proteids in the urine. On the next two days the urine was free of proteids but gave a faint reduction. On the third day after the last injection the urine gave a very marked reduction, equivalent to *18 per cent. of glucose. Fermentation was distinct and reduced the specific gravity of the urine from to Proteids were present to the extent of per cent., estimated by Esbach's 'Method. On the next day, the fourth after injection, there was 19-2

11 296 D. N. PA TON. no reduction, but a trace of proteid was still present. On the next day there was no reduction and proteids were absent, buit they re-appeared again on the following day when a faint reduction was also observed. TABLE V. Day Ad- Sugar Nitrogen of urine renalin in grms. -- per day Per cent. - Per cent. Total Urea N. of NH:, N. of in grms. in grms. urea N. in grms. NH8, N c c.c c.c The average daily excretion of nitrogen was as follows: Sulphur of urine Phos- /- "A phorus Total Acid Per cent. of urine S. in S. in of asp2o5 grms. grms. Acid S. in grms * Before the injections grms. On days of injections and three succeeding days (the third day of injection is omitted since some urine was lost) 3-82 Pt On last three days of experiment 3-50,, Although the excretion of sugar was small the proteid katabolism was distinctly increased. The distribution of nitrogen was altered much in the same manner as in Exp. XI. On the days on which proteids were present in the urine the proportion was not determined. Before injection First day of injection Second,. of Third,. 9, First day after injection Fifth and sixth days after injection Per cent. of total N. I Urea N. Aimmonia N. Other N

12 ADRENALIN GLYCOS URIA. This experiment shows very clearly that the fall in the proportion of nitrogen in urea is chiefly due to the increase of nitrogen in ammonia.- We had already found' that with such disturbances in the distribution of nitrogen when these were caused by diphtheria toxine, the proportion of unoxidised sulphur to oxidised sulphur is increased. The amnounts of these were determined in the urine of the day following the injection and in that of fifth day after: Acid sulphur per cent of total Day after injection 53 Fifth day after injection 65 The excretion of phosphoric acid was determined and it was found to run parallel to the excretion of nitrogen. P105 to 100 parts of N. Before injection 32 With injection and during three succeeding days 31 Last three days 38 Since the preceding experiments had yielded somewfliat contradictory results as to the changes in proteid katabolism under the administration of adrenalin, and since the possible influence of the administration of adrenalin on the absorption of proteids had not been studied, it was thought desirable to make another set of observations. Exp. XIII. An old collie bitch. Weight 14-9 kilos. Nitrogen contained Per cent. Total Diet. Oatmeal 150 grms Milk 500 c.c Water 600 c.c. 4*05 On the days indicated the dog got 10 c.cm. of adrenalin chloride in two doses. On these days there was an abundant excretion of sugar, 31 grm. being excreted on the first day and 208 grm. on the second. Proteids and diacetic acid were absent from the urine but from the first day onwards to the seventh day a dark purple ring with HNO3 was visible. 1 This Journal, xxiv. p

13 298 D. N. PA TON. Day Adrenalin Sugar in grms. per diem c.c C.C. 20'8 Total in grms. 2'15 2' '88 Lost 3'69 4'78 3'72 3'62 32' }1X97 TABLE VI. Nitrogen of urine _ <~~~~- 1 Per cent. Urea N. of NHi, N. in grms. Urea N ' ' '10 3'50 2' Per cent. of in grms. NH8, N. ' '216 5'4 ' *179 6'2 *170 4X6 *277 5X7 ' '236 6'5 '134 5'2 '170 4'1 '154 4'8 '120 6'0 The nitrogen balance is given below: Nitrogen N of faces N. not in grmi in urea or NHS in grms. 3'95 or 0p '9per 8.8 diem 11'4 12' '5 11' J 90) 2'73 or 0'68 per diem 2'24 or 0'56 per diem Total N. excreted, average per diem grms. Nitrogen balance per diem in grms '66 - ' '47 Intake per diem First Period (before injection) 4'05 Second Period (days of injection and two subsequent days) 4'05 Third Period (four succeeding days) 4'05 Output per diem Urine Feeces Total Balance 2'48 '99 3'47 + '58 3'95 '68 4'63 -'58 2'97 '56 3'53 +'52 The experiment does not show any disturbance in the absorption of nitrogen, which seems to have steadily improved as the dog becomes more accustomed to the oatmeal diet. The very marked increase in the excretion of nitrogen under the administration of adrenalin is seen to be due to an iniereased proteid katabolism, the output exceeding the intake by 0 63 grm. of nitrogen or 3'9 grms. of proteid. In this experiment the disturbance in the distribution of nitrogen is less marked than in the others although it is in the same direction. Before injection Days of injection and two succeeding days Four succeeding days Urea N. Ammonia N '5 83' '2 5'0 Other N '8

14 ADRFNALIN GL YCOSURIA. 299 CONSIDERATION OF THE EXPERIMENTS ON PROTEID METABOLISM. These experiments indicate that the sugar excreted is not entirely derived from the proteids of the food or of the body. Throughout the series there is a striking absence of any relationship between the amount of sugar and the amount of nitrogen excreted. In Exp. XIII. where the sugar eliminiated was large in amount-50 grms. in two days -and where the proteid katabolism was distinctly increased, the decomposition of proteid, grms., was quite insufficient to yield the sugar excreted. The most marked change in the proteid metabolism is the increase in the proportion of ammonia nitrogen and the concomitant fall in the proportion of urea nitroaen under the administration of adrenalin. This occurred both in rabbits and in dogs, and in every case, except in the last experiment, it was well marked. In this respect the metabolism under the influence of adrenalin resembles the condition in true diabetes. The very marked increase in the ammonia found in Exps. X. and XI. as compared with that in Exp. XII. is rendered explicable by Dr Scott's investigation made in this laboratory, on the action of large doses of glucose on the metabolism'. He shows that the subcutaneous injection of such doses produces an increased proteid metabolism and generally an increased production of ammonia, and he refers to Harley's demonstration of the production of lactic acid2 as an intermediate product in the metabolism of sugar and points out the probability that the disturbances in the proteid metabolism observed by him are due to such a production of acids. If then the administration of adrenalin interferes with the proper utilization of glucose by the tissues, as these experiments show to be the case, then, if the tissues are absolutely unable to metabolise sugar even imperfectly and it is at once eliminated, the toxic effects of its acid products will be absent as in Exp. XII.; but if the utilization of sugar is simply interfered with, then as in Exps. XI. and XII. the toxic effects of intermediate acid products will manifest themselves by the increased formation of ammonia. The proteid mietabolism was not increased in either of the rabbits or in the first dog used. But it was distinctly increased in the last two I This Journal, xxviii. p This Journal, xxi. p

15 Soo D. N. PA TON. dogs. The explanation of this is simple. In the rabbits and in the first dog the diet was liberal, but in the last two dogs used an insufficient diet was given. The following Table shows the marked difference in the diets of the dogs. Weight ol Dogs and Proteid absorbed. W. of Dog N. excreted Proteid used in grns. in kilos. in grmas. Total Per kilo Exp. XI XII XIII A In Exp. XI. the supply of food was so liberal that the withdrawal of 33 grms. of glucose caused no increase in the proteid metabolism, while in Exps. XII. and XIII. where the supply of food was insufficient to maintain the weight of the animal, the onset of glycaamia caused an increased proteid metabolism. CONCLUSIONS. The subcutaneous administration of adrenalin in dogs and rabbits causes a true glycosuria and glycaemia, the degree of which depends largely upon the amount of carbohydrates in the body but which occur when stored carbohydrates have beeu eliminated. The glycosuria is apparently due to a diminished utilization of sugar in the tissues since it is not due to a mere increased formation of glucose or to increased excretion of sugar by the kidneys. That the effect is due to a toxic action of the adrenalin and that it is not caused by an interference with the processes of oxidation due to the vascular changes is indicated, first by the extent of the glycosuria -which is far more marked than that observed as the result of mere interference with oxidation, and secondly, by the fact that the glycosuria is slight in guinea-pigs where the vascular changes are much more prominent. The observations of Herter support the view that the toxic action is not a direct one, but that it operates through the pancreas. During the prolonged daily administration of adrenalirl, days may occur on which sugar does not appear in the urine. A distinct tolerance of the drug is established.

16 ADRENALIN GLYCOSURIA. 301 Diacetic acid and acetone have not been detected in the uriue of dogs, but a dark red ring at the junction of the urine with nitric acid is constantly present. The study of the proteid metabolism shows (1) that the sugar is not entirely derived from the breaking down of proteids, (2) that there is a markedly increased production of ammonia, and (3) that, on an insufficient diet, the decomposition of proteids is markedly increased, while the absorption of proteids is not interfered with. The proteid metabolism under adrenalin thus behaves as it does in ordinary diabetes. Dr Drum m ond is at present investigating the structural changes in the tissues produced by the administration of adrepnalin in these experiments.