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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 subcutaneousadministration of extracts of the suiprarenal bodies produces diabetesin rabbits and dogs. He found that such extracts given by the mouthhad no influence upon the proteid metabolism as indicated by theexcretion of nitrogen in the urine and that neitber sugarnor albuminappeared in the urine. He concludes from a series of 22 experimentsthat given subcuitaneously, suprarenal extract causes marked glycosurianot only on a diet free of carbohydrates but also after a fastso proloniged that all the glycogen has disappeared from the liver. Hestates, but without giving experimental data, that, in the fewexperiments in which the excretion of nitrogen was observed, noabnormal increase was noticed. He further states that acetone anddiacetic acid were not present and that oxy-butyric acid was thereforenot tested for. In a more recent paper2 he records some furtherexperiments upon adrenalin diabetes which confirm his previousobservations and show that even after repeated administration anadditional dose will produce glycosuria.
Zuelzer3 confirms Blum in all particuLlars and finds an increase ofsugar in the blood. He argues that, since B1 u m has shown that thecondition is not a toxic glycosuria duie to increased conversion ofglycogen, and since his own observationis prove that it is not renal inorigin like phloridzin glycosuria, it must be a true diabetes. Out ofmaniy cases in which lhevulose was administered in only three waslevolusuria observed. He states that he noticed pigmentation of themucous membranes of two cats injected for four weeks.
M etzger' gives a series of observations on dogs and rabbits showingthat the glycosuria is due to an increase in the glucose of the blood.
1 Deutsch. Arch. f. klin. Med. LXXI. p. 146.2 Pfluiger's Arch. xc. p. 617. 1902. 3 Berlin. klin. Wochen. p. 1209. 1901.4 Muinch. med. Wochenschr. p. 478. 1902.
ADRENALIN GLYCOSURIA.
Herter and Richards' record a series of experiments on theintra-peritoneal injection of the adrenalin chloride of Takamine in dogs.They found that sugar appeared in the urine even after fasting, andthat the animals manifested symptoms of excitement, that they vomited,and that in several cases they died in the couirse of twelve hours. Inthese cases they describe "destructive lesions of the gastro-enteric tractand pancreas" and a granular degeneration of the cells of the islands ofLangerhans. In a footnote they further describe the effect of paintingadrenalin on the surface of the pancreas. This caused a blanchingfollowed by a congestion simultaneous with the appearance of glucosein the urine.
In a more recent paper2 Herter and Wakeman record the resultsof further experiments, which do not fully corroborate all the previousconclusions. They found that the glycositria produced by adrenalin ina dog fasted and then treated with phloridzin was very slight. Whilerepeated injections in some cases did not induce glycosuria, this appearedto them to be due to malnutrition and not to the establishment of anytolerance of the substance. They confirmed the previous observationthat adrenalin painted on the pancreas produces glycosuria and theyfurther discovered that the application of many reducing or toxicsubstances acted in the same way. The observations on the changesin the islands of Langerhans described in their previous paper are notconfirmed.
Throughout my own experiments the preparation used was theadrenalin chloride 1 in 1000 of Takamine supplied by Parke,Davis & Co.
1. A true glycosuria is produced. My observations fully confirmthe statement of Blum as to the production of a glycosuria by thesubcutaneous itnjection of adrenalin in dogs and rabbits. The nature ofthe reducing substance in the urine was repeatedly tested byfermentation and by the phenyl-hydrazin test and in every case it wasfound to be dextrose.
2. A glyccemia is produced. The observations of Metzger andZuelzer are confirmed by the following observations.
1 New York Medical News, p. 201. 1902.2 Virchow's Arch. cIxx2X. p. 479. 1902.
287
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 weighed1065 grms.
A was killed at 12 noon. It had passed a little urine which gave a verystrong reduction.
B was killed at 12.30. It had passed 60c.c. urine containing 3-120/0glucose.
The blood was collected into a measured quantity of methylated spirit bysevering 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. 0.5 0/0 glucose in blood.B. 0-46 /0 ,.
Exp. II. Two rabbits, A and B of Exp. VII. which had been receivingdaily doses of from 1 to 5 c.c. of adrenalin chloride for more than a monthhad their last dose of 3 c.c. at 12 noon on the 5th. At 12 on the 6th, theywere killed, the thorax rapidly opened and the blood caught in methylatedspirit and treated as described above.
Blood of A contained 0175 0/0 glucoseB ,, 0205 /0/
The urine in the bladder of each containedA. 1-7 0/0 glucoseB. 11 0/0
Exp. III. In the two rabbits used in Exp. IV. the blood containedA. 0X21 0/0 of glucoseB. 0 25 ,S ,,
See also Exp. V.
3. The extent of the glycosuria is dependent on the amount ofcarbohydrates in the body.
Exp. IV. Two large rabbits were put in cages for the collection of urineon Dec. 8th.
A weighed 1650 grms. and was fed on small quantities of cabbage leavesand water.
B weighed 1950 grms. and was fed on turnips in large quantities.
288
ADRENALIN GLYCOSURIA. 289
Next day the urine of A gave no reduction, while the urine of B gave adoubtful reduction. A got 2 1 c.c. adrenalin chloride and B got 25 c.c.
TABLE I.A B
Sugar in urine Sugar in urineWeight Adrenalin at Weight - Adrenalin atat end Per Total beginning at end Per Total beginning
Day of day cent. in grms. of day of day cent. in grms. of day
1 1650 0 0 1950 0 0 -
2 1570 1'20 1-75 2-1 1900 5 00 4-5 2-53 15702 1X85 191
2'1 1835) 1-42 1.13 )_4 1550 5- 1770( '2 13 5.
Here the effect of adrenalin was to cause a much more copiousexcretion of sugar in the animal liberally fed on turnips in whichan accumnulation of glycogen in the liver had occurred.
The animals were killed at the end of the 4th day and the glucose of theblood determined:
A. 0*21 °toB. 0-25e/0.
The liver of A still contained 1 28 per cent. of carbohydrates expressedas glucose.
4. The glycosuria and glycceania are not due to a mere increase inthe conversion of glycogen to glucose. The method of experiment was tokeep the animal on a diet of a material from which glycogen could notbe formed, and to clear out the carbohydrates stored in the body withphloridzin and then to administer adrenalin.
Exp. V. A rabbit weighed 1690 grins. on Dec. 8th and it was fed onspongin and water and 025 grmns. of phloridzin were administered hypo-dermically. Next day very little urine was procured, and it gave a strongreduction. The urine passed next day gave no reduction, and the animal got2 c.c. adrenalin. On the following day the urine gave a strong reduction, and2 c.c. adrenalin were again given at 1 and the animal was killed at 3.30.
Urine in bladder gave a strong reduction and a marked fermentation.Blood contained 0 39 0/0 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 onthe 14th the urine gave a strong reduction. Another 0'3 grm. of phloridzinwas administered and the animal got spongin and water as food. On the15th and 16th the urine gave a marked reduction. On the 18th the urinegave no reduction.
2. N. PA TON.
2-2 c.c. of adrenalin chloride were injected at 3.30 p.m. The animal wasfound dead at 7 p.m., about 50 c.c. of urine having been passed. This gave aslight 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 27 0/0 of glucose.
5. The repeated administration of adrenalin is not always followedby 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 andthe presence + or absence 0 of reducing substances in the urine.The animals were fed on cabbage leaves, unless otherwise indicated.
A. Adrenalin. 1 1 1 1 1 1 1 1 1 1 0 1 2 2Sugar. +++++++t-0+++0+
The weight on the 1st day was 1280 grms., on the 14th, on which day it died,1090 grms.
B. Adrenalin. 1 1 1 1 1 1 1 1 1 1 0 0 2 2 2 25 22121 101 0 02 32 32 32Sugar. +++++++++00++++ ++++ 0 0 +++ +Adrenalin. 4 4 0 5 5 5 5 5 5 3Sugar. ++ 0 +++++++
The weight on the 1st day was 1740 grms., on the last (36th) day, when it was killed,1580 grms.
C. Adrenalin. 1 1 1 1 1 1 1 1 1 1 0 1 2 2 2 2 2 21 21 31 3 31,2 42 52 42Sugar. ++++++++++0+++++++ + 0 00 +++Adrenalin. 5 5 0 5 5 5 5 5 5 5 3Sugar. 0+0++++++++
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. per300 grins. of body weight, or 0 0003 grm. of adrenalin chloride per kilo.
In Exp. VIII. two small iabbits of 470 and 455 grms. had respectivelythe 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.
290
ADRENALIN GLYCOSURIA.
As a general rule a dose of 1 c.c. per 300 or 400 grms. of rabbit israpidly fatal.
7. In my experiments upon dogs I have not detected the presenceof diacetic acid or of acetone in the urine. The urine of hutch rabbitsfed on cabbage was fouind almost invariably to give the reaction withferric chloride both when under the influence of adrenalin and withoutthe drug.
A very constant reaction of the urine both in rabbits and in dogsis the development of a dark red ring when nitric acid is poured belowthe urine in testing for albumin. The nature of the pigment and ofthe chromogen yielding it has not been investigated.
8. The proteid metabolism under the administration of adrenalinundergoes the changes which are characteristic of a true diabetes. Oneof the most characteristic features of true diabetes is the inicrease in theammonia of the urine. This, von Noorden' maintains, is due to theincreased production of phosplhoric and sulphuric acid from the in-creased disintegration of proteids and the formation of lactic, diacetic,oxybutyric and other orgarnic acids.
It was therefore deemed desirable to investigate somewhat in detailthe influence of adrenalin on the proteid inetabolism.
The experiments were made upon rabbits and upon dogs, and theanalytic methods employed were those described in our various papersupon the changes in proteid metabolism already published in thisJaurnal.
Throughout the observations Merck's phosphotungstic acid, whichcompletely 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 9thday the rabbit was found dead. There were 23 c.c. of urine in the collectingbottle which contained a distinct trace of hmnmoglobin and of coagulable proteidsand which gave a strong reduction. The few drops of urine in the bladder alsogave a strong reduction and a distinct coagulum on boiling. The animalweighed 2050 grms. No serous exudation in any of the cavities. Thepancreas, liver and lungs seemed congested.
1 Pathologie des Stoffwechsels.
291
D. N. PA TON.
TABLE II.Nitrogen of urine Glucose per day
in grm.Total Urea N. Per cent.
Day in grm. in grm. of urea N.
1 1ill 1.05 942 *98 88 903 *54 *49 90
+4 1-47 1P31 905 '90 *84 84 206 *70 *64 92
+ 7 1P69 1-33 79 Reduction+8 1P65 1P14 69 6-75
The daily excretion of urine and of nitrogen was irregular but theaverage nitrogen excretion was as follows:
Before first injection ... 1'02Day of injection ... ... 0'994Next day ... ... ... 0'70Two last days of injection 1'67
The single injection of 2 c.c. although it caused an excretion ofno less than 20 grms. of glucose produced no marked change in theexcretion of nitrogen, but the second administration was accompaniedby a very marked increase.
The urea nitrogen before the first injection averaged 91 e/oOn the day of injection it was ... ... ... 84On the next day ... ... ... ... ... 92 ,,
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 therabbit, and the ammonia nitrogen was not estimated. These pointsare specially studied in the next experiment.
Exp. X. Rabbit, weight 1630grms.; had 500grms. of cabbage-leavesdaily. On the third day it was found that all the cabbage was not beingeaten 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 hydrochloricacid was put in the collecting bottle and this served to keep the urine nearlyneutral. On the 14th day the rabbit was found dead, weight 1500 grms.There was some serous fluid in the pleura and pericardium. The bladdercontained 24 c.c. of urine which gave a faint cloud with cold HNO. and, in
292
ADRENALIN GLYCOSURIA. 293
Esbach's tube, gave a precipitate equivalent to 0025 0/0 of proteids. Proteidswere not found in thewere very large.
Day
123456
+789101112
013014
f otaiin grMs.
2'102'071'791-651'372'101-371'610'701-831'231-421'380'40
urine during the life of the animal. The suprarenals
Urea N.Urea N.in grms
2'041-941'00
1'262'031'311'470'60
0'921-231'26
TABLE III.Nitrogen of urine
Per cent.of urea N.
9093
9296969185
758691
NHS, N. Per centin grms. of NH8, N.
'014'032
'019'033'015'039'047
'170'065'028'042
The daily excretion of urine and of nitrogen was more regular thanin the last experiment. The average nitrogen excretion was as follows:
Four days before injectionThree days of injectionThree days after injectionFirst day of second injection
1'72 grms.... 1'22 ,
1'46 ,,... 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 presentin the urine, but the distribution of nitrogen was markedly altered.The second series of injections was accompanied by the excretion of3'57 grms. of glucose on the first day and by the presence of glucose on
the second day as well.
Four days before injectionFirst day of injectionSecond ,. ..Third ,. is
First day followingSecond ,,
Third ,,First day of second injectionSecond ,. it .
PH. XXIX.
Urea N. Ammonia N.
94 1'4
96 1'1
91 2'4
85 6'9
75 13'986 4'591 2'0
10'0
19
Glucosein grMs
1'7210'00
3.57reduction
0'61'5
1'31'61.12-46'9
13'94.52'010'0
294 D. N. PATON.
In this experiment the excretion of sugar was comparatively smalland the decomposition of proteids as indicated by the nitrogen elimi-nated was not increased, but the modification of the nitrogenousmetabolism was profoundly altered, the proportion of ammonia nitrogenand of nitrogen not in ammonia or urea being steadily increased forfive days in the first series of injections, and on the second day withthe second series.
B. Dogs.
Exp. XI. This was really the Srst experiment performed. The weatherwas warm at the time and on the fifth, sixth, seventh, and eighth days theurine was distinctly alkaline and appeared to bave undergone ammoniacaldecomposition. Since in a previous experiment with the administration ofextracts of suprarenal sickness had been produced, an attempt was first madeto compare the metabolism on a day of fasting with the metabolism on a dayof 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 partof the experiment a larger dose, 10 c.c. or 0 7 c.c. per kilo, was administeredwithout fastinig the animal. The experiment was conicluded with the admini-stration 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.
Sugar
Totalin grms.
5A486-585-853-02
6'775-88
5'48
0-66
9'2933 grms. 6'38
4-564-875'96
45 grms. 6'134'67
Nitrogen of urine
Urea N. Per cent. NH8, N.in grms. of urea N. in grms.
4'50 84 *3105'37 83 -
4'92 84 '3972-54 84
7'58 80 *7485'20 81 '5743'72 81 '5763-83 79 '7724.59 77 *882
5-33 87 '684
4'00 85 *316
Day Inj ect.
1
2
3
4
5
6
7
8
9101112
1314
15
Fast
Fast & 4'2 C.c.
10 c.c.
1-3 phl.
Per cent.of NH3, N.
5-6
6-8
8-09 012-015-014-011-06-8
ADRENALIN GLYCOSURIA.
Leaving out of account the fourth day on which the dog fasted, theexcretion of nitrogen per diem averaged as follows:
First six days. ... ... ... ... ... 600 grins.Day of injection and three succeeding days ... ... 5-44 ,Day of phloridzin injection and following day ... ... 5 40
Although the excretion of glucose was considerable-30 grms. onthe day of injection-the excretion of nitrogen was not increased, andit was found that the dog, which was on a very liberal diet, had increasedin 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 84 6-2 9.8Day of injection 81 9 0 100
following 81 12 8X079 15 6.077 14 9go
Day after phloridzin 85 6'8 8'2
This shows a disturbance in the nitrogenous metabolism in the dogsimilar to that found in the rabbit, except that in the dog the decreasein the proportion of uirea nitrogen is entirely due to an increase in theammonia nitrogen.
Since special precaution was not taken to prevent ammoniacaldecomposition it was considered advisable to make another series ofobservations in which the urine was caught in a solution of hydrochloricacid.
Exp. XII. An Irish terrier bitch. Weight 10-87 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 practicallyabsent, and on the third day it was something over 5 grm. On this day therewas a slight cloud with cold HNO3 indicating the presence of a trace ofproteids in the urine. On the next two days the urine was free of proteidsbut gave a faint reduction. On the third day after the last injection the urinegave a very marked reduction, equivalent to *18 per cent. of glucose. Fer-mentation was distinct and reduced the specific gravity of the urine from1015 to 1012. Proteids were present to the extent of 0 025 per cent., estimatedby Esbach's 'Method. On the next day, the fourth after injection, there was
19-2
295
296 D. N. PA TON.
no reduction, but a trace of proteid was still present. On the next day therewas no reduction and proteids were absent, buit they re-appeared again onthe following day when a faint reduction was also observed.
TABLE V.
Day Ad- Sugar Nitrogen of urinerenalin ingrms. -- -per day Per cent. Per cent.
Total Urea N. of NH:, N. ofin grms. in grms. urea N. in grms. NH8, N.
123466789101112131415
-5 c.-.-5 c.c.-5 c.C.
2-3
+5
1-200
2-263-102-103-322-943-415-01
3-832-744-00
3-863-503-24
1-941-982-662-854-172-042-992-15
3.332-99
8885908383837878
8685
-120-145-196-263-378
-466-319
5.76-26-77-77-5
14-711-5
-249 6-4-313 8-9
Sulphur of urine Phos-/- "A phorusTotal Acid Per cent. ofurineS. in S. in of asP2O5grms. grms. Acid S. in grms.
0-860-801-001-081-08
-549 -295 53 1-281-041-56
*611 -398 65 1-681-281-08
The average daily excretion of nitrogen was as follows:
Before the injections . . .On days of injections and three succeeding days (the
third day of injection is omitted since some urinewas lost)
On last three days of experiment
2-68 grms.
3-82 Pt
3-50 ,,
Although the excretion of sugar was small the proteid katabolismwas distinctly increased.
The distribution of nitrogen was altered much in the same manneras in Exp. XI. On the days on which proteids were present in the urinethe proportion was not determined.
Before injectionFirst day of injectionSecond ,. of
Third ,. 9,
First day after injectionFifth and sixth days after injection
Per cent. of total N.I
Urea N. Aimmonia N. Other N.
87 6-2 6-883 7-7 9-383 7-5 9-583 - -78 11-5 8-585-5 7-6 6-9
ADRENALIN GLYCOS URIA.
This experiment shows very clearly that the fall in the proportionof nitrogen in urea is chiefly due to the increase of nitrogen inammonia.-
We had already found' that with such disturbances in the distributionof nitrogen when these were caused by diphtheria toxine, the proportionof unoxidised sulphur to oxidised sulphur is increased. The amnounts ofthese were determined in the urine of the day following the injectionand in that of fifth day after:
Acid sulphurper cent of total
Day after injection 53Fifth day after injection 65
The excretion of phosphoric acid was determined and it was foundto run parallel to the excretion of nitrogen.
P105 to100 parts of N.
Before injection 32With injection and during three succeeding days 31Last three days 38
Since the preceding experiments had yielded somewfliat contradictoryresults as to the changes in proteid katabolism under the administrationof adrenalin, and since the possible influence of the administration ofadrenalin on the absorption of proteids had not been studied, it wasthought 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. 2-15 3-22Milk 500 c.c. 0-366 1-83Water 600 c.c.
4*05
On the days indicated the dog got 10 c.cm. of adrenalin chloride in twodoses. 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 anddiacetic acid were absent from the urine but from the first day onwards tothe seventh day a dark purple ring with HNO3 was visible.
1 This Journal, xxiv. p. 331. 1899.
297
D. N. PA TON.
TABLE VI.
Day Adrenalin Sugarin grms.per diem
12345678910111213
10 c.c. 3110 C.C. 20'8
Nitrogen of urine_ <~~~~-1
Totalin grms.
2'152'152-772'88Lost3'694'783'723'6232'5314-08§3-16}1X97
Per cent.Urea N. ofin grms. Urea N.
2-32 842-46 85
3'103.943'103-022'103'502'671-68
8482838383858485
Per cent.NHi, N. ofin grms. NH8, N.
'216 5.4'216 5'4'148 5-3*179 6'2
*170 4X6*277 5X7'260 7-0'236 6'5'134 5'2'170 4'1'154 4'8'120 6'0
NitrogenN of faces
N. not in grmiin ureaor NHSin grms.
3'95 or0p99
1007'9per8.8 diem
11'412'310.010'511'810.91112J90)
2'73 or0'68perdiem
2'24 or0'56perdiem
The nitrogen balance is given below:
Intake per diem Output per diem
Urine Feeces Total
First Period (before injection) 4'05Second Period (days of injectionand two subsequent days) 4'05
Third Period (four succeeding days) 4'05
2'48 '99 3'47 + '58
3'95 '68 4'63 -'582'97 '56 3'53 +'52
The experiment does not show any disturbance in the absorption ofnitrogen, which seems to have steadily improved as the dog becomesmore accustomed to the oatmeal diet. The very marked increase inthe excretion of nitrogen under the administration of adrenalin is seento be due to an iniereased proteid katabolism, the output exceeding theintake by 0 63 grm. of nitrogen or 3'9 grms. of proteid. In this experi-ment the disturbance in the distribution of nitrogen is less marked thanin the others although it is in the same direction.
Before injectionDays of injection and two
succeeding daysFour succeeding days
Urea N. Ammonia N.
84-5 5'5
83'0 5.984'2 5'0
298
Total N.excreted,averageper diem
grms.
Nitrogenbalanceper diemin grms.
3.47 +-57
4'66 - '66
3.53 +'47
Balance
Other N.
10
11-110'8
ADRFNALIN GLYCOSURIA.
CONSIDERATION OF THE EXPERIMENTS ON PROTEID METABOLISM.
These experiments indicate that the sugar excreted is not entirelyderived from the proteids of the food or of the body. Throughout theseries there is a striking absence of any relationship between theamount 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 decom-position of proteid, 14-35 grms., was quite insufficient to yield the sugarexcreted.
The most marked change in the proteid metabolism is the increasein the proportion of ammonia nitrogen and the concomitant fall in theproportion of urea nitroaen under the administration of adrenalin. Thisoccurred both in rabbits and in dogs, and in every case, except in thelast experiment, it was well marked. In this respect the metabolismunder the influence of adrenalin resembles the condition in truediabetes.
The very marked increase in the ammonia found in Exps. X. andXI. as compared with that in Exp. XII. is rendered explicable byDr Scott's investigation made in this laboratory, on the action of largedoses of glucose on the metabolism'. He shows that the subcutaneousinjection of such doses produces an increased proteid metabolism andgenerally an increased production of ammonia, and he refers toHarley's demonstration of the production of lactic acid2 as anintermediate product in the metabolism of sugar and points out theprobability that the disturbances in the proteid metabolism observed byhim are due to such a production of acids.
If then the administration of adrenalin interferes with the properutilization of glucose by the tissues, as these experiments show to bethe case, then, if the tissues are absolutely unable to metabolise sugareven imperfectly and it is at once eliminated, the toxic effects of its acidproducts will be absent as in Exp. XII.; but if the utilization ofsugar is simply interfered with, then as in Exps. XI. and XII. thetoxic effects of intermediate acid products will manifest themselvesby the increased formation of ammonia.
The proteid mietabolism was not increased in either of the rabbitsor in the first dog used. But it was distinctly increased in the last two
I This Journal, xxviII. p. 107. 1902.2 This Journal, xxi. p. 391. 1891.
299
D. N. PA TON.
dogs. The explanation of this is simple. In the rabbits and in thefirst dog the diet was liberal, but in the last two dogs used aninsufficient diet was given.
The following Table shows the marked difference in the diets ofthe 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. 14-95 6-0 37-5 2-0XII. 10-87 2-68 16-7 1.5XIII. 14-95 2A48 16-7 1.1
In Exp. XI. the supply of food was so liberal that the withdrawalof 33 grms. of glucose caused no increase in the proteid metabolism,while in Exps. XII. and XIII. where the supply of food was insufficientto maintain the weight of the animal, the onset of glycaamia caused anincreased proteid metabolism.
CONCLUSIONS.
The subcutaneous administration of adrenalin in dogs and rabbitscauses a true glycosuria and glycaemia, the degree of which dependslargely upon the amount of carbohydrates in the body but which occurwhen stored carbohydrates have beeu eliminated. The glycosuria isapparently due to a diminished utilization of sugar in the tissues sinceit is not due to a mere increased formation of glucose or to increasedexcretion of sugar by the kidneys.
That the effect is due to a toxic action of the adrenalin and thatit is not caused by an interference with the processes of oxidation dueto the vascular changes is indicated, first by the extent of the glycosuria-which is far more marked than that observed as the result of mereinterference with oxidation, and secondly, by the fact that the glycosuriais slight in guinea-pigs where the vascular changes are much moreprominent.
The observations of Herter support the view that the toxic actionis not a direct one, but that it operates through the pancreas.
During the prolonged daily administration of adrenalirl, days mayoccur on which sugar does not appear in the urine.
A distinct tolerance of the drug is established.
Soo
ADRENALIN GLYCOSURIA. 301
Diacetic acid and acetone have not been detected in the uriue ofdogs, but a dark red ring at the junction of the urine with nitric acid isconstantly present.
The study of the proteid metabolism shows (1) that the sugar is notentirely derived from the breaking down of proteids, (2) that there is amarkedly increased production of ammonia, and (3) that, on an insuf-ficient diet, the decomposition of proteids is markedly increased, whilethe absorption of proteids is not interfered with. The proteid metabolismunder adrenalin thus behaves as it does in ordinary diabetes.
Dr Drumm ond is at present investigating the structural changesin the tissues produced by the administration of adrepnalin in theseexperiments.
