6I I:6I hypophysectomy. This diminution of diabetes is shown particularly as. hypophysectomized or totally decerebrated [Houssay and

Transcription

1 6I I:6I KETOSIS IN THE PANCREATIC AND PHLORRHIZIN DIABETES OF HYPOPHYSECTOMIZED DOGS. BY CIRO T. RIETTI. (Institute of Physiology, Faculty of Medicine, Buenos Ayres.) IN the hypophysectomized toad total extirpation of the pancreas either does not produce diabetes or causes merely a slight rise in the blood sugar. The implantation of the anterior lobe of the pituitary definitely produces or increases the diabetes of the pancreatectomized toad, whether previously hypophysectomized or totally decerebrated [Houssay and Biasotti, 1931 a]. Work done by Houssay and Biasotti [1931 b and c] shows that the diabetes catsed by pancreatectomy or by injection of phlorrhizin is considerably diminished in dogs which have previously been subjected to hypophysectomy. This diminution of diabetes is shown particularly as regards the glycosuria, blood sugar, time of survival and D: N ratio. The present data as to the excretion of ketones in the diabetic dog indicate also a decrease in the severity of the diabetes in hypophysectomized animals. They also show that the anterior lobe of the pituitary is concerned in the ability of the organism to form ketone bodies. Animals and Method. 74 dogs were used. The samples of urine were taken almost entirely from the animals experimented on by Drs Houssay and Biasotti. The operative methods are described in the work quoted, from which the figures relating to the sugar in blood and urine given in Tables I to III have been taken. The method of determination of the total ketone bodies was that of van Slyke [1917] modified by using only 10 c.c. of urine instead of 25 c.c., reducing in equal ratio the reagents used in the first part of the method. RESULTS. 1. Ketosis in pancreatectomized dogs. Under this heading we include a summary of the data already published [1931] with the addition of the results obtained in six other dogs. Examining Table I, it is seen that in the controls there is an average daily excretion of 76 mg. of ketone bodies per kg.; this is low compared

2 KETOSIS AFTER H YPOPH YSECTOM Y. 93 TABLE I. Ketosis in pancreatic diabetes in dogs. With hypo. physis With tuber excised Controls cauterized (9 dogs) (6 dogs) (5 dogs) Ketosis (acetone in mg./kg.) Glycosuria (sugar in g./kg.) Blood sugar (average mg./100 c.c.) with the values obtained by Hedon [1930], who found on suspending the administration of insulin to a pancreatectomized dog the ketone bodies in 24 hours amounted to more than 0 5 g. per kg. per diem. MacLeod [1928] quotes data of Chaikoff, who found about 0 3 g. of ketone bodies per kg. excreted daily from the third to the sixth day after deprivation of insulin and food in pancreatectomized dogs. Our dogs received insulin in the post-operative period during healing of the wounds. Each day they had 100 g. of fresh bovine pancreas and about 300 g. of meat. During the days when the observations recorded in Table I were made, they did not have insulin. All our determinations give lower ketone values than those obtained by the workers quoted, which must be attributed to the different treatment of the animals. The average weight of the hypophysectomized dogs was 8-3 kg., the smallest 6*4 kg., the heaviest 11*9 kg.; that of the controls ranged from 6 to 15 kg., with average 9*3 kg.; the dogs with cauterized tuber were a little lighter (average 5*7 kg.). The pituitary had been removed several weeks or even months previously. The observations on the urine extended over several days, in three cases over three weeks or more. TABLE II. Ketosis in phlorrhizin diabetes in fasting dogs. With With With hypo- tuber With postphysis cauter- thyroid lobe excised Controls ized excised removed (6 dogs) (6 dogs) (7 dogs) (6 dogs) (4 dogs) Ketosis (acetone in mg./kg.) Glycosuria (sugar in g./kg.) Blood sugar (average mg./100 c.c.) Of the nine hypophysectomized dogs, which never received insulin, five excreted ketone bodies equivalent to 13 mg./kg. or less in 24 hours: two of the, remaining four excreted 25 and 28 mg., which is less than the smallest amount obtained from any of the controls, and the other two 44 and 54 mg. In these latter four dogs the diabetes came on with great rapidity and intensity and there was a high blood sugar; the one that

3 94 C. T. RIETTI. gave 44 mg. had the highest degree of glycosuria of all (2.83 g./kg.). In three of the dogs with very low degree of ketosis the diabetes was slight with but little hyperglyceemia; from time to time in these animals hypoglyesemic attacks came on which were of some severity and finally caused death. The average ketone excretion for the whole group was only 28 p.c. of that for the controls, and the average blood sugar and average urinary sugar were, as shown in Table I, conspicuously lower than in the controls. In the hypophysectomized dogs the total ketone elimination varied to some extent with the blood sugar and with the urinary elimination of sugar. Pancreatectomized dogs with lesion of the tuber cinereum (produced by galvano-cauterization from the pituitary stalk to the posterior limits of the corpora mammillaria) showed an average ketone elimination intermediate between that of hypophysectomized and of control animals. A somewhat similar effect of lesion of the tuber cinereum has been observed by Houssay and Biasotti in the glyceemia of phlorrhizin diabetes, which seems to indicate a slight inhibition of the anterior pituitary. Three results are lower than the average for the hypophysectomized. The blood sugar is higher than in the hypophysectomized dogs. 2. Ketosis in phlorrhizin diabetes duringfasting. Most of the dogs used were those experimented on by Drs Houssay and Biasotti, who showed that the diabetes due to phlorrhizin injection was diminished in hypophysectomized dogs. Before the experiments the dogs were kept in separate metabolism cages and received daily 400 to 500 g. of beef. At the beginning of the experiment they were starved, but were allowed water ad lib.; that day they received intravenously 1 g. of Kahlbaum's phlorrhizin dissolved in 25 c.c. of 1-2 p.c. sodium bicarbonate solution and on each succeeding day 1 g. of phlorrhizin suspended in 20 c.c. of olive oil was injected under the skin of abdomen or flank. Phlorrhizin was injected into controls and into dogs which had been hypophysectomized more than two weeks and up to as much as nine weeks before, or thyroidectomized eight weeks or more previously, or had lesions of the tuber cinereum which were three weeks or more old or had been deprived of the posterior lobe for two or three months. The observations on the urine of each day extended generally over four or five days, but sometimes over a period longer than that. The results are shown in Table II, from which it can be seen that the hypophysectomized eliminate much less ketone bodies (5 mg./kg. in 24 hrs.) than the other animals ( mg./kg.). They also have a lower blood sugar and less glycosuria. There is

4 KETOSIS AFTER HYPOPHYSECTOMY. probably less production of sugar as the respiratory quotient and basal metabolism do not show an increase in the consumption of carbohydrate according to the experiments of Houssay and Biasotti. 3. Ketosis in phlorrhizin diabetes in fed animals. The total ketone bodies present in the urine of twenty-five dogs was determined, completing the work of Drs Houssay and Biasotti. The food daily received by the dogs is shown in Table III. The phlorrhizin was given in the same way and amounts as described for the fasting dogs. TABLE III. Ketosis in phlorrhizin diabetes in (a) hypophysectomized, (b) control dogs. Fed with Fat, 100 c.c. olive Meat, 300 g. daily Sugar, 50 g. daily oil emulsion daily (a) 5 dogs (b) 4 dogs (a) 5 dogs (b) 4 dogs (a) 4 dogs (b) 3 dogs Ketosis (acetone in mg./kg.) Glycosuria (sugar in g./kg.) Blood sugar (aver. age mg./100 c.c.) On the whole, food increases the ketone elimination in hypophysectomized animals and decreases it in the controls (see Table III). In both groups the blood sugar and glycosuria are raised. The hypophysectomized always eliminate much less ketone bodies than the controls on a similar diet Ṁeat diet. The hypophysectomized dogs show only slight increase in ketosis (from 5 mg. in fasting to 12 mg.) in spite of great increase in the glycosuria; the controls show slight diminution (88 mg. in fasting and 56 mg. on meat diet). Sugar diet. The controls show much lower ketone elimination (35 mg.) than in fasting (88 mg.) in accordance with the known anti-ketogenic action of glucose. This action apparently fails in the hypophysectomized where the ketone elimination is more than three times that in fasting (18 mg., compared with 5 mg.). Fat diet. The controls eliminate similar amounts (88 mg. in fasting and 74 mg. on fat diet). The hypophysectomized show a slight increase (from 5 to 11 mg.), but it is not possible to draw definite conclusions owing to the brevity of the observations as hypophysectomized dogs on a fat diet die rapidly in hypoglycsemia (on the second, third and fifth days), while they survive on meat or sugar. 95

5 96 C. T. RIETTI. GENERAL CONCLUSIONS. 1. Ketone elimination is notably less (1: 3.6) in the pancreatice diabetes of hypophysectomized dogs than in the controls. It bears a. relationship to the level of the blood sugar. It is intermediate in animals with lesions of the tuber cinereum. 2. The ketone elimination is much less (1: 17) in the phlorrhizin diabetes of hypophysectomized fasting dogs than in the normal controls; in thyroidectomized animals, in those without the posterior pituitary lobe, and those with lesions of the tuber cinereum ketone elimination isgreater than in the controls. 3. In hypophysectomized dogs on meat, sugar or fat diets the ketone elimination in phlorrhizin diabetes is always less than in the correspondingcontrols. 4. The intake of sugar diminishes the ketone elimination in thecontrols, but in the hypophysectomized there is a slight rise. 5. The ketone elimination of hypophysectomized fed dogs under phlorrhizin does not increase as much as does the glycosuria during meat intake. 6. Pituitary insufficiency always diminishes the urinary elimination of ketone bodies. This work was suggested by Professor Ho us say in connection with his researches on diabetes in hypophysectomized dogs. He gave me the opportunity of carrying it out and constant help and valuable suggestions for which I am deeply grateful. REFERENCES. Hedon, E. (1930). J. Phy8iol. Path. g!n. 28, 1. Houssay, B. A. and Biasotti, A. (1930). Congr. Internat. Biol., Montevideo, Oct Arch. Soc. Biol., Montevideo, 1931, Suppl. II, 277. Houssay, B. A. and Biasotti, A. (1931 a). Pffiger8 Arch. 227,239. C. R. Soc. Biol., Paris, 1930, 105, 407. Rev. Soc. Arg. Biol. 1930, 6, 66. Houssay, B. A. and Biasotti, A. (1931 b). PflJiger Arch. 227, 657. C. R. Soc. Biol., Paris, 1930, 105, 126. Rev. Soc. Arg. Biol. 1930, 6, Nos. 5 and 6, 326. Houssay, B. A. and Biasotti, A. (1931 c). Pfluigers Arch. 227, 664. C. R. Soc. Biol., Paris, 1930, 105, Rev. Soc. Arg. Biol. 1930, 6, 251. MacLeod, J. J. R. (1928). Fuel of Life, 73. Princeton. Rietti, C. T. (1930). Congr. Internat. Biol., Montevideo, Oct Arch. Soc. Biol.,. Montevideo, 1931, Suppl. II, 332. Van Slyke, D. D. (1917). J. biol. Chem. 32, 455.