JOUR. D . D . VOLUME VII NOVEMBER, 1940 NUMBER 11

II. An Experimental Study of the Effects of the Pituitary and Thyroid Glands on Carbohydrate Metabolism

A Preliminary Report* By

SAMUEL MORRISON, M.D.t and

MAURICE FELDMAN, M.D.S BALTIMORE, MARYLAND

I N the same group of dogs utilized for the preceding study (Section 1. See page 451) investigations

were made on the effect of anterior lobe pituitary gland extract (anterior lobe pituitary body, see final note) and desiccated whole thyroid gland (U.S.P.) therapy upon sugar metabolism.

THE E F F E C T OF ANTERIOR LOBE PITUITARY EXTRACT ON NORMAL DOGS

Blood sugar tolerance tests, following the adminis- tration of 100 grams of dextrose by stomach tube, were carried out on four normal dogs at the end of a 21 day period of daily subcutaneous injections of an- terior lobe pituitary extract to a total dosage of 31 cc. The blood sugar values (determined by the Folin- Wu method) and the corresponding curves are pre- sented in Chart 1.

From this chart it is seen that the animals have a decreased sugar tolerance with a diabetic type ,~f curve, illustrating the diabetogenic (hyperglycemic) effect of this anterior lobe pituitary extract on the normal dog. These findings are in accord with those obtained by Houssay (1) and others (2, 3) who have shown that anterior lobe pituitary extract can produce diabetes in normal mammals. In discussing the dia- betogenic action of anterior pituitary lobe extract Houssay reports that in the dog the blood sugar begins to rise gradually from the second or third day of in- jection until it reaches levels of 0.18 to 0.30 per cent.

HYPOPHYSECTOMIZED DOGS - - "PLUS"w In two hypophysectomized-vagotomized dogs, one

with and one without thyroidectomy, in which no medication was given, blood sugar tolerance tests yielded the data presented in Chart 2.

These findings indicate an increased tolerance and increased mobilization with a hypoglycemic tendency. Since they are based on only two animals no definite conclusions can be drawn, but fur ther work is in progress on this phase of the problem. The obser- vation has been established that in the absence of the pi tui tary gland there is a tendency to hypoglycemia and hypersensitivity to insulin. Moreover, hypophy- sectomized dogs rapidly develop hypoglycemia when fasted (5).

It has also been found that larger doses of sugar by

* From the Gastro-Enterological Division of the Depar tment of Medi- cine, University of Maryland, School of Medicine.

tAssistant Professor of Gastro-Enterology. SAssistant Professor of Gastro-Enterology. Note : This work was supported by the Julius Friedenwald Research

Fund. w refers to the other operations. Presented before the American Gastro-Enterological Association, At-

lantic City, June 10, 1940.

mouth or glucose by injection were necessary to pro- duce glycosuria in hypophysectomized than in normal dogs, although this increase in tolerance was not con- firmed by all investigators.

In dogs, Houssay observed that 2 grams of glucose administered by mouth per kilo of body weight pro- duced in the normal a sugar curve which rises higher and descends lower while in the hypophysectomized animal the curve rises lower and descends more gradu- ally although there are some variations, such as our work demonstrates. After the intravenous adminis- tration of 1 gram of glucose per kilo the sugar curve in the hypophysectomized dog rises higher and de- scends more slowly. On the other hand, if hypophy- sectomized rabbits receive glucose by mouth the blood sugar rises less and the secondary fall in blood sugar is greater than in normal rabbits.

It has already been demonstrated by us (4) that vagotomy alone does not significantly influence car- bohydrate metabolism. Houssay has also reported that the vagus has only a secondary and accessory role causing a more rapid and perfect regulation in these cases. After section of the vagus nerves, for example, it was found that the blood sugar is maintained within normal limits and the curve of sugar tolerance is only slightly affected.

ANTERIOR LOBE P I T U I T A R Y E X T R A C T T H E R A P Y IN HYPOPHYSECTOMIZED

DOGS - - "PLUS" Blood sugar tolerance tests were carried out in three

hypophysectomized dogs with and without thyroidec- tomy; each had two weeks of subcutaneous treatment (total dosage 21 cc.) with anterior lobe pi tui tary ex- tract. The results are presented in Chart 3.

In this chart one observes relatively normal curves and it appears that in the absence of the pi tui tary gland the medication acts as replacement therapy.

E F F E C T OF THYROID T H E R A P Y ON CARBOHYDRATE METABOLISM

It was of interest to observe what effect thyroid therapy would have upon the normal dog and upon those which have been thyroidectomized-hypophysecto- mized. Desiccated whole thyroid gland (U.S.P.) was administered daily by mouth in a dosage of 0.4 gin. per kilo body-weight.

THE E F F E C T OF THYROID THERAPY ON NORMAL DOGS

In four normal dogs sugar tolerance tests were done. One had no thyroid therapy and three had thyroid

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Chart 1. Blood sugar tolerance curves on four normal dogs showing the diabetogenic hyperglycemic effect pro- duced by the subcutaneous administration of the extract of anterior lobe of the pituitary gland.

t reatment for a period of 18 days. The results are presented in Chart 4. These values indicate that thy- roid therapy produces a thyroid hyperglycemia effect. I t has been reported by others (1) that thyroid treat- ment increases the resistance of normal or thyroid- ectomized animals to insulin but decreases it if given in excessive doses.

THYROID T H E R A P Y IN HYPOPHYSECTO- MIZED DOGS - - "PLUS"

In three hypophysectomized dogs, with and without thyroidectomy, similar thyroid therapy over a period of 18 days yielded the results shown in Chart 5.

These values indicate that the effect of thyroid therapy in the absence of the pi tui tary or thyroid glands or both differs markedly from that which occurs in the normal following thyroid medication. The striking hyperglycemic curve which was observed in the normal is no longer present. Similar obser- vations were made in these same animals following the administration of anterior lobe pitui tary extract. In each case therapeutic administration of either an- terior pi tui tary or thyroid extract overcomes the effect of the gland r e m o v e d (i.e. acts as replacement therapy) and allows the latent hypoglycemic effect of

the remaining glandular deficiency to assert itself. In other words, by therapy we actually produce the same effect on the blood sugar as would follow the replace- ment of the gland itself. I t would seem that with re- gard to carbohydrate metabolism anterior pituitary gland and thyroid gland medications are not medicated through either gland necessarily b e c a u s e in two instances both have been removed. Furthermore, Long, Katzin and F ry (6) report experiments on the dia- betogenic effect of anterior pi tui tary extract in ad- renalectomized-pancreatized animals which indicate that such activity is not mediated entirely by the adrenal cortex but that a synergism between the two hormones may explain the mechanism. On the other hand, Houssay believes that the so-called diabetogenic hormone has a direct action independent of its in- fluence on the thyroid or adrenals although its el- fectiveness, like that of. other agents, is less or may even fail in profound adrenal insufficiency. The direct action is to stimulate and facilitate the production of sugar and perhaps to regulate its utilization. In other words, the anterior lobe of the pituitary has a glucose regulating effect.

BASAL METABOLISM In the three hypophysectomized dogs, one vago-

tomized, one thyroidectomized and one vagotomized- thyroidectomized, basal metabolism tests carried out by Dr. D. C. Smith, yielded the following results:

Dog 02 consumed per min. per kg. R.Q. 1 4.4 .84 2 4.8 .80 4 3.4 .81

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454 AMERICAN JOURNAL OF DIGESTIVE DISEASES VOLUME VII NUMBER 11

Chart 2. Blood sugar tolerance curves on two untreated hypophysectomized-vagotomized dogs, and (A) with thy- roidectomy and one (B) without thyroidectomy showing a hypoglycemia.

JOUR. D . D . MORRISON AND FELDMAN--EFFECTS OF THE PITUITARY AND THYROID GLANDS ON METABOLISM 455 NOVEMBER, 1940

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456 AMERICAN JOURNAL OF DIGESTIVE DISEASES VOLUME VII NUMBER 11

However , fo r our subsequent s tudies we have made a r r a n g e m e n t s fo r the p r epa ra t i on of a defini tely s tandard ized a n t e r i o r p i t u i t a r y product .

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Chart 5. Blood sugar tolerance curves after thyroid t reatment on three hypophysectomized dogs: (A) with thyroidectomy, (B) with thyroidectomy and vagotomy and (C) with vagotomy showing curves approximating the normal.

R E F E R E N C E S

1. Houesay, B. A. : Diabetes as a Disturbance of Endocrine Regu- lation. Am. J . M. So., 193:581, May, 1937. Carbohydrate Metab- olism. New Eng. J. Med., 214:971, 1936.

2. Rynearson, E. H. and Hodgson, C. G. : Recent Advances in Knowledge of the Anter ior Lobe of the Hypophysis. Arch. Int. Med., 62:160, 1938.

3. Young, F. G. : LXVI I I . The Diabetogenic Action of Crude Anter ior P i tu i ta ry Extracts . Biovhem. J., 32:513, 1938.

4. Friedenwald, J . , Feldman, M., Morrison, S. and Ullman, A . : Sugar Metabolism and Blood Studies Following Vagotomy. Am. J. Clin. Path., 3:271, 1933.

5. Long, C. N. H. and Lukens, F. D. W . : The Effects of Adrenalec- tomy and Hypophysectomy Upon Exper imenta l Diabetes in the Cat. J. Exp. Med., 63:465, 1936.

6. Long, C. N. H., Katzin, B. and Fry, E. G.: The Adrenal Cortex and Carbohydrate Metabolism. Endocrinology, 26:309, 1940.

7. Verzar , F. and Wahl, V. : W i r k u n g des Hypophysenvorderlappen- hormons auf den O~ Verbrauch yon Meerschweinchen. Biochem. Ztschr., 240:37, 1931.

D I S C U S S I O N

DR. J U L I U S F R I E D E N W A L D (Bal t imore) : Mr. President: In their presentation last year Drs. Morrison and Feldman presented experimental evidence to indicate that increased thyroid activity increased gastro-intestinal motility. At that time I suggested that this problem was fa r from simple since the thyroid rarely functioned alone and that fur ther studies were necessary to clarify the role played by various glands on gastro-intestinal function.

In their more recent study the problem concerned itself with the effect of the pi tui tary on the motility of the gastro-intestinal tract. Unlike the thyroid, the gastro-in- testinal motility does not appear to be affected by the administration of anterior pi tui tary extract. On the other hand, the administration of anterior lobe pituitary extract was found to bring about a hyperglycemic state in normal dogs, whereas hypophysectomy was followed by a hypo- glycemia.

The close relationship of certain of the endocrines to the digestive systems is still obscure in many respects. I t is to be hoped that fur ther studies of these problems may more clearly define the relationship that exists between the gastro-intestinal endocrine systems.

The Fate oF Ingested Glucose Solutions of Various Concentrations at Different Levels of the Small Intestine ~

By

HARRY SHAY, M.D., J. GERSHON-COHEN, M.D., D.Sc.' (Med.), SAMUEL S. FELS, LL.D. and

F. L. MUNRO, Ph.D. P H I L A D E L P H I A , P E N N S Y L V A N I A

R E C E N T L Y we (1) repor ted on the behavior of va r ious concent ra t ions of glucose in the gas t ro-

duodenal segment . In the pas t year we have extended our s tudies to the o the r segment s of the small in-

tes t ine. E X P E R I M E N T A L D A T A

Our experimental technic was essentially that previ- ously reported (1). However, instead of the three-lumen tube, a four-lumen tube was used. This tube was con- structed for us on our specifications by George P. Pilling and Son. Through lumen 1, at the distal end, a balloon was inflated; above this a distance of 3" with holes �89 apart opened into lumen 2; above these holes, a second balloon connected to lumen 3; and finally, a distance of 3" with holes � 89 apart opening into lumen 4. (Diagram I) .

~ F r o m the Medical Research Laboratory Samuel S. Fels Fund, and the Gastro-Intest inal Division Medical Service I, Mt. Sinai H o s p i t a l .

Presented before the American Gastro-Enterological AssociatiQn, :At~ lantic City, N. J . , J u n e 1O, 1940.

This arrangement reduced failures from seepage past the balloon connected to lumen 3, since this material was re- tained by the distal balloon and collected through the openings in the segment between the balloons.

This precaution of an additional balloon and the collec- tion of material are essential in any quantitative intesti- nal studies done in man. While a single balloon may be sufficient at times, we have seen repeatedly, by using the phenol red indicator, that slight seepage beyond a single balloon occurs very often.

In use, suction was applied to lumina 2 and 4 by means of a differential water level of about 70 cm. and a mercury manometer inserted in the circuit to make certain that the suction was constant. Af te r partial inflation, the bal- loon lumina were connected to a constant-level device similar to that described by Abbott, Kar r and Miller (2). This permitted flexibility in balloon-volume in response to peristaltic contractions while insuring constant balloon- contact with the intestinal walls.