The effect of chronic prolactin administration upon the blood sugar,insulin and free fatty acid response to a glucose load in the dog

Summary The effect of chronic prolactin treatment on blood sugar, serum immunoreactive insulin and free fatty acid levels has been studied in normal dogs in the post-absorptive condition and during an i.v. glucose tolerance test. It was observed that: 1) the chronic administration of prolactin failed to affect either blood sugar or serum immunoreactive insulin levels in these animals in the post-absorptive condition and induced a very minor non-significant increase in serum free fatty acid concentration; 2) although prolactin chronic administration induced a moderate reduction in the blood sugar response in the first fifteen min after the glucose load, the average glucose level, k_glucose, and serum IRI profile were unaffected; 3) prolactin administration slightly accelerated the fall of FFA levels during glucose administration as well as the return to baseline values in spite of the high blood glucose and insulin levels. In dogs having undergone chronic prolactin treatment the serum FFA concentration was higher than in non injected animals in the final stages of the test, i.e. at the moment when blood glucose and insulin had returned to basal levels. The physiological significance of these changes is discussed. Traduzione a cura degli AA.     

The mechanism of insulin secretion after oral glucose administration

Summary Concentrations of immunoreactive insulin activity and of blood glucose were measured in portal and peripheral venous blood in six conscious dogs after oral administration of 1.0 g/kg glucose. Portal venous samples were obtained either by chronic catheterization or by direct puncture of the portal vein through a London-cannula. Portal venous IRI was already significantly increased 5 min after the onset of the stimulus. Peripheral venous IRI pattern reflected this early increase, but the peripheral venous blood glucose level was unchanged. The results indicate that the early peripheral venous IRI increase reflects a pancreatic insulin secretory reflex.Investigations supported by the research project Diabetes mellitus and diseases of lipid metabolism of the Ministry of Health of the GDR     

Blood glucose control and insulin clearance in unrestrained diabetic dogs portally infused with a portable insulin delivery system

Summary Long term glucose control in pancreatectomised dogs has been obtained with portal insulin therapy. When compared to a previous similar study using peripheral infusions, 20% less exogenous insulin was required and peripheral fasting insulin levels were 30% lower. Animals (n = 5) were unrestrained, conscious and carried a programmable insulin pump for 163–224 days. In the post-absorptive state blood glucose was normal (87±5 mg/dl) as was plasma insulin (10±1 mU/l) with porcine insulin infused at a basal rate of 0.36±0.01 mU/kg/min. Following ingestion of a standard mixed meal the infusion rate was increased to 2.47±0.09 mU/kg/ min for 7 1/2 h resulting in post-prandial normalisation of blood glucose. Peripheral plasma insulin levels were twice normal during the post-prandial infusion, but only half those previously reported with peripheral infusions. Insulin clearance rates were 37 ml/kg/min in the basal state and rose significantly post-prandially. In the absence of extra meal-time insulin the clearance rate was unaffected by the resulting post-prandial hyperglycaemia and similar to values observed with insulin infused peripherally at 0.45±0.03 mU/kg/min. No significant increase in the post-prandial rate of insulin clearance relative to the fasting rate was observed with peripherally administered insulin. It was thus concluded that portal insulin replacement in pancreatectomised dogs could normalise both blood glucose and insulin in the fasting state, but post-prandial peripheral insulin levels remained elevated.     

Increased serum immunoreactive insulin in rabbits fed a protein- and mineral-rich diet

Summary In rabbits fed a diet of pellets containing approximately 12% protein, 4% fat, 44% nitrogen-free extracts and 1% calcium carbonate, serum immunoreactive insulin (IRI) was found to increase to values as high as 1134 U/ml three hours after the intake of food. After oral glucose (1.75 g/kg), glucose increased by an average of 105 mg% and IRI by 57 U/ml, whereas after 100 g of pellets these levels increased on the average by 45 mg% and 210 U/ml, respectively. There was a significant correlation between the IRI levels and the amount of food consumed, and a significant correlation (P<0.001) between the glucose and IRI levels after intake of food. In rabbits that were fed natural diet such as sugar beet and oats, the increases in glucose and IRI were small. Addition of meat and bone meal as well as the mineral-vitamin supplement containing up to 2 g calcium carbonate caused a considerable increase in glucose and IRI. It is suggested that the high amount of calcium in the feed stimulated the glucose-induced insulin release.     

Efecto de la terapia crónica con cortisol sobre le respuesta insulínica a la hiperglucemia en el perro tiroprivo

Résumé Nous avons étudié l'effet du traitement cronique avec cortisol sur la response insulinique à l'hiperglycémie chez le chien thyroïdectomisé. L'hiperglycémie a été provoquée par une injection rapide intraveineuse de glucose chez des chiens normaux et thyroïdectomisés, ces derniers traités ou non au cortisol. Sur les prises de sang veineux obtenues dans les 90 min qui ont suivi la surcharge de glucose nous avons mesuré: a) la glycémie; b) l'insuline sérique immunoréactive; c) la concentration d'acides gras libres dans le sérum. La glycémie à jeun était normale chez les chiens thyroïdectomisés non injectés et a augmentés modérément après le traitement avec cortisol. Cette augmentation n'était pas significative dans nos conditions experimentales. La constantek de Conard n'a pas été affectée par la thyroïdectomie, combinée ou non avec le traitement au cortisol. L'insuline sérique inmmunoréactive était aussi normale chez les chiens thyroïdectomisés non injectés et à jeun, mais a augmentée après le traitement de cortisol. Chez les chiens thyroïdectomisés la response insulinique à l'hiperglycémie était à peine au dessus du normal et plus maintenue que chez les controles normaux, et a augmenté davantage après le traitement au cortisol. La concentration d'acides gras libres dans le sérum était normale chez les chiens thyroïdectomisés à jeun, avant et après le traitement au cortisol et a disminué dans les trois groupes après l'administration de glucose. Pendant la preuve nous avons detecté chez les chiens thyroïdectomisés une tendance sous-normale des acides gras libres sériques; après le traitement au cortisol, l'importance de cette diminution n'a pas changé, seulement qu'elle s'est maintenue jusqu'à la conclusion de la preuve.

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Summary We have studied the effect of chronic cortisol treatment on the insulin response to hyperglycaemia in thyroidectomized dogs. Hyperglycaemia was induced by rapid i.v. glucose injection in cortisol-treated thyroidectomized dogs, in uninjected thyroidectomized dogs, and in normal controls. Blood sugar, serum immunoreactive insulin (IRI) and free fatty acids (FFA) were measured in each blood sample over 90 min following glucose load. Blood sugar was found to be normal in overnight fasted uninjected thyroidectomized dogs. Mildly increased blood sugar levels were detected after cortisol therapy; this rise was, however, non-significant in our experimental conditions. Conard'sk constant remained unaffected by thyroidectomy whether combined with cortisol treatment or not. Serum IRI was also normal in uninjected thyroidectomized dogs in the post-absorptive condition, but it rose after cortisol treatment. In thyroidectomized dogs, the insulin response to hyperglycaemia (i.v. glucose tolerance test) was barely above normal and more persistent than in normal controls; it rose strikingly after cortisol therapy. Serum FFA levels were normal in both cortisol-injected and uninjected thyroidectomized dogs in the post-absorptive condition; they fell after glucose administration in all three groups. A tendency for serum FFA to drop below normal throughout this test in thyroidectomized dogs prior to cortisol treatment was detected. After therapy, the magnitude of the depression in serum FFA after glucose load was within the normal range, only it was maintained till the test was over. The results are discussed.

Member of the Carrera del Investigador Científico, Consejo Nacional de Investigaciones Científicas y Técnicas de la República Argentina.     

A new benzothiadiazine derivative,LN 5330: effects on pancreatic hormones

Summary LN 5330 is a new benzothiadiazine which is a structural analogue of diazoxide. Its effects in vivo were studied on blood glucose levels and insulin, glucagon and somatostatin secretion in normal dogs, and in vitro on glucagon and insulin secretion from the isolated perfused rat pancreas. The results were compared with those obtained with diazoxide at equimolar dose or concentration. In the normal anaesthetized dog having a T-shaped catheter inserted in the pancreaticoduodenal vein, the infusion of LN 5330 (87.8 mol/kg for 20 min) induced (1) a progressive increase in blood glucose levels, (2) a rapid decrease in insulin and somatostatin output rate, (3) an immediate increase in pancreatic glucagon secretion, and (4) a delayed decrease of arterial blood pressure. The equimolar dose of diazoxide provoked the same effects on blood glucose levels, insulin and somatostatin output, but a marked decrease in glucagon output and in arterial blood pressure. In the isolated rat pancreas perfused with 8.3 mmol/l glucose, the infusion of LN 5330 (440 mol/l for 30 min) induced a drastic fall in insulin and a rapid and persistent increase in glucagon output. This stimulatory effect on glucagon secretion was not found with diazoxide at equimolar concentration. These findings show that LN 5330 is a substance which is distinct from diazoxide and interesting because of its double action: inhibition of insulin secretion and stimulation of glucagon secretion.     

Pancreatic endocrine responses to nutrients and bombesin after segmental pancreas autotransplantation in dogs

The capacity of autotransplanted (ATP) distal pancreas segments with systemic venous and peritoneal exocrine drainage to support physiologic control of plasma glucose levels was tested, and compared with the functions of "simulated autotransplants" (SATP) prepared with similar dissection and peritoneal exocrine drainage, but with hepatic portal venous drainage, in dogs. In ATP in the postabsorptive state, plasma levels of glucose, immunoreactive insulin (IRI) and immunoreactive glucagon (IRG1) were normal. Autotransplants resulted in impaired glucose tolerance after meals with impaired early insulin responses, and the normal brisk rise of IRG1 in the plasma was delayed and reduced through the first 30 min of feeding. In ATP, also, the response to bombesin was abnormal; the normal stimulation of release of both IRI and IRG1 was delayed in both cases. In studies of responses to oral and intravenous glucose in ATP and SATP dogs, similar mild degrees of glucose intolerance were found with both routes of administration; however, whereas in ATP dogs increases of IRI were highly exaggerated with both routes of administration of glucose, in SATP dogs plasma IRI rose from subnormal levels in the postabsorptive state through subnormal increments with both routes of administration. Further studies are necessary to determine the relative importance of denervation and reduction of the mass of the pancreas in these effects, and to assess the significance of the differences in blood insulin levels in the two preparations.     

Effects of chronic TSH treatment on blood sugar,serum IRI and FFA levels of thyroidectomized dogs. Glucose and insulin tolerance tests

Summary The effects of TSH treatment (0.1 USPU/kg body weight/die, for 3–4 days) on the blood sugar, serum IRI and circulating FFA responses to glucose and insulin were studied. Blood sugar and serum FFA levels of the dogs, in basal conditions and at any time interval during the test were slightly modified by TSH treatment. The kinetics of insulin disappearance from blood was not affected while the mean serum IRI during the insulin tolerance test was moderately reduced, which suggests that insulin space is moderately raised by TSH. The serum IRI response to glucose (OGTT, IVGTT) was found to be significantly and intensely reduced. The possibility of an inhibitory action of TSH on the insulin response to glucose in dogs, excluding the participation of the thyroid, exerted via insulin space and secretion is discussed. This work, partly published in abstract form (I Congreso Latino-americano de Diabetes, Montevideo, October 22–25, 1972;VI Congreso Argentino de Biología, San Miguel de Tucumán, April 9–13, 1973, abstract # 131; 8th Congr. of the Int. Diabetes Fed., Bruxelles, July 15–20, 1973, abstract # 86), was sponsored by theConsejo Nacional de Investigaciones Científicas y Técnicas, Argentina. Established Investigator,Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. Postgraduate Fellow, University of Buenos Aires, Argentina.     

Alteration by fasting of the effects of methylprednisolone on carbohydrate metabolism in the normal dog

Replacement regimen of cortisol was found to increase hepatic glucose release and overall glucose uptake by tissues (glucose turnover) in the postabsorptive adrenalectomized or hypophysectomized dog, but had no effect in the normal dog. A more potent glucocorticoid, methylprednisolone, has been reported to increase glucose turnover in the normal dog. In the present study, measurements of glucose turnover are correlated with measurements of liver glycogen and of plasma glucose, lactate and insulin. The studies were done in normal postabsorptive and starved dogs, in the control state and during a methylprednisolone regimen. Glucose turnover was measured in unanesthetized, trained dogs, using glucose -6-¹⁴C, which was administered in tracer amounts as a priming injection following immediately by a constant infusion. Methylprednisolone (2–2.5 mg/kg/day for 3–4 days) increased glucose turnover in the postabsorptive state. Plasma glucose concentration was unchanged, but lactate and insulin levels were elevated and liver glycogen was markedly increased. Fasting for 5 days decreased glucose turnover as well as liver glycogen and plasma insulin, with little change in plasma levels of glucose and lactate. Administration of methylprednisolone for 3–4 days with continuation of the fast did not alter significantly the plasma levels of glucose and lactate, but insulin levels increased to values seen in the postabsorptive state. The most striking effect was the increase in liver glycogen from the low values of the long-fasted state to values exceeding those in the postabsorptive state. Despite the elevated glycogen content hepatic glucose release (and turnover) was not increased above the depressed values of the long-fasted state. It was established that these glycogen stores could be mobilized by glucagon infusion.     

Changes in insulin secretion shortly after injury of the ventromedial hypothalamus

In 8 series of the experiments on 95 rats changes in the immunoreactive insulin (IRI) and blood sugar content, as well as of the indices of insulin deposition in pancreatic islands, were studied 5 hours after the injure to the hypothalamic ventromedial nuclei (HVMN) and subsequent two-hour feeding of the animals. It was found that the blood sugar- and IRI levels are significantly lowered in rats 5 hours after HVMN affection, caused by vigorous emotional and motor excitation. The 2-hour feeding of the animals 5 hours after HVMN disturbance led to an increase in the glycemia and insulinemia (almost 5 times) levels.     

Non-suppressible insulin-like activity during acute metabolic and endocrine changes in dogs

Non-suppressible insulin-like activity (NSILA-S) was determined in dogs after acute changes in the blood sugar and after injection of growth hormone. Serum was chromatographed over Sephadex G-50 columns equilibrated in 1 M acetic acid and NSILA-S was determined in the fractions between 55 and 85% column volume using a protein binding assay and the conventional fat pad assay. The results obtained with these two methods correlated rather well (r = 0.74). Hyperglycaemia induced by an intravenous glucose load, by intravenous administration of mannoheptulose or both was not followed by an increase in NSILA-S levels. The injection of insulin and human growth hormone did not lead to alterations of the NSILA-S levels. It is concluded that total NSILA-S levels in the dog do not change acutely following manipulations of the blood sugar and that, in all likelihood, NSILA-S plays no role in the regulation of blood glucose.     

Chronic treatment with thyroid-stimulating hormone. Its effects on blood sugar,serum insulin and free fatty acid levels in normal dogs tested for oral glucose tolerance

Summary The effects of bovine TSH (0.1 USP U/kg body weight/die, s.c., for 3–4 days), on blood sugar (BS), serum immunoreactive insulin (IRI) and free fatty acids (FFA) in normal dogs, in basal conditions and during an oral glucose tolerance test were studied. Basal BS, serum IRI and FFA values were not affected by the treatment. Neither were BS and serum FFA levels at any time after glucose loading, over a 3-h period. The insulin response to glucose was fully inhibited by TSH administration: the serum IRI peak was low and non significant. Results are discussed. The inhibitory role of TSH onin vivo insulin secretion is emphasized. This work, published in abstract form (Comm. No. 86, 8th Congress of the International Diabetes Federation, Brussels, Belgium, July 15–20, 1973), was sponsored by theConsejo Nacional de Investigaciones Científicas y Técnicas, Argentina.     

Estudios sobre la velocidad de desaparición de la insulina exógena de la sangre en el perro II. efecto de la tiroxina

Résumé Nous avons étudié l'effet d'un traitement chronique sous-cutané avec thyroxine (100 µg/kg de poids corporel/jour, pendant 10 jours) sur le taux de disparition de l'insuline du sang chez le chien totalement dépancréatisé à jeun. Chaque chien a reçu une dose i.v. de 0,25 UI/kg de poids d'insuline crystalline, et depuis a été saigné cinq fois, pendant une période totale de 75 min. Nous avons déterminée l'insuline immunoréactive sérique aussi bien que la glycémie, d'après les méthodes de Melani et Coll. et de Nelson respectivement. Les résultats obtenus nous on montré que, chez le chien dépancréatisé, l'hyperthyroïdisme ne produit aucun changement, soit dans: a) le taux constant de disparition de l'insuline du sang; b) la moyenne générale d'insuline immunoréactive sérique après l'injection de glucose, ou c) l'espace de l'insuline.

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Summary A study of the effect of chronic subcutaneous thyroxine treatment (100 µg/kg body weight daily for 10 days) on the rate of exogenous insulin disapperance from blood in totally depancreatized dogs in the fasting condition was performed. Each animal received 0.25 IU crystalline insulin/kg body weight i.v. and was bled five times within 75 min. Serum IRI and blood sugar were assayed according to Melani et al. and to Nelson respectively. The results enable us to conclude that in depancreatized dogs hyperthyroidism fails to induce any change in: a) the rate-constant for insulin disappearance from the blood, b) the general serum IRI mean after insulin injection or c) the insulin space.

This work was partly supported by Research grant no. 2304-B from the Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina).     

Receptor binding and effects of insulin and NSILA-S on glucose transport and metabolism in adipocytes from hypophysectomized rats

Summary Isolated fat cells from normal and hypophysectomized rats have been compared with respect to: 1) binding of insulin and NSILA-S, and 2) effects of these two hormones on glucose transport and metabolism. Although both insulin and NSILA levels were decreased in the serum of hypophysectomized rats, insulin binding was decreased to about 63% of normal, whereas NSILA-S binding remained unchanged. Basal lipogenesis was similar in adipocytes of normal and hypophysectomized rats, but was not stimulated by either insulin or NSILA-S. Similarly, neither of the two hormones stimulated the net gas exchange of intact fat pads from hypophysectomized rats. In striking contrast to these findings, 3-O-methylglucose transport in unstimulated fat cells of hypophysectomized rats proceeded at a maximal rate which was not further enhanced by insulin or NSILA-S. These results suggest that the lack of one or several hormones of the pituitary causes one or several enzyme deficiencies responsible for the limited rate of lipogenesis, which otherwiese would proceed at a very rapid rate because of unrestrained glucose transport.     

Effect of interaction between insulin and glucagon on glucose turnover and FFA concentration in normal and depancreatized dogs

We showed previously that arginine increased glucose production (R_a) and utilization (R_d) synchronously in normal dogs and suggested that this was due to concurrent insulin and glucagon release. In order to investigate the metabolic effects of coincidently elevated insulin and glucagon levels on R_a and R_d, glucagon was infused (1.55 μg/kg/hr) into normal dogs and into depancreatized dogs coincident with graded amounts of insulin (250–3000 μU/kg/min) until the metabolic response of the normal dog was achieved in depancreatized dogs. Main observations: Concurrent insulin and glucagon elevations increased glucose turnover (100%) in normal and depancreatized dogs while maintaining normoglycemia. Glucagon had no appreciable effect on peripheral glucose clearance in depancreatized dogs maintained on basal insulin. The effect of glucagon on R_a was not inhibited by concurrent insulin infusion at rates up to 3000 μU/kg/min. The effect of glucagon on R_a waned with time, indicating that a given insulin/glucagon ratio did not have a sustained effect. Near normal metabolic effects with respect to glucose turnover and FFA concentration were achieved in depancreatized dogs when the normal IRI response to glucagon was reproduced, indicating that the spike pattern of insulin release reflects not only the inherent secretory characteristic of β cells, but also serves an important glucoregulatory function. Glucagon induced an increase in ¹⁴C-glucose recycling, suggesting that it enhanced gluconeogenesis.     

The metabolic and hormonal responses to glucose infusion in anaesthetized normal and diabetic dogs controlled by an artificial B-cell

Summary The metabolic response to glucose infusion in anaesthetized normal and pancreatectomized dogs has been assessed. Normoglycaemia was achieved in the diabetic dogs with an external artificial B-cell which administered insulin into the peripheral circulation. No differences were found in the levels of blood glucose, glucagon, lactate, pyruvate and plasma non-esterified fatty acids, either in the fasting state or in response to glucose infusion. However, compared to normal animals normoglycaemic diabetic dogs had significantly elevated circulating levels of insulin and alanine at all times. Fasting levels of the same hormones and metabolites were also measured in conscious dogs. Blood pyruvate levels were higher, and plasma non-esterified fatty acid levels lower, in the anaesthetized animals. There were also minor but consistent changes in blood glucose and plasma insulin while glucagon, lactate and alanine levels were unaffected by anaesthesia. In conclusion, controlled barbiturate anaesthesia has relatively minor effects on the metabolic and hormonal status of the dog. The metabolic and hormonal response to glucose infusion in pancreatectomized dogs treated with an artificial B-cell was almost entirely normalized, except for peripheral hyperinsulinaemia and hyperalaninaemia.     

Secretin and insulin: Response to intraduodenal acid

Summary Immunoreactive secretin (IRS) and immunoreactive insulin (IRI) levels were measured in humans and dogs following the intraduodenal instillation of hydrochloric acid. IRS levels rose after acid in both instances, but a concomitant rise in peripheral IRI levels was not noted. Premedication of the humans with Scopolamine prevented a rise of IRS in the human subjects. It is concluded that the endogenous release of IRS alone does not result in increased IRI levels in peripheral blood and that IRS release may be under vagal control.     

Effect of bombesin infused intrapancreatically on glucagon and insulin secretion

Synthetic bombesin was infused at a dose of 20 pmoles/kg/min for 10 min into the cranial pancreaticoduodenal artery of anesthetized dogs. Plasma immunoreactive glucagon concentrations in the cranial pancreaticoduodenal vein as well as in the femoral artery were concurrently and slowly elevated. However, the net release of glucagon from the pancreas did not increase significantly during infusion of bombesin. Plasma immunoreactive insulin concentrations in the pancreatic vein were transiently raised, and a delayed rise was noted in arterial plasma IRI. Net release of insulin was significantly augmented during infusion of the tetradecapeptide. Plasma glucose levels did not change after bombesin. These results indicate that the gastrointestinal tetradecapeptide may stimulate secretion of both insulin and gut glucagonlike immunoreactivity in the dog.     

Influence of methionine-enkephalin analogue (FK-33-824) on the secretion of pancreatic hormones

To determine the effects of methionine-enkephalin on secretion of pancreatic hormones, five healthy male adults were intramuscularly given 0.5 mg of FK 33-824, a methionine-enkephalin analog and blood levels of pancreatic hormones were measured at different time intervals. FK 33-824 significantly lowered basal levels of plasma insulin (IRI) and pancreatic polypeptide and decreased IRI secretion in 75 g-OGTT. It also delayed the elevation of blood sugar level in 75 g-OGTT. No change occurred in the basal levels of plasma glucagon, somatostatin and blood sugar. These results imply that methionine-enkephalin in the pancreas and alimentary tract may act as an inhibitor on the secretion of insulin and pancreatic polypeptide and hence relates to the absorption of sugar.     

Serum immunoreactive insulin after the oral administration of single dose of tolbutamide. II. Pancreatic vein immunoreactive insulin in dogs (author's transl)]

The mode of action of sulfonylureas as hypoglycemic agent is not clarified yet. But it has been said in general to act by increasing the secretion of insulin from the beta cells. While, some believe that their effect is independent on insulin secretion. In the previous report, it was demonstrated that the oral administration of single dose of tolbutamide failed to increase immunoreactive insulin (IRI) in the peripheral vein in spite of significant decrease of blood glucose and free fatty acid levels both in normal and diabetic subjects. In order to observe changes of IRI level in the pancreatic vein following the oral administration of single dose of tolbutamide, the present study was carried out to determine serum IRI level of the pancreatic and peripheral vein in dogs. Mongrel dogs of both sexes, weighing 7-12 kg were anesthetized with sodium pentobarbital. A catheter was inserted into the superior pancreatico-duodenal vein through its duodenal branch after a laparotomy. Another catheter was inserted into the femoral vein for the collection of peripheral venous blood. The experiment was started one hour after the operation. Blood glucose level decreased gradually to 39 per cent reduction of the previous level at 180 minutes after intragastric administration of single dose of tolbutamide (0.1 g per kg). Serum IRI level in the peripheral vein showed only slight increase, similar to the response in man. While, pancreatic vein IRI level increased gradually and showed a fourfold increment after 180 minutes (from 143 muU per ml to 556 muU per ml), associated with a constant elevation of plasma tolbutamide concentration which showed 6.4 mg per 100 ml after 180 minutes. Simultaneous administration of 0.1 g per kg of tolbutamide and the same dose of sodium bicarbonate caused 49 per cent reduction of blood glucose level and a doubling of the basal IRI level in the peripheral vein. Serum IRI level in the pancreatic vein rose sharply and demonstrated a peak at 90 minutes (620 per cent increase). The elevation of plasma tolbutamide concentration was somewhat more rapid than that after tolbutamide alone. From these observations, it was confirmed that an apparent secretion of insulin into the pancreatic vein was induced by the oral administration of tolbutamide alone, in spite of the lack of increase in the peripheral vein IRI. And it is emphasized that the changes of insulin level in the pancreatic vein should be taken into account in a study of insulin dynamics.