Somatostatin neutralization stimulates glucagon and insulin secretion from the avian pancreas

Using the isolated perfused chicken pancreas, somatostatin antiserum was infused to neutralize the effects of endogenous somatostatin secretion on neighboring endocrine cells. At normal and high glucose concentrations, somatostatin antiserum significantly stimulated both glucagon and insulin secretion. These findings suggest that somatostatin continuously inhibits A and B cell output, and that glucose suppression of glucagon release is partially dependent upon local somatostatin secretion.     

Effects of galanin on islet cell secretory responses to VIP, GIP, 8-CCK, and glucagon by the perfused rat pancreas

Exogenous galanin has been shown to suppress insulin secretion as elicited by a number of secretagogues such as glucose, arginine, tolbutamide, carbachol, and oral nutrients. To achieve further insight into the influence of galanin on the endocrine pancreas, we have investigated the effect of synthetic porcine galanin (a 200 ng bolus followed by constant infusion at a concentration of 16.8 ng/mL for 16 to 24 minutes) on unstimulated insulin, glucagon, and somatostatin release, as well as on the responses of these hormones to 1 nmol/L vasoactive intestinal peptide (VIP), 1 nmol/L gastric inhibitory peptide (GIP), 1 nmol/L 26 to 33 octapeptide form of cholecystokinin (8-CCK) or 10 nmol/L glucagon in the perfused rat pancreas. Galanin infusion reduced unstimulated insulin secretion by 60% without modifying glucagon and somatostatin output. Galanin also blocked insulin release elicited by VIP, GIP, and 8-CCK, it did not affect the glucagon responses to VIP and GIP, or the somatostatin responses to VIP, GIP, and 8-CCK. Finally, galanin inhibited the insulin output, but not the somatostatin release induced by glucagon. In conclusion, in the perfused rat pancreas, galanin appears to behave as a general inhibitor of insulin secretion. Since this neuropeptide does not modify glucagon or somatostatin release, a direct effect of galanin on the B-cell seems plausible.     

Difference in calcium dependency of insulin,glucagon and somatostatin secretion in response to glibenclamide in perfused rat pancreas

Summary The extracellular calcium requirements for insulin, glucagon and somatostatin release induced by 1 g/ml of glibenclamide have been compared in the perfused, isolated rat pancreas. In the absence of glucose, the drug evoked insulin release equally well at physiological (2.6 mmol/l) and low (0.25 mmol/l) levels of total calcium. In contrast, glibenclamide evoked somatostatin release at 2.6 but not at 0.25 mmol/l of calcium. At 2.6 mmol/l of calcium, glibenclamide evoked bimodal effects (stimulation followed by inhibition) on glucagon secretion. At 0.25 mmol/l of calcium, basal secretory rates of glucagon were elevated and a small stimulatory effect of glibenclamide was seen. Addition of 0.5 mmol/l of EGTA to media with low calcium concentrations uniformly abolished the A, B and D cell secretory responses to glibenclamide. The possible modulation of calcium dependency by a non-stimulatory concentration of glucose was tested by its addition at 3.3 mmol/l to the perfusion media. Glucose enhanced glibenclamide-induced insulin secretion, both at 0.25 and 2.6 mmol/l of calcium. However, at 0.25 mmol/l of calcium, the enhancing effect of glucose was more pronounced than at 2.6 mmol/l. At 2.6 mmol/l of calcium, glucose diminished the somatostatin and abolished the glucagon response to glibenclamide. At 0.25 mmol/l of calcium, glucose did not influence somatostatin release while the presence of the sugar diminished basal and glibenclamide-induced glucagon secretion. The present data confirm the requirement of extracellular calcium for A, B and D cell secretion, demonstrating different calcium dependencies for the cell types and indicate that this dependency can, in part, be modulated by glucose.     

Sulfonylurea-induced inhibition of glucagon secretion from the perfused rat pancreas: evidence for a direct,non-paracrine effect

Summary The effects of sulfonylurea on glucagon secretion were characterized in the perfused rat pancreas using glibenclamide (1 g/ml) or tolazamide (10 g/ml) in the presence of 3.3 mmol/1 glucose. Glucagon release, which was unaffected by glibenclamide at 2.75 mmol/1 calcium, was suppressed at 1.19 and 0.64 mmol/l but transiently stimulated at 0.25 mmol/l extracellular calcium. The insulinogenic effect of glibenclamide at 0.64 and 0.25 mmol/1 calcium was enhanced by 35% and 89%, respectively, compared to the response at 2.75 mmol/1 calcium. The stimulatory effect of the compound on somatostatin secretion, however, was lost at the lower calcium levels. The effects of tolazamide at 2.75 and 0.64 mmol/1 calcium mimicked those of glibenclamide, thus indicating that our results with the latter compound may be representative for all sulfonylureas. In pancreata from insulin-deficient alloxan diabetic rats, glibenclamide completely lost its inhibitory effect on glucagon release at 0.64 mmol/1 calcium. Inhibition was not restored by adding insulin (25 U/1) to the perfusate. However, when diabetic rats had been treated with insulin for 6–7 days, glibenclamide suppressed glucagon release at low calcium levels in the absence of stimulated insulin and somatostatin release. It is concluded that, at low calcium concentrations, sulfonylureas suppress glucagon secretion by a direct action on the A cell and not through paracrine interactions by insulin and somatostatin. Prolonged insulin deficiency impairs the sulfonylurea action on glucagon secretion.     

Acute effects of alloxan- and streptozotocin-induced insulin deficiency on somatostatin and glucagon secretion by the perfused isolated rat pancreatico-duodenal preparation

Summary The secretion of somatostatin and glucagon by the perfused rat pancreatico-duodenal preparation was examined in situ under control conditions and after the induction of acute insulin deficiency by alloxan or streptozotocin. A 10 min 0.625 mmol/l alloxan perfusion resulted in an immediate and transient increase in basal insulin and glucagon release and a slightly delayed and persistent increase in basal somatostatin secretion. The insulin responses to 16.7 mmol/l glucose, 1 mmol/l theophylline, and 19 mmol/l arginine alone or in combination were virtually eliminated by alloxan treatment, Somatostatin secretion in response to the stimuli was completely inhibited or markedly attenuated. The glucagon-suppressive effect of glucose was unaltered by alloxan and the stimulatory effect of arginine was enhanced. Addition of 1 g/ml porcine insulin to the perfusion medium did not modify the alterations in somatostatin and glucagon responses to arginine. Streptozotocin treatment 90 min prior to the onset of perfusion resulted in changes in somatostatin, glucagon, and insulin responses to glucose and arginine similar to those of alloxan. The present results are consistent with an effect of alloxan and streptozotocin on the D cell similar to that on the B cell, namely, interference with a glucose-mediated effect on hormone secretion.     

Characterisation of somatostatin release from the pancreas

Summary The effect of calcium on somatostatin secretion was investigated in the isolated, perfused canine pancreas preparation and compared with those of acetylcholine, glucose, isoproterenol and arginine. Calcium (5 mmol/l) stimulated somatostatin release in a typical biphasic response pattern being about 5 times as potent as acetylcholine (1 mol/l), arginine (5 mmol/l), and isoproterenol (2 ng/ml) while the release of insulin and glucagon in response to calcium and the other secretagogues were of the same magnitude. Somatostatin release increased progressively when perfusate calcium was increased step-wise from 0 through 1.25 and 2.5 to 5.0 mmol/l. Calcium stimulated the secretion of somatostatin in the absence of glucose. The stimulatory effect of calcium was, however, modulated by the glucose concentration being about twice as large at 200 mg/100 ml as at 25 mg/100 ml glucose in the perfusion medium.     

Effects of exogenous insulin, glucagon, and somatostatin on islet hormone secretion in the perfused chicken pancreas

The effects of exogenous insulin were examined in the isolated perfused chicken pancreas with the duodenum excluded. At low background glucose (50 mg/dl), exogenous insulin infused at a concentration of 20,000 microU/ml elicited clear stimulation of somatostatin secretion while simultaneously inhibiting glucagon release. When the background glucose concentration was elevated to 750 mg/dl, exogenous insulin, had no effect on either somatostatin or glucagon release. When graded doses of exogenous insulin were infused into the chicken pancreas at low background glucose, low concentrations (200 microU/ml) had little effect on somatostatin or glucagon release, but higher concentrations (2000 and 20,000 microU/ml) had clear effects on both somatostatin and glucagon secretion. Glucagon infused at 100 ng/ml stimulated both insulin and somatostatin release. When somatostatin was infused at 25 ng/ml, clear inhibition of glucagon was seen with insulin inhibited to a lesser extent. This study supports the notion of a negative feedback relation between B and D-cells of the pancreatic islets and suggests a paracrine mediation.     

Effects of calcitonin gene-related peptide (CGRP) on islet hormone secretion in the pig

Summary Calcitonin gene-related peptide occurs in intrapancreatic nerves and endocrine cells. The peptide is therefore a candidate for being of physiological importance for pancreatic function. We examined the direct effects of calcitonin gene-related peptide on islet hormone secretion in the pig by infusing the peptide into the superior pancreatic artery. We found that 15 min intrapancreatic infusion of calcitonin gene-related peptide (22 pmol/min) decreased baseline pancreatic insulin output from 48±10 U/min to 8±7U/min (p<0.01). Moreover, calcitonin gene-related peptide inhibited glucose-induced insulin secretion by 45% compared to controls (p<0.01), yet left terbutaline (₂-adrenoceptor)-stimulated insulin secretion unaffected. Furthermore, while being without effect on baseline glucagon output, calcitonin gene-related peptide potentiated terbutaline-induced glucagon secretion more than seven-fold (p<0.001). In contrast, the peptide did not affect baseline or stimulated pancreatic somatostatin output. We conclude that in pigs calcitonin gene-related peptide inhibits insulin secretion and potentiates glucagon secretion by direct effects on the pancreas that are not mediated by primary alterations in pancreatic somatostatin secretion. We suggest that the neuropeptide calcitonin gene-related peptide might be of importance for the intrapancreatic regulation of insulin and glucagon secretion in pigs.     

Effects of galanin on hormone secretion from the in situ perfused rat pancreas and on glucose production in rat hepatocytes in vitro

Galanin is a novel peptide, widely distributed throughout the central and peripheral nervous system, including nerve endings surrounding the pancreatic islets. In dogs, galanin infusion has been reported to induce hyperglycemia along with a reduction of circulating insulin. In this work, we have studied the effect of galanin (a 200 ng bolus followed by constant infusion at a concentration of 16.8 ng/ml for 22-24 min) on insulin, glucagon, and somatostatin secretion in the perfused rat pancreas. In addition, we have investigated the effect of galanin (10 and 100 nM) on glycogenolysis and gluconeogenesis in isolated rat hepatocytes. In the rat pancreas, galanin infusion marked inhibited unstimulated insulin release as well as the insulin responses to glucose (11 mM), tolbutamide (100 mg/liter) and arginine (5 mM). Galanin failed to alter the glucagon and somatostatin responses to glucose, tolbutamide, and arginine. In isolated rat hepatocytes, galanin did not influence glycogenolysis or glucagon phosphorylase a activity. Gluconeogenesis and the hepatocyte concentration of fructose 2,6-bisphosphate were also unaffected by galanin. In conclusion: in the perfused rat pancreas, galanin inhibited insulin secretion without modifying glucagon and somatostatin output, thus pointing to a direct effect of galanin on the B cell; and in rat hepatocytes, galanin did not affect glycogenolysis or gluconeogenesis; hence, the reported hyperglycemia induced by exogenous galanin does not seem to be accounted for by a direct effect of this peptide on hepatic glucose production.     

The effect of growth hormone-releasing factor (GRF) on secretion of insulin, glucagon and somatostatin from perfused rat pancreas

To examine the effects of growth hormone-releasing factor (GRF) on islet hormone release, rat pancreas was perfused. rhGRF at the concentration of 10(-7) M or more enhanced insulin secretion stimulated by 16.7 mM glucose, hpGRF slightly enhanced insulin secretion as well. The insulin secretion induced by 10(-6) M rhGRF was completely inhibited by 10(-6) M propranolol. rhGRF at the concentration of 10(-8) M or more stimulated glucagon secretion even in the presence of 16.7 mM glucose. The glucagon secretion stimulated by 10(-6) M rhGRF was inhibited in the early period but increased thereafter by 10(-6) M propranolol. 10(-6) M rhGRF slightly stimulated glucagon secretion in the presence of 16.7 mM glucose when STZ diabetic rat pancreas was perfused. rhGRF at the concentration of 10(-6) M enhanced somatostatin secretion stimulated with 16.7 mM glucose. We concluded that rhGRF stimulated insulin, glucagon and somatostatin secretion and the insulin secretion was inhibited by beta-blocker. hpGRF stimulated insulin and glucagon secretion as well.     

Immunoneutralization of somatostatin, insulin, and glucagon causes alterations in islet cell secretion in the isolated perfused human pancreas

INTRODUCTION: In this study, immunoneutralization of endogenous insulin, glucagon, and somatostatin with specific antibodies was used in an isolated perfused human pancreas (IPHP) model. AIMS: To study intrapancreatic cellular interactions and pancreatic hormonal secretion. METHODOLOGY: Randomized, sequential 10-minute test intervals of single-pass perfusion with each antibody were performed at 3.9 mM or 11.5 mM steady-state glucose concentrations. Somatostatin, insulin, and glucagon levels were measured in the effluent during basal and immunoneutralization intervals. RESULTS: At 3.9 mM glucose concentration, somatostatin antibody (SS-Ab) stimulated insulin and glucagon secretion, insulin antibody (IN-Ab) inhibited glucagon secretion, and glucagon antibody (GN-Ab) stimulated insulin secretion. At 11.5 mM glucose concentration, SS-Ab stimulated insulin secretion, IN-Ab stimulated glucagon and inhibited somatostatin secretion, and GN-Ab stimulated insulin secretion. CONCLUSION: The variation in hormonal responses to immunoneutralization during stimulated and nonstimulated glucose conditions suggests that a dynamic association exists between the pancreatic cells.     

Effect of cysteamine on insulin release and exocrine pancreatic secretionin vitro

Cysteamine is known to deplete somatostatin from pancreatic D cells. In the isolated perfused rat pancreas we investigated its effects on somatostatin and insulin release as well as exocrine pancreatic secretion in the presence of 16.7 mM glucose and 180 pM CCK-8. At a concentration of 0.1 mM, cysteamine had no significant effect on pancreatic endocrine and exocrine functions. At 10 mM, however, cysteamine released somatostatin (380±70 vs 100±20 fmol/20 min), inhibited insulin output (890±120 vs 13210±3260 units/20 min) and reduced exocrine pancreatic secretion (volume: 12±2 vs 20±2 l/20 min; lipase: 31±3 vs 60±7 units/20 min). We conclude that the complex changes induced by cysteamine are consistent with a physiological role of endogenous somatostatin in the regulation of insulin release. The reduction of exocrine pancreatic secretion, however, was at least in part, if not completely, mediated via the insuloacinar axis rather than a direct effect of cysteamine-released somatostatin on pancreatic acinar cells.This study was supported by the Deutsche Forschugsgemeinschaft (DFG grant Mu 543/3-3).     

Effects of rat pancreatic polypeptide on islet-cell secretion in the perfused rat pancreas.

Pancreatic polypeptide (PP) secretory cells are abundant in the islets of Langerhans. Results concerning the effects of exogenous PP on islet-cell secretion are controversial. This might be due in part to species specificity, given that most reports refer to studies performed using PP of bovine, porcine, or human origin in a heterologous animal model. Thus, we have investigated the influence of synthetic rat PP (80 nmol/L) on unstimulated insulin, glucagon, and somatostatin release, and on the responses of these hormones to glucose (11 mmol/L) and to arginine (3.5 mmol/L) in a homologous animal model, the perfused rat pancreas. Infusion of rat PP (rPP) reduced unstimulated insulin release by 35% (P = .03), and the insulin responses to glucose by 65% (P = .029) and to arginine by 50% (P = .026), without modifying glucagon output. rPP did not affect somatostatin secretion, either in unstimulated conditions or in the presence of 11 mmol/L glucose. However, it induced a clear-cut increase in somatostatin release during 3.5 mmol/L arginine infusion. Our observation that rPP inhibited insulin secretion without affecting glucagon and somatostatin output points to a direct effect of PP on B-cell function. However, during aminogenic priming of the D cell, the inhibition of insulin output induced by rPP was accompanied by an increase in somatostatin release. Thus, in this circumstance, it might be considered that the blocking effect of PP on B-cell secretion could be, at least in part, mediated by a D-cell paracrine effect.     

Glucose-clamp by artificial pancreas in the study and management of a patient with insulinoma

Summary Four euglycemic glucose-clamp studies by artificial pancreas (Biostator, Miles) have been performed during prolonged fast before and after pharmacological treatment in a patient with insulinoma. In the basal state a high glucose infusion rate (8.9 g/h) was unable to achieve the preselected blood glucose plateau of 80 mg/100 ml. The plasma insulin levels during this first glucose-clamp were comprised between 18 and 50 U/ml. On the first day of diazoxide treatment (300 mg/die),. the glucose infusion rate decreased to 6.4 g/h, without variation in plasma insulin level, thus suggesting a diazoxide effect independent of the inhibition of insulin secretion. After 7 days of diazoxide treatment, a further reduction of glucose infusion (5.8 g/h), together with a lowering of plasma insulin levels (7–18 U/ml) was observed. Both in the basal state and during diazoxide treatment a circadian pattern of glucose requirement was noted, with lower glucose need and plasma insulin levels during the night. Surgery was undertaken with glucose-clamp by artificial pancreas; blood glucose level being higher than the preselected value of 80 mg/100 ml, simple monitoring of glycemia was performed. The excision of a single adenoma was followed by a substantial rise in blood glucose 20 min later. An additional glucose-clamp, performed 3 months after surgery showed a dramatic fall of the glucose infusion rate (2.9 g/h) needed to achieve the preselected blood glucose plateau, confirming the completeness of the intervention. This experience shows that glucose-clamp by artificial pancreas may be of great value in the study as well as in the pharmacological and surgical treatment of patients with insulinoma.Deceased on March 3, 1981.     

The interaction of Vasoactive Intestinal Polypeptide (VIP), glucose and arginine on the secretion of insulin,glucagon and somatostatin in the perfused rat pancreas

Summary Vasoactive Intestinal Polypeptide (VIP) increased the release of insulin, glucagon and somatostatin from the perfused rat pancreas. The amount of these hormones released was dependent upon the prevailing glucose concentration. VIP stimulated glucagon release in the absence of glucose, while insulin and somatostatin release were increased by VIP only in the presence of glucose concentrations of 4.4 mmol/l and above. Glucagon secretion stimulated by arginine in the presence of 4.4 mmol/l glucose was potentiated by VIP. In contrast, VIP did not induce any further increase in the secretion of insulin and somatostatin over that stimulated by arginine. At higher concentrations of glucose (6.7, 16.7, and 33.3 mmol/l) VIP continued to stimulate insulin and somatostatin release, this effect being synergistic on early-phase insulin release. The effects of VIP on islet cells thus depend on the levels of modulating nutrients.     

Effects of a thiazide diuretic (hydroflumethiazide) and a loop diuretic (bumetanide) on the endocrine pancreas: studies in vitro

Treatment with thiazide diuretics causes an impairment of the glucose metabolism. To study whether this is due to a direct effect on the endocrine pancreas, the effects of the thiazide hydroflumethiazide on the release of glucagon, insulin, and somatostatin from the isolated perfused pancreas of normal and alloxan diabetic dogs were examined. Hydroflumethiazide at concentrations ranging from 1 to 50 micrograms/mL stimulated the normal secretion of glucagon (P less than 0.001), insulin (P less than 0.001), and somatostatin (P less than 0.001) in a dose-dependent manner. The normal hormone responses evoked by 50 micrograms/mL of the thiazide were, however, modified by the prevailing glucose level: higher insulin (P less than 0.05) and somatostatin (P less than 0.05) and lower glucagon (P less than 0.05) were obtained at the high glucose concentration of 11 mmol/L rather than at the low glucose concentration of 1.3 mmol/L. In alloxan diabetes, insulin secretion was almost extinct and did not respond to hydroflumethiazide, whereas glucagon was dose-dependently stimulated (P less than 0.001). In addition, we looked at the effect of the loop diuretic, bumetanide. The infusion of bumetanide at doses ranging from 0.5 to 3 micrograms/mL did not alter the release of glucagon, insulin, and somatostatin in the presence of 5.5 mmol/L glucose. The results suggest that hydroflumethiazide possesses the ability to directly stimulate A cell secretion in the normal and alloxan diabetic pancreas. Whether this effect is of clinical importance for the diminution in glucose tolerance observed during thiazide therapy remains, however, uncertain.     

Effects of galanin on the release of insulin, glucagon and somatostatin from the isolated, perfused dog pancreas

Galanin is a 29 amino acid peptide which has been found in intrapancreatic nerves. The effects of galanin, adrenergic and cholinergic blockade as well as somatostatin on the hormone release from the isolated perfused dog pancreas were studied. It was found that galanin dose-dependently inhibited insulin (P less than 0.001) and somatostatin (P less than 0.001) but not glucagon secretion at normal glucose levels. The lowest galanin concentration that caused a significant suppression of insulin and somatostatin secretion was 10(-11) and 10(-10) mol/l, respectively. Similar effects were evident during stimulation with 2.5 mmol/l arginine. Galanin (10(-9) mol/l) caused a more pronounced inhibition of insulin and somatostatin secretion at high (10 mmol/l) and normal (5 mmol/l) than at low glucose (1.3 mmol/l). In contrast, suppression of the glucagon secretion was only seen at low glucose (1.3 mmol/l). Perfusion of 10(-6) mol/l of atropine, phentolamine and propranolol had no effect on the galanin-mediated (10(-10) mol/l) inhibition of insulin and somatostatin secretion. Galanin (10(-12)-10(-10) mol/l) and somatostatin (10(-12)-10(-10) mol/l) were equipotent in inhibiting insulin secretion whereas only somatostatin exerted a suppression of the glucagon secretion at normal glucose. Thus, galanin exerts a differential effect on islet hormone secretion and may participate in the hormonal control of insulin, glucagon and somatostatin secretion.     

Pancreastatin inhibits insulin secretion as induced by glucagon, vasoactive intestinal peptide, gastric inhibitory peptide, and 8-cholecystokinin in the perfused rat pancreas

Pancreastatin is a 49-amino acid straight chain molecule isolated from porcine pancreatic extracts. In the perfused rat pancreas, this peptide has been shown to inhibit unstimulated insulin release and the insulin responses to glucose, arginine, and tolbutamide. To further explore the influence of pancreastatin on islet cell secretion, the effect of synthetic porcine pancreastatin (a 2-micrograms priming dose, followed by constant infusion at a concentration of 15.7 nmol/L) was studied on the insulin, glucagon, and somatostatin responses to 1 nmol/L vasoactive intestinal peptide (VIP), 1 nmol/L gastric inhibitory peptide (GIP), and 1 nmol/L 26 to 33 octapeptide form of cholecystokinin (8-CCK). The effect of pancreastatin on the insulin and somatostatin secretion elicited by glucagon (20 nmol/L) was also examined. Pancreastatin infusion consistently reduced the insulin responses to VIP, GIP, and 8-CCK without modifying glucagon or somatostatin release. It also inhibited the insulin release but not the somatostatin output induced by glucagon. These observations broaden the spectrum of pancreastatin as an inhibitor of insulin release. The finding that pancreastatin does not alter glucagon or somatostatin secretion supports the concept that it influences the B cell directly, and not through an A cell or D cell paracrine effect.     

Effect of tolbutamide on insulin, glucagon, and somatostatin release from the diabetic rat pancreas with special reference to glucose concentration

The effects of tolbutamide on insulin, glucagon, and somatostatin secretion were investigated in the isolated perfused pancreas from normal and diabetic rats under low (30 mg/dl), normal (100 mg/dl), and high (300 mg/dl) glucose conditions. In the normal rat pancreas, tolbutamide-induced insulin release was increased when the glucose concentration in the perfusion medium was increased from 30-300 mg/dl. Tolbutamide had an inhibitory effect on glucagon release at the low (30 mg/dl) glucose concentrations, although a stimulatory effect was observed under normoglycemic conditions. The total amount of somatostatin secretion above baseline during tolbutamide infusion was higher under the normal glucose than under the low glucose condition. However, further augmentation of somatostatin release was not found at the high glucose concentration. In the diabetic rat pancreas, insulin release was diminished and tolbutamide-induced somatostatin release was enhanced with increasing glucose concentrations. Glucagon release was stimulated at the normal glucose concentration, but inhibited temporarily at the high glucose concentration. The maximum somatostatin response in the early phase was significantly decreased in the diabetic pancreas under low and normal glycemic conditions, when expressed as an incremental change (percentage) above baseline. From these results, one can conclude: (1) tolbutamide has a stimulatory effect on the pancreatic D cell in both the normal and diabetic pancreas; (2) the early response of somatostatin is decreased in the diabetic pancreas, except under conditions of high glucose concentration; and (3) the pancreatic A cell response to tolbutamide was not uniform and was quite different from the response of the D cell.     

Abnormal regulation by glucose of somatostatin secretion in the perfused pancreas of NIDDM rats

We have investigated the influence of non-insulin-dependent diabetes on the regulation of somatostatin secretion from the pancreatic D cell. These results were compared with the concomittantly measured secretory responses from A and B cells. Rats were rendered non-insulin-dependent diabetic by neonatal injection of streptozotocin (STZ). Secretion was studied in perfused pancreas at 6-10 weeks of age. At this age, STZ rats were mildly hyperglycemic, their nonfasting blood glucose being 9.0 +/- 0.8 vs. 5.6 +/- 0.2 mM in control rats. In perfused pancreas from the latter rats, high glucose, i.e., 16.7 mM, stimulated somatostatin secretion but completely failed to do so in STZ rats. Arginine (in the presence of low glucose, i.e., 3.3 mM) moderately stimulated somatostatin secretion in controls but fourfold more in STZ rats. Preperfusion with high glucose markedly potentiated subsequent arginine-induced somatostatin secretion in controls but failed to do so in STZ rats. Basal glucagon release was inhibited by ambient high glucose in control and STZ rats alike. Arginine-induced glucagon release was profoundly inhibited both by ambient and previous exposure to glucose in controls but only slightly and nonsignificantly in STZ rats. The insulin response to high glucose in controls was reduced by 90% in STZ. The insulin response to arginine (in the presence of low glucose) was 3.3-fold enhanced in STZ. Ambient and previous high glucose markedly enhanced arginine-induced insulin secretion in controls but only moderately so in STZ rats. We conclude that already mild hyperglycemia is associated with marked D-cell insensitivity to glucose that is qualitatively similar to A- and B-cell insensitivity.