Stimulatory effect of xenin-8 on insulin and glucagon secretion in the perfused rat pancreas

Xenin is a 25-amino acid peptide of the neurotensin/xenopsin family identified in gastric mucosa as well as in a number of tissues, including the pancreas of various mammals. In healthy subjects, plasma xenin immunoreactivity increases after meals. Infusion of the synthetic peptide in dogs evokes a rise in plasma insulin and glucagon levels and stimulates exocrine pancreatic secretion. The latter effect has also been demonstrated for xenin-8, the C-terminal octapeptide of xenin. We have investigated the effect of xenin-8 on insulin, glucagon and somatostatin secretion in the perfused rat pancreas. Xenin-8 stimulated basal insulin secretion and potentiated the insulin response to glucose in a dose-dependent manner (EC(50)=0.16 nM; R(2)=0.9955). Arginine-induced insulin release was also augmented by xenin-8 (by 40%; p<0.05). Xenin-8 potentiated the glucagon responses to both arginine (by 60%; p<0.05) and carbachol (by 50%; p<0.05) and counteracted the inhibition of glucagon release induced by increasing the glucose concentration. No effect of xenin-8 on somatostatin output was observed. Our observations indicate that the reported increases in plasma insulin and glucagon levels induced by xenin represent a direct influence of this peptide on the pancreatic B and A cells.     

Zinc Supplementation Does Not Affect Glucagon Response to Intravenous Glucose and Insulin Infusion in Patients with Well-Controlled Type 2 Diabetes

Glucagon dysregulation is an essential component in the pathophysiology of type 2 diabetes. Studies in vitro and in animal models have shown that zinc co-secreted with insulin suppresses glucagon secretion. Zinc supplementation improves blood glucose control in patients with type 2 diabetes, although there is little information about how zinc supplementation may affect glucagon secretion. The objective of this study was to evaluate the effect of 1-year zinc supplementation on fasting plasma glucagon concentration and in response to intravenous glucose and insulin infusion in patients with type 2 diabetes. A cross-sectional study was performed after 1-year of intervention with 30 mg/day zinc supplementation or a placebo on 28 patients with type 2 diabetes. Demographic, anthropometric, and biochemical parameters were determined. Fasting plasma glucagon and in response to intravenous glucose and insulin infusion were evaluated. Patients of both placebo and supplemented groups presented a well control of diabetes, with mean values of fasting blood glucose and glycated hemoglobin within the therapeutic goals established by ADA. No significant differences were observed in plasma glucagon concentration, glucagon/glucose ratio or glucagon/insulin ratio fasting, after glucose or after insulin infusions between placebo and supplemented groups. No significant effects of glucose or insulin infusions were observed on plasma glucagon concentration. One-year zinc supplementation did not affect fasting plasma glucagon nor response to intravenous glucose or insulin infusion in well-controlled type 2 diabetes patients with an adequate zinc status.     

Hepatic glucagon clearance during insulin induced hypoglycemia

Studies concerning the importance of glucagon secretion in hypoglycemic counterregulation have assumed that peripheral levels of glucagon are representative of rates of pancreatic glucagon secretion. The measurement of peripheral levels of this hormone, however, may be a poor reflection of secretion rates because of glucagon's metabolism by the liver. Therefore, in order to understand the relationship between pancreatic glucagon secretion and levels of glucagon in the peripheral blood during hypoglycemia, we evaluated hepatic glucagon metabolism during insulin induced hypoglycemia. Four dogs received an insulin infusion to produce glucose levels less than 50 mg/dl for 45 minutes. In response to this, the delivery of glucagon to the liver increased from 36.7 +/- 5.9 ng/min in the baseline to 322.6 +/- 6.3 ng/min during hypoglycemia. Hepatic glucagon uptake increased proportionally from 13.6 +/- 7.2 ng/min to 103.1 +/- 28.3 ng/min and the percentage of delivered hormone that was extracted did not change (30.8 +/- 13.8% vs 32.9 +/- 11.6%). The absolute amount of glucagon metabolized by the liver was dependent on the rate of delivery and was not directly affected by plasma glucose level per se. To directly study the effect of hypoglycemia on hepatic glucagon metabolism, five dogs were given an exogenous infusion of somatostatin followed by an infusion of glucagon and then administered insulin to produce hypoglycemia. The percent of glucagon extracted by the liver (19.5 +/- 4.9% and 21.3 +/- 6.4%) was not affected by a fall in the plasma glucose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pancreatic hormones and plasma glucose: regulation mechanisms in the goose under physiological conditions. II. Glucose-glucagon and glucose-insulin feed-back mechanisms

We have studied the pancreatic hormone-glucose feed-back mechanisms by infusing glucagon (G), insulin (I) and glucose into normal fasting geese. The controls received saline. Whilst a NaCl 9% infusion is devoid of effect, the pancreatic hormones, used at physiological doses, modify the plasma glucose level, glucagon being hyperglycaemic and insulin hypoglycaemic. In addition, a physiological increase in plasma glucose provokes a drop in plasma glucagon and a rise in plasma insulin, thus a marked decrease in the G/I ratio. The results show that the pancreatic hormone-glucose feed-back mechanisms are effective under physiological conditions.     

Secretion of glucagon and insulin in hypophysectomized rats: effect of tolbutamide.

Normal and hypophysectomized (hypox) rats, fed ad libitum, received intraperitoneal injections of tolbutamide (75 mg/kg/day) or of saline for 6 weeks. 24 h after the last injection, blood samples were taken for glucose, insulin and glucagon determinations. In normal rats, tolbutamide treatment did not alter serum glucose, insulin and glucagon, although it suppressed the secretion of insulin and glucagon by the pancreatic islets. In hypox rats, tolbutamide decreased serum glucose and insulin, elevated serum glucagon and stimulated the secretion of glucagon, but not that of insulin by the pancreatic islets. In addition, tolbutamide treatment increased the glucagon response to arginine in normal, but not in hypox rats. The serum glucose response to arginine was decreased by tolbutamide treatment and by hypophysectomy and, thus, appeared independent of the glucagon rise or preexisting glucagon level. We conclude that tolbutamide treatment decreased the secretion of glucagon and insulin in normal rats and stimulated that of glucagon in hypox rats, perhaps because of the low levels of insulin in the serum and in the pancreas of the latter. Our results are compatible with the hypothesis that the pancreatic action of tolbutamide is influenced by the pituitary.     

Phe-met-arg-phe-amide (FMRF-NH2) inhibits insulin and somatostatin secretion and anti-FMRF-NH2 sera detects pancreatic polypeptide cells in the rat islet

FMRF-NH2-like immunoreactivity was localized in the pancreatic polypeptide containing cells of the rat islet. FMRF-NH2 was investigated with regard to its effect on insulin, somatostatin and glucagon secretion from the isolated perfused rat pancreas. FMRF-NH2 (1 microM) significantly inhibited glucose stimulated (300 mg/dl) insulin release (p less than 0.005) and somatostatin release (p less than 0.01) from the isolated perfused pancreas. FMRF-NH2 (1 and 10 microM) was without effect on glucagon secretion, either in low glucose (50 mg/dl), high glucose (300 mg/dl), or during arginine stimulation (5 mM). These findings indicate that these FMRF-NH2 antisera recognize a substance in the pancreatic polypeptide cells of the islet which may be capable of modulating islet beta and D cell activity.     

Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (Ra) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [3H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 +/- 14 vs. 113 +/- 11 pM; 0.153 +/- 0.029 vs. 0.156 +/- 0.026 nM; and 64.7 +/- 11.5 vs. 65.8 +/- 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steady-state levels of 4.8 +/- 0.2 to a nadir of 4.1 +/- 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in Ra, from 22.6 +/- 2.8 to 19.1 +/- 2.8 micromol. kg-1. min-1 (P < 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.     

Insulin secretion and islet endocrine cell content at onset and during the early stages of diabetes in the BB rat: effect of the level of glycemic control.

Although it is agreed that autoimmune destruction of pancreatic islets in diabetic BB rats is rapid, reports of endocrine cell content of islets from BB diabetic rats at the time of onset of diabetes vary considerably. Because of the rapid onset of the disease (hours) and the attendant changes in islet morphology and insulin secretion, it was the aim of this study to compare islet beta-cell numbers to other islet endocrine cells as close to the time of onset of hyperglycemia as possible (within 12 h). As it has been reported that hyperglycemia renders the beta cell insensitive to glucose, the early effects of different levels of insulin therapy (well-controlled vs. poorly controlled glycemia) on islet morphology and insulin secretion were examined. When measured within 12 h of onset, insulin content of BB diabetic islets, measured by morphometric analysis or pancreatic extraction, was 60% of insulin content of control islets. Despite significant amounts of insulin remaining in the pancreas, 1-day diabetic rats exhibited fasting hyperglycemia and were glucose intolerant. The insulin response from the isolated perfused pancreas to glucose and the glucose-dependent insulinotropic hormone, gastric inhibitory polypeptide (GIP), was reduced by 95%. Islet content of other endocrine peptides, glucagon, somatostatin, and pancreatic polypeptide, was normal at onset and at 2 weeks post onset. A group of diabetic animals, maintained in a hyperglycemic state for 7 days with low doses of insulin, were compared with a group kept normoglycemic by appropriate insulin therapy. No insulin could be detected in islets of poorly controlled diabetics, while well-controlled animals had 30% of the normal islet insulin content.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulinoma in a Patient with Normal Results from Prolonged Fast and Glucagon-Induced Hypoglycemia

ObjectiveTo describe a man with a functioning insulinoma and normal results from two 72-hour fasts who developed hypoglycemia secondary to exaggerated insulin response following glucagon stimulation.MethodsWe report the patient’s clinical findings, laboratory findings, and clinical course. We also review the literature for previously reported cases and possible mechanisms.ResultsA 49-year-old man presented with hypoglycemic symptoms initially occurring after jogging and well-documented symptomatic hypoglycemia occurring during an evening meal. A 72-hour fast was associated with a serum glucose concentration of 50 mg/dL, suppressed insulin and C-peptide levels, and mildly elevated β-hydroxybutyrate. Another documented episode of hypoglycemia occurring 3 hours postprandially was associated with elevated insulin and C-peptide and suppressed β-hydroxybutyrate. A second 72-hour fast provoked asymptomatic hypoglycemia (glucose concentration at 60 hours: 32 mg/dL) with suppressed insulin and measurable β-hydroxybutyrate. After 72 hours of fasting, glucagon administration led to a decrease in glucose from 50 to 18 mg/dL, elevations in insulin and C-peptide, and suppression of β-hydroxybutyrate. Computed tomography revealed a mass lesion in the pancreatic tail. Distal pancreatectomy was performed, and the resected specimen demonstrated immunostaining for insulin. Hypoglycemic symptoms resolved postoperatively.ConclusionsNormal results from a prolonged fast do not preclude an insulinoma and may demonstrate exaggerated insulin secretion from the insulinoma following glucagon administration. In addition to examining the glucose response to glucagon as a surrogate for insulinoma diagnosis, measurement of serum insulin levels following glucagon administration may provide a further clue to the diagnosis of insulinoma. (Endocr Pract. 2010;16:838-841)     

Pancreatic hormone response to neuropeptide Y (NPY) perifusion in vitro

Available data on the effect of neuropeptide Y (NPY) on insulin release are conflicting and little data exist regarding the effect of NPY on glucagon secretion. The purpose of the present study, therefore, was to characterize the direct effect of NPY on the release of these pancreatic hormones and to examine the role of glucose on these interactions. Using a perifused mouse islet system, we found that NPY suppressed both basal and glucose-stimulated insulin secretion. Thus, basal insulin release assessed as mean integrated area under the curve/20 min (AUC/20 min) decreased from 1446 +/- 143 pg to 651 +/- 112 pg (P less than 0.05) with the addition of 2 x 10(-8) M NPY and the AUC/20 min for glucose stimulated insulin output decreased from 1973 +/- 248 pg to 1426 +/- 199 pg (P less than 0.05). In both cases, this inhibitory effect was followed after removing NPY by a stimulation of insulin secretion which was typical of a 'rebound off-response'. In contrast, NPY exerted a stimulatory effect on basal glucagon release and significantly reversed the suppressive effect of high glucose on glucagon output. The basal glucagon AUC/20 min increased from 212 +/- 103 pg to 579 +/- 316 pg (P less than 0.05), while glucagon secretion in the presence of 27.7 mM glucose increased from 75 +/- 26 pg to 255 +/- 28 pg (P less than 0.01). In conclusion, we have shown that the direct effect of NPY on the endocrine pancreas is to suppress insulin but stimulate glucagon secretion. These data are compatible with a role for NPY in the regulation of pancreatic hormone output.     

Basal insulin, glucagon, and growth hormone replacement

Conclusions drawn from the pancreatic (or islet) clamp technique (suppression of endogenous insulin, glucagon, and growth hormone secretion with somatostatin and replacement of basal hormone levels by intravenous infusion) are critically dependent on the biological appropriateness of the selected doses of the replaced hormones. To assess the appropriateness of representative doses we infused saline alone, insulin (initially 0.20 mU.kg(-1).min(-1)) alone, glucagon (1.0 ng.kg(-1).min(-1)) alone, and growth hormone (3.0 ng.kg(-1).min(-1)) alone intravenously for 4 h in 13 healthy individuals. That dose of insulin raised plasma insulin concentrations approximately threefold, suppressed glucose production, and drove plasma glucose concentrations down to subphysiological levels (65 +/- 3 mg/dl, P < 0.0001 vs. saline), resulting in nearly complete suppression of insulin secretion (P < 0.0001) and stimulation of glucagon (P = 0.0059) and epinephrine (P = 0.0009) secretion. An insulin dose of 0.15 mU.kg(-1).min(-1) caused similar effects, but a dose of 0.10 mU.kg(-1).min(-1) did not. The glucagon and growth hormone infusions did not alter plasma glucose levels or those of glucoregulatory factors. Thus, insulin "replacement" doses of 0.20 and even 0.15 mU.kg(-1).min(-1) are excessive, and conclusions drawn from the pancreatic clamp technique using such doses may need to be reassessed.     

Diminished glucagon suppression after β-cell reduction is due to impaired α-cell function rather than an expansion of α-cell mass

Impaired suppression of glucagon levels after oral glucose or meal ingestion is a hallmark of type 2 diabetes. Whether hyperglucagonemia after a β-cell loss results from a functional upregulation of glucagon secretion or an increase in α-cell mass is yet unclear. CD-1 mice were treated with streptozotocin (STZ) or saline. Pancreatic tissue was collected after 14, 21, and 28 days and examined for α- and β-cell mass and turnover. Intraperitoneal (ip) glucose tolerance tests were performed at day 28 as well as after 12 days of subcutaneous insulin treatment, and glucose, insulin, and glucagon levels were determined. STZ treatment led to fasting and post-challenge hyperglycemia (P < 0.001 vs. controls). Insulin levels increased after glucose injection in controls (P < 0.001) but were unchanged in STZ mice (P = 0.36). Intraperitoneal glucose elicited a 63.1 ± 4.1% glucagon suppression in control mice (P < 0.001), whereas the glucagon suppression was absent in STZ mice (P = 0.47). Insulin treatment failed to normalize glucagon levels. There was a significant inverse association between insulin and glucagon levels after ip glucose ingestion (r(2) = 0.99). β-Cell mass was reduced by ～75% in STZ mice compared with controls (P < 0.001), whereas α-cell mass remained unchanged (P > 0.05). α-Cell apoptosis (TUNEL) and replication (Ki67) were rather infrequently noticed, with no significant differences between the groups. These studies underline the importance of endogenous insulin for the glucose-induced suppression of glucagon secretion and suggest that the insufficient decline in glucagon levels after glucose administration in diabetes is primarily due to a functional loss of intraislet inhibition of α-cell function rather than an expansion of α-cell mass.     

Pancreatic and gut hormones during fasting: insulin, glucagon, and somatostatin

When adult male rats were fasted for 24 or 72 h there was no change in the pancreatic content of insulin or glucagon, but the somatostatin content increased at 72 h. This contrasts with earlier reports of reduced pancreatic somatostatin after fasting. After a 48-hour fast there was an increase in the concentration of duodenal somatostatin, and a tendency toward reduced concentrations in stomach, jejunum, and ileum. When duodenal mucosa and muscle extracts were chromatographed the relative amounts of putative somatostatin-28 and somatostatin-14 were unchanged. Insulin secretion from the perfused pancreata of 72-hour-fasted rats was markedly reduced, but glucagon and somatostatin secretion was indistinguishable from that of fed controls. These results indicate that in spite of the marked alterations of nutrient metabolism and insulin secretion which occur during fasting, the pancreatic content of insulin, glucagon and somatostatin and the gut concentration of somatostatin are well maintained.     

Insulin as a physiological modulator of glucagon secretion

Glucose homeostasis is regulated primarily by the opposing actions of insulin and glucagon, hormones that are secreted by pancreatic islets from beta-cells and alpha-cells, respectively. Insulin secretion is increased in response to elevated blood glucose to maintain normoglycemia by stimulating glucose transport in muscle and adipocytes and reducing glucose production by inhibiting gluconeogenesis in the liver. Whereas glucagon secretion is suppressed by hyperglycemia, it is stimulated during hypoglycemia, promoting hepatic glucose production and ultimately raising blood glucose levels. Diabetic hyperglycemia occurs as the result of insufficient insulin secretion from the beta-cells and/or lack of insulin action due to peripheral insulin resistance. Remarkably, excessive secretion of glucagon from the alpha-cells is also a major contributor to the development of diabetic hyperglycemia. Insulin is a physiological suppressor of glucagon secretion; however, at the cellular and molecular levels, how intraislet insulin exerts its suppressive effect on the alpha-cells is not very clear. Although the inhibitory effect of insulin on glucagon gene expression is an important means to regulate glucagon secretion, recent studies suggest that the underlying mechanisms of the intraislet insulin on suppression of glucagon secretion involve the modulation of K(ATP) channel activity and the activation of the GABA-GABA(A) receptor system. Nevertheless, regulation of glucagon secretion is multifactorial and yet to be fully understood.     

Modulation of A and B cell functions by tolbutamide and arginine in the pancreas of thiamine-deficient rats

The effects of administration of glucose orally and tolbutamide or arginine intravenously on insulin and glucagon secretion and blood glucose level were studied in normal and thiamine-deficient rats. In thiamine deficiency, insulin secretion and glucose tolerance were impaired during glucose ingestion. Tolbutamide decreased the blood glucose level in both control and thiamine-deficient rats but its stimulatory effect on insulin secretion was minimal in thiamine-deficient rats unlike the control animals. Arginine did not alter substantially the blood glucose or insulin in thiamine-deficient rats, whereas it increased the insulin level in control rats. The fasting plasma glucagon level was high in thiamine deficiency. Tolbutamide increased the plasma glucagon in control rats, but did so only marginally in thiamine-deficient rats. Arginine also increased the glucagon secretion throughout the period of study in control rats. In thiamine-deficient rats the glucagon secretion was pronounced only after 20 min of arginine administration. These results suggest that an unimpaired glucose metabolism is a prerequisite to induce proper insulin secretion. Only proper insulin secretion can check the glucagon secretion rather than the increased glucose level. Hypoglycemia can induce glucagon secretion independent of the insulin level.     

Gastrin releasing peptide (GRP): effects on basal and stimulated insulin and glucagon secretion in the mouse

GRP is a pancreatic neuropeptide and may be of importance for the neural control of insulin and glucagon secretion. In this study, we investigated the effects of GRP on basal and stimulated insulin and glucagon secretion in the mouse. Intravenous injections of GRP at dose levels exceeding 2.12 nmol/kg were found to rapidly increase basal plasma levels of both insulin and glucagon. Furthermore, at a low dose level without effect on basal plasma insulin levels, GRP was found to potentiate the insulin response to both glucose (by 40%; p less than 0.05) and to the cholinergic agonist carbachol (by 57%; p less than 0.01). Also, GRP was at this dose level found to potentiate the glucagon response to carbachol (p less than 0.01). Glucose abolished GRP-induced glucagon secretion. Moreover, methylatropine given at a dose level that totally abolishes carbachol-induced insulin secretion inhibited GRP-induced insulin secretion by 39% (p less than 0.05) and GRP-induced glucagon secretion by 25% (p less than 0.01). L-Propranolol at a dose level that totally abolishes beta-adrenergically-induced insulin secretion inhibited GRP-induced insulin secretion by 52% (p less than 0.01) and GRP-induced glucagon secretion by 15% (p less than 0.05). In summary, we have shown that GRP stimulates basal and potentiates stimulated insulin and glucagon secretion in mice, and that the stimulatory effects of GRP on insulin and glucagon secretion are partially inhibited by muscarinic blockade by methylatropine or by beta-adrenoceptor blockade by propranolol. We conclude that GRP activates potently both insulin and glucagon secretion in the mouse by mechanisms that are partially related to the muscarinic and the beta-adrenergic receptors.     

A Central Role for GRB10 in Regulation of Islet Function in Man

Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.     

Serum insulin concentration and arginine tolerance test in the cynomolgus monkey (Macaca fascicularis)

The standard value of serum insulin was determined to be less than 75 microU/ml with ninety-eight female adult cynomolgus monkeys of wild origin. Then, fifteen apparently healthy laboratory-bred female cynomolgus monkeys aged 6-8 years were studied to know the usefulness of the arginine tolerance test (ATT) by measuring blood glucose, insulin and glucagon. Prior to ATT, all animals had been diagnosed as non-diabetic by the intravenous glucose tolerance test (IVGTT). Arginine hydrochloride was infused intravenously at a dose of 0.5 g/kg. BW under anesthesia. According to the standard value of insulin, fifteen animals were divided into two groups, that is, the low (n = 7) and the high (n = 8) value groups. In the low value group, glucose and insulin value did not change significantly after arginine infusion and their responses were similar to those in the control group (saline infused, n = 4). But glucagon markedly increased from 10 to 45 minutes post infusion. In the high value group, glucagon response was similar to that in the low value group, while glucose and insulin values significantly decreased. It is concluded that the pancreatic alpha-cell function (glucagon secretion) can be judged by the ATT in the cynomolgus monkey but the beta-cell function (insulin secretion) can not be diagnosed.     

The pancreatic glucagon and C-peptide secretion during hyperinsulinemia in euglycemic glucose clamp with or without somatostatin infusion in normal man

6 normal subjects received two times of 2 hr euglycemic glucose clamp studies (insulin infusion rate 40 mU/M2/min) one with and the other without somatostatin (SRIF) infusion (500 microgram/hr). Serum C-peptide and glucagon levels were measured during clamp to study the sensitivity of pancreatic alpha and beta cells to the suppressive effects of exogenous hyperinsulinemia during normoglycemia in normal subjects and to find whether SRIF had any modulative effects on endocrine pancreas secretion at the status of hyperinsulinemia. The results showed that in normal man the degree of suppression of pancreatic glucagon secretion by hyperinsulinemia (approximately 100 uU/ml) during euglycemic glucose clamp without SRIF infusion was less than that of C-peptide with mean value of 62 +/- 4% of basal glucagon remained at the end of clamp study; while only about 30 +/- 2% of basal C-peptide concentrations remained. But during SRIF infused glucose clamp studies (SRIF was infused from 60 to 120 min), 32 +/- 2% of mean basal C-peptide concentrations and 38 +/- 6% of mean basal glucagon concentrations left at the end of 2 hr clamp studies when serum insulin level was about 100 uU/ml. For the glucose infusion rate (M value), it was significantly greater in our normal subjects in response to insulin + SRIF as compared to insulin alone (12.0 + 0.9 vs 8.8 +/- 1.4; P less than 0.01). We concluded: during hyperinsulinemia (100 uU/ml), the sensitivity of pancreatic alpha cells to insulin seems less than that of beta cells in normal man at normoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)