Glyburide but not ciglitazone enhances insulin action in the liver independent of insulin receptor kinase activation

To test the hypothesis that sulfonylureas enhance insulin action by activating the insulin receptor tyrosine kinase, the effects of glyburide, a second generation sulfonylurea, and ciglitazone, a nonsulfonylurea hypoglycemic agent, were determined in primary cultures of rat hepatocytes on insulin action and insulin receptor structure and function. Twenty hours of preincubation with glyburide (1 microgram/mL) resulted in increased insulin (1 X 10(-7) mol/L) stimulation of [14C] acetate incorporation into lipids and [14C] alpha-aminoisobutyric acid uptake without any change in basal activity. Ciglitazone (1 microgram/mL) was without any effect. Glyburide's actions were mediated without altering the following: (1) 125I-insulin binding; (2) the electrophoretic mobility of the affinity labeled alpha-subunit or the autophosphorylated beta-subunit of the insulin receptor; and (3) the insulin-stimulated insulin receptor kinase activity using histone or the beta-subunit of the insulin receptor as phosphoacceptors. These data suggest that the action of sulfonylureas is distal to the insulin receptor tyrosine kinase. Ciglitazone in vitro is ineffective in the liver, which suggests the peripheral tissues as the possible site of action.     

Resistance to insulin suppression of plasma free fatty acid concentrations and insulin stimulation of glucose uptake in noninsulin-dependent diabetes mellitus

The ability of insulin to stimulate tissue glucose uptake and lower plasma FFA concentrations was quantified in 12 individuals with normal glucose tolerance and 12 patients with noninsulin-dependent diabetes mellitus (NIDDM), further subdivided into obese and nonobese subjects. Measurements were made during 5-h glucose clamp studies, carried out at plasma insulin concentrations of about 10 microU/ml (0-150 min) and about 60 microU/ml (150-300 min). Differences between the patient groups were compared by two-way analysis of variance. The ability of insulin to either suppress plasma FFA concentrations or stimulate glucose uptake was significantly reduced (P less than 0.001) in patients with NIDDM, and this was true of both the obese and nonobese groups. The defect in the ability of insulin to suppress plasma FFA concentrations in patients with NIDDM was more apparent at the lower insulin concentration, whereas resistance to insulin-stimulated glucose uptake in NIDDM was more dramatic at the high insulin concentration. Finally, a significant correlation (r = -0.67; P less than 0.001) between insulin-stimulated glucose uptake and plasma FFA concentration was found in the entire group. These data emphasize the fact that patients with NIDDM are resistant to multiple actions of insulin, and that the magnitudes of the defect in insulin suppression of plasma FFA levels and stimulation of tissue glucose uptake are roughly comparable.     

Modulation of insulin secretion by insulin and glucose in type II diabetes mellitus

We studied the dose-response characteristics of insulin's ability to modulate its own secretion in normal and type II diabetic (NIDDM) subjects by measuring suppression of serum C-peptide levels during insulin infusions with the plasma glucose level held constant. In normal subjects at euglycemia, primed continuous insulin infusion rates of 15, 40, 120, and 240 mU/M2 X min acutely raised serum insulin to steady state levels of 37 +/- 2 (+/- SE), 96 +/- 6, 286 +/- 17, and 871 +/- 93 microU/ml, respectively. During each infusion, maximal suppression of C-peptide to 30% of basal levels occurred by 130 min. At the higher insulin levels (greater than or equal to 100 microU/ml), C-peptide levels fell rapidly, with an apparent t1/2 of 13 min, which approximates estimates for the t1/2 of circulating C-peptide in man. This is consistent with an immediate 70% inhibition of the basal rate of insulin secretion. At the lower insulin level (37 +/- 2 microU/ml), C-peptide levels fell to 30% of basal values less rapidly (apparent t1/2, 33 min), suggesting that 70% inhibition of basal insulin secretion rates was achieved more slowly. In NIDDM subjects, primed continuous insulin infusion rates of 15, 40, 120, and 1200 mU/M2 X min acutely raised serum insulin to steady state levels of 49 +/- 7, 93 +/- 11,364 +/- 31, and 10,003 +/- 988 microU/ml. During studies at basal hyperglycemia, only minimal C-peptide suppression was found, even at pharmacological insulin levels (10,003 +/- 988 microU/ml). However, if plasma glucose was allowed to fall during the insulin infusions, there was a rapid decrease in serum C-peptide to 30% of basal levels, analogous to that in normal subjects. Three weeks of intensive insulin therapy did not alter C-peptide suppression under conditions of hyperinsulinemia and falling plasma glucose. The following conclusions were reached. 1) In normal subjects, insulin (40-1000 microU/ml) inhibits its own secretion in a dose-responsive manner; more time is required to achieve maximal 70% suppression at the lower insulin level (40 microU/ml). 2) In NIDDM studied at basal hyperglycemia, insulin has minimal ability to suppress its own secretion. Thus, impaired feedback inhibition could contribute to basal hyperinsulinemia. 3) Under conditions of hyperinsulinemia and falling plasma glucose, insulin secretion is rapidly suppressed in NIDDM (analogous to that in normal subjects studied during euglycemia.     

Effects of salicylate, tolbutamide, and prostaglandin E2 on insulin responses to glucose in noninsulin-dependent diabetes mellitus

To assess whether the beneficial effects of salicylates compounds and sulfonylureas on insulin secretion in patients with noninsulin-dependent diabetes mellitus could be ascribed to inhibition of prostaglandin E (PGE) synthesis, insulin responses to iv glucose pulses were determined in diabetic patients during infusion of lysine acetylsalicylate (LAS) or tolbutamide, with or without a concurrent infusion of PGE2. In these diabetic patients, the augmenting effects of LAS on glucose-induced insulin secretion were abolished by PGE2 infusion. Partial restoration by tolbutamide infusion of the first and second phases of glucose-induced insulin secretion was not affected by the administration of PGE2. The stimulatory effects of LAS and tolbutamide on insulin secretion were additive, suggesting separate mechanisms of action. Since salicylates and sulfonylureas lower plasma glucose concentrations, we also evaluated whether prevention of the fall in the prestimulus glucose level could result in a further amplification of insulin release. Resetting the prestimulus glucose level to control values by infusing glucose caused a further increase in the second, but not the first, phase of glucose-induced insulin secretion, indicating that the prestimulus glucose level had a role in regulating subsequent insulin release. These results indicate that salicylates, but not sulfonylureas, exert their acute insulinotropic effect in noninsulin-dependent diabetic patients by inhibiting endogenous PGE synthesis and support the idea that endogenous PGE may play a role in the impaired insulin response to glucose in this form of human diabetes.     

Growth hormone treatment of children with short stature increases insulin secretion but does not impair glucose disposal

Pediatricians willing to administer GH to non-GH-deficient children with short stature are concerned about the potential adverse effects of this hormone on glucose homeostasis and insulin action. This study was designed to determine the effects of GH therapy on carbohydrate metabolism in 10 prepubertal non-GH-deficient children with short stature. After 12 months of treatment with 0.3 U GH/kg BW.day, which resulted in an increase in height velocity from 4.0 +/- 0.3 (+/- SE) to 11.0 +/- 0.4 cm/yr, glucose tolerance was not impaired in these children. Not only were their fasting and postprandial plasma glucose concentrations unchanged from the pretreatment values, but basal glucose turnover did not vary; it was 0.53 +/- 0.04 before and 0.64 +/- 0.06 mmol/m2.min after GH treatment. Using the euglycemic clamp technique, the dose-response curves describing the effects of insulin on glucose disposal were comparable before and after GH treatment. There was a consistent 1.5- to 2-fold increase in plasma insulin and C-peptide concentrations during GH treatment, in both the basal and postprandial states, and after oral glucose or iv glucagon stimulation. We conclude that the GH regimen employed was remarkably effective in increasing growth velocity and devoid of detectable diabetogenic effects during a 1-yr treatment period in these non-GH-deficient children. (glucose, 1 mmol/L = 18 mg/dL; insulin, 1 pmol/L = 0.139 microU/mL; C-peptide, 1 pmol/L = 0.003 ng/ml).     

Impaired glucose tolerance precedes but does not predict insulin-dependent diabetes mellitus: a study of identical twins

Summary Non-diabetic identical twins of insulin-dependent diabetic patients were studied within five years of the diagnosis of their index twin in order to determine whether changes in intermediary metabolism precede the onset of insulin-dependent diabetes mellitus. Two studies were performed: a cross-sectional study of 12 non-diabetic twins and a prospective study of a separate group of 41 non-diabetic twins. Ofthe 12 twins tested in the cross-sectional study six developed insulin-dependent diabetes and six did not; the six who developed diabetes were given an oral glucose load a mean of 10 months before diagnosis; they then had normal fasting blood glucose levels but worse glucose tolerance than control subjects (120 min post-load (mean±SD) blood glucose 8.5±3.5 vs 4.9±0.9 mmol/l respectively, p<0.05). However, blood lactate, pyruvate, alanine, glycerol, 3-hydroxybutyrate and serum insulin levels were similar. In contrast, the six twins in this cross-sectional study who did not develop diabetes and are now unlikely to do so, as a group, had no significant changes compared with the control subjects though one had impaired glucose tolerance. To determine the predictive value of impaired glucose tolerance a separate group of 41 non-diabetic twins was studied prospectively for 8 to 22 years having a total of 147 glucose tolerance tests in this period; in this group six developed diabetes. Eight of the 41 had impaired glucose tolerance; impaired glucose tolerance was found in four of the six who developed diabetes as compared with only four of the 35 who did not (p<0.01). Impaired glucose tolerance in these non-diabetic identical twins had a positive predictive value of33% for developing diabetes. The four twins with impaired glucose tolerance who remain nondiabetic now have normal glucose tolerance. We conclude that impaired glucose tolerance may precede the onset of insulin-dependent diabetes mellitus by many months but the change does not specifically predict the disease even in identical twins of diabetic patients. These observations are consistent with the possibility that in some twins the disease process can occur yet remit without leading to diabetes.     

Twelve weeks' treatment with diazoxide without insulin supplementation in Type 2 diabetes is feasible but does not improve insulin secretion.

AIMS: Treatment with K-ATP channel openers, such as diazoxide, can have beneficial effects on insulin secretion in both Type 1 and Type 2 diabetes. However, the precise conditions for obtaining beneficial effects without untoward events have not been determined. We tested the hypothesis that intermittent administration of diazoxide at bedtime for 12 weeks could produce beneficial effects in the absence of side-effects in Type 2 diabetic patients who were not taking insulin. METHODS: After an 8-week run-in period, during which treatment with repaglinide and metformin was optimized, we randomized 26 patients to either diazoxide, 100 mg at bedtime, or placebo. RESULTS: Side-effects were absent or minimal. HbA(1c) did not change. However day-time glucose concentrations by home glucose monitoring were approximately 1.5 mmol/l higher with diazoxide vs. placebo. Stimulation tests (C-peptide-glucagon and breakfast) did not indicate improved pancreatic B-cell function, except by posthoc analysis, in a subgroup of younger age. CONCLUSION: Compared with previous results with diazoxide together with bedtime insulin, the present results are less favourable and indicate that concomitant insulin treatment is needed during intervention with K-ATP channel openers.     

Effect of exogenous insulin on glucose kinetics in rats with noninsulin-dependent diabetes

Noninsulin-dependent diabetes (NIDD) was induced in adult female rats by neonatal administration of streptozotocin. Despite elevated basal plasma glucose values in the postabsorptive state (196 +/- 16 mg/100 mL as compared to 118 +/- 7 in the controls), the glucose disappearance rate measured after the intravenous glucose load was not significantly lower in the diabetic than in control rats. In contrast, in vivo glucose-induced insulin release was drastically reduced, thus suggesting that endogenous insulin was more effective on the target tissues of the diabetic rats. Glucose kinetics (glucose production, utilization, and clearance) in response to intravenous insulin injection were studied in anesthetized postabsorptive diabetic and control female rats using [6-3H] glucose. With a maximal dose of insulin (0.5 U/kg body weight) no difference in blood glucose-lowering effect of insulin was found between the 2 groups. With 2 submaximal insulin doses (0.15 and 0.3 U/kg body weight), glucose production was inhibited more rapidly and more efficiently in diabetic rats than in control rats: 2 minutes after the 0.15 U/kg insulin injection, endogenous glucose production fell by 79 +/- 5% in the diabetics while being unchanged in the controls and the maximal decrease of glucose production after the same insulin injection was significantly greater in the diabetic rats (79 +/- 5% at 2 minutes) compared to the controls (33 +/- 4% at 6 min). The rise of glucose clearance in response to insulin was not significantly different in the 2 groups. These findings are discussed in view of the increased insulin clearance rate in these diabetic females.(ABSTRACT TRUNCATED AT 250 WORDS)     

Trace and toxic element patterns in nonsmoker patients with noninsulin-dependent diabetes mellitus, impaired glucose tolerance, and fasting glucose

PROJECT:

Noninsulin dependent diabetes mellitus is supposed to be associated with fluctuations in the plasma levels of several trace elements. There is accumulating evidence that the metabolism of several trace elements is altered in patients with noninsulin dependent diabetes mellitus and that these nutrients might have specific roles in the pathogenesis and progression of this disorder.

PROCEDURE:

The aim of the present study is to compare the levels of essential trace and toxic elements including lead (Pb), arsenic (As), cadmium (Cd), chromium (Cr), aluminium (Al), nickel (Ni), cobalt (Co), iron (Fe), copper (Cu), selenium (Se), zinc (Zn), vanadium (V), manganese (Mn), barium (Ba), silver (Ag), and mercury (Hg) in patients with noninsulin dependent diabetes mellitus (n = 31), impaired glucose tolerance (n = 20), impaired fasting glucose (n = 14), and healthy controls (n = 22). Plasma concentrations of the elements were measured by using inductively coupled plasma mass spectrometry.

RESULTS:

The results indicated that values of lead, nickel, aluminium, copper, and chromium were significantly higher, but not above toxic levels, in the plasma of nonsmoker patients with noninsulin dependent diabetes mellitus (P < 0.05). The values for these elements were found to be significantly higher (P < 0.05) in patients with impaired fasting glucose than in controls. Moreover, a statistically significant correlation was found between plasma levels of glycated hemoglobin and of some trace elements like lead, nickel, aluminium, copper, chromium, cadmium, and mercury.

CONCLUSIONS

Thus, it was concluded that chronic complications of glucose metabolism disorders might be associated with alterations in the levels of some trace elements. Nevertheless, some more timely and extensive studies are required to clarify the exact mechanisms of each of these changes.     

Serum sex-hormone-binding globulin is related to hepatic and peripheral insulin sensitivity but not to beta-cell function in men and women with Type 2 diabetes mellitus

This study examined the relationship of hepatic and peripheral insulin sensitivity and β-cell secretory function with serum sex hormone-binding globulin (SHBG) in men and women with Type 2 diabetes mellitus (DM). Fasting insulin, glucose and SHBG were measured in 58 Type 2 diabetic patients of both sexes (36 men) who were on diet treatment only and terms for insulin sensitivity and β-cell secretion obtained by modelling. There was no significant difference in SHBG between men and women despite similar degree of obesity. SHBG was positively correlated (r = 0.41, p < 0.01) to hepatic insulin sensitivity derived from mathematical modelling of fasting glucose and insulin data using the homeostasis assessment model (HOMA). This relationship was independent of gender (men, r = 0.48, p < 0.01; women, r = 0.45, p < 0.05). Fasting insulin correlated negatively with SHBG in men (r = −0.34, p < 0.05). There were also significant negative correlations between SHBG and either plasma glucose (r = −0.29, p < 0.05) or body mass index (r = −0.34, p < 0.05). SHBG did not correlate with HOMA-modelled beta-cell function. In a multiple regression analysis, SHBG was independently correlated only with insulin sensitivity (p < 0.05). Further studies in 15 of the diabetic patients (11 men), showed a significant positive correlation (r = 0.52, p < 0.05) between SHBG and peripheral insulin sensitivity derived by continuous infusion of glucose with model assessment (CIGMA) but not between SHBG and CIGMA-modelled β-cell function. These results indicate that both hepatic and peripheral insulin sensitivity are similarly related to serum SHBG in Type 2 diabetes of both sexes. The sex-difference in SHBG was abolished in the patients. © 1998 John Wiley & Sons, Ltd.     

Associations of glucose control with insulin sensitivity and pancreatic beta-cell responsiveness in newly presenting type 2 diabetes.

We examined the ability of indices of insulin sensitivity and pancreatic beta-cell responsiveness to explain interindividual variability of clinical measures of glucose control in newly presenting type 2 diabetes. Subjects with newly presenting type 2 diabetes (n = 65; 53 males and 12 females; age, 54 +/- 1 yr; body mass index, 30.5 +/- 0.7 kg/m(2); mean +/- SE) underwent an insulin-modified iv glucose tolerance test to determine minimal model-derived insulin sensitivity (S(I)), glucose effectiveness, first-phase insulin secretion, and disposition index. Subjects also underwent a standard meal tolerance test (MTT) to measure fasting/basal (M(0)) and postprandial (M(I)) pancreatic beta-cell responsiveness. Stepwise linear regression used these indices to explain interindividual variability of fasting and postprandial plasma glucose and insulin concentrations and glycated hemoglobin (HbA(1C)). All measures of pancreatic beta-cell responsiveness (M(0), M(I), and first-phase insulin secretion) were negatively correlated with fasting plasma glucose (P < 0.01) and positively correlated with fasting plasma insulin (FPI) and insulin responses to MTT (P < 0.05). S(I) demonstrated negative correlation with FPI (P < 0.001) but failed to correlate with any glucose variable. M(I) followed by disposition index (composite index of insulin sensitivity and pancreatic beta-cell responsiveness) were most informative in explaining interindividual variability. It was possible to explain 70-80% interindividual variability of fasting plasma glucose, FPI, HbA(1C), and insulin responses to MTT, and only 25-40% interindividual variability of postprandial glucose. In conclusion, postprandial insulin deficiency is the most powerful explanatory factor of deteriorating glucose control in newly presenting type 2 diabetes. Indices of insulin sensitivity and pancreatic beta-cell responsiveness explain fasting glucose and HbA(1C) well but fail to explain postprandial glucose.     

Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose

Subjects with impaired fasting glucose (IFG) are at increased risk for type 2 diabetes. We recently demonstrated that IFG subjects have increased hepatic insulin resistance with normal insulin sensitivity in skeletal muscle. In this study, we quantitated the insulin secretion rate from deconvolution analysis of the plasma C-peptide concentration during an oral glucose tolerance test (OGTT) and compared the results in IFG subjects with those in subjects with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). One hundred and one NGT subjects, 64 subjects with isolated IGT, 24 subjects with isolated IFG, and 48 subjects with combined (IFG + IGT) glucose intolerance (CGI) received an OGTT. Plasma glucose, insulin, and C-peptide concentrations were measured before and every 15 min after glucose ingestion. Insulin secretion rate (ISR) was determined by deconvolution of plasma C-peptide concentration. Inverse of the Matsuda index of whole body insulin sensitivity was used as a measure of insulin resistance; 56 subjects also received a euglycemic hyperinsulinemic clamp. The insulin secretion/insulin resistance (disposition) index was calculated as the ratio between incremental area under the ISR curve (∆ISR[AUC]) to incremental area under the glucose curve (∆G[AUC]) factored by the severity of insulin resistance (measured by Matsuda index during OGTT or glucose disposal during insulin clamp). Compared to NGT, the insulin secretion/insulin resistance index during first 30 min of OGTT was reduced by 47, 49, and 74% in IFG, IGT, and CGI, respectively (all < 0.0001). The insulin secretion/insulin resistance index during the second hour (60–120 min) of the OGTT in subjects with IFG was similar to that in NGT (0.79 ± 0.6 vs. 0.72 ± 0.5, respectively, P = NS), but was profoundly reduced in subjects with IGT and CGI (0.31 ± 0.2 and 0.19 ± 0.11, respectively; P < 0.0001 vs. both NGT and IFG). Early-phase insulin secretion is impaired in both IFG and IGT, while the late-phase insulin secretion is impaired only in subjects with IGT.     

Impaired glucose tolerance and mild hyperglycemia in sucrose-fed rats does not impair insulin secretion

We fed normal rats a high sucrose diet in order to test the hypothesis that mild hyperglycemia can induce defects in pancreatic beta-cell function and impair glucosestimulated insulin release. Rats provided with free access to a sucrose solution (35%) voluntarily consumed 50% more carbohydrate than control per day. After 7 days of sucrose feeding, glucose tolerance was significantly impaired; the area under the glucose tolerance test curve (GTT) was 683±61 mmol/120 min compared with 472±56 mmol/120 min in controls (P<0.05). Impaired glucose tolerance was still present after a further 12 days (area under the GTT: 749±99 mmol/120 min). Sucrosefed rats were significantly (P<0.05) hyperglycemic by 1.5 mmol/l over controls. When insulin secretion was assessed in vivo and in vitro in control and sucrose-fed rats, no significant differences were apparent in plasma samples collected over a 1-h period or in statically incubated or perifused isolated pancreatic islets. In addition, the rates of glucose utilisation and oxidation were normal in islets from sucrose-fed rats. These data do not support the hypothesis that minimal hyperglycemia is sufficient to impair glucose-stimulated insulin release.     

Increased gastric inhibitory polypeptide is not reduced in patients with noninsulin-dependent diabetes mellitus treated with intense insulin therapy

Serum glucose and gastric inhibitory polypeptide (GIP) responses during mixed test meals and primed continuous infusion of insulin using the insulin clamp technique were studied in nine patients with noninsulin-dependent diabetes mellitus (NIDDM) before and after vigorous insulin treatment. Fasting serum glucose concentrations fell an average of 167 mg/dl (P less than 0.001), and there was a 67% reduction (P less than 0.001) in the postprandial glucose response. Mean hemoglobin A1c declined and paralleled the fall in serum glucose concentrations (9.2 +/- 0.5% to 5.9% +/- 0.3%; P less than 0.01). This improvement in glycemic control, however, was not associated with any appreciable change in GIP secretion. Basal and meal-stimulated serum GIP levels were not reduced after intense insulin therapy. Furthermore, hyperinsulinemia at physiological (100 microU/ml) and superphysiological (1000 microU/ml) levels failed to reduce GIP secretion before and after insulin therapy. Before insulin therapy, seven patients had elevated basal GIP levels and five had increased GIP levels after meals compared to values in nondiabetic subjects. Insulin administration did not alter these elevated GIP levels. These findings suggest that the increased meal-stimulated GIP secretion in some patients with NIDDM is not due to a failure of insulin feedback on GIP secretion.     

Adiponectin is functionally active in human islets but does not affect insulin secretory function or beta-cell lipoapoptosis

CONTEXT: The adipokine adiponectin has insulin-sensitizing, antiatherogenic, and antiinflammatory properties. Mouse and human adiponectin receptor-1 and -2 have been cloned, both of which are expressed in various tissues and mediate effects of globular and full-length adiponectin. Whether adiponectin affects insulin secretion and beta-cell apoptosis and whether plasma adiponectin is associated with beta-cell function in humans is under investigation. DESIGN AND METHODS: In human islets from multiorgan donors, we investigated expression of adiponectin receptor-1 and -2. Furthermore, glucose-stimulated insulin secretion was determined by RIA. In addition, we investigated fatty acid-induced beta-cell apoptosis by terminal dUTP nick end labeling and flow-cytometric cell cycle analysis (sub-G1 formation). In humans in vivo, insulin secretory function was measured during hyperglycemic clamps in 65 normal glucose-tolerant subjects. We determined first and second phase of glucose-stimulated, glucagon-like peptide-1-stimulated, and arginine-stimulated insulin secretion. RESULTS: Adiponectin receptor-1 and -2 are expressed in human islets at the mRNA and protein level. Moreover, full-length adiponectin induces phosphorylation of acetyl coenzyme A carboxylase. However, adiponectin did not affect basal or glucose-stimulated insulin secretion or basal or fatty acid-induced beta-cell apoptosis. In vivo, fasting plasma adiponectin concentrations were not associated with glucose-stimulated first- and second-phase insulin secretion or with glucagon-like peptide-1- or arginine-stimulated insulin secretion (all P > 0.42). CONCLUSIONS: These data support a regulatory role of adiponectin in human islets; however, adiponectin does not seem to affect insulin secretion or basal/fatty acid-induced beta-cell apoptosis in humans.     

Alpha 2-adrenoceptor blockade does not enhance glucose-induced insulin release in normal subjects or patients with noninsulin-dependent diabetes

Studies with phentolamine, an alpha-adrenergic antagonist, in normal subjects and diabetic patients have indicated that insulin secretion may be inhibited by tonic alpha-adrenergic stimulation of pancreatic B-cells. We evaluated, with the use of the highly selective alpha 2-adrenoceptor antagonist idazoxan, the role of alpha 2-adrenergic receptors in the regulation of glucose-induced insulin secretion. A glucose infusion test (GIT) was performed after the administration of idazoxan or placebo in normal men (n = 15) and men with noninsulin-dependent diabetes mellitus (n = 6). The normal men were divided into two groups on the basis of high (n = 8) and low (n = 7) insulin responses to prior GITs. The blood glucose and plasma insulin and C-peptide responses to the GIT were similar after idazoxan (40 mg, orally) or placebo treatment in all three groups, although the responses differed among the groups. In the diabetic group iv administration of idazoxan 20 min before the GIT did not alter the insulin response to the GIT. We conclude that alpha 2-adrenergic blockade does not affect glucose-induced insulin secretion in normal men, nor does it improve the impaired first phase of insulin secretion in low insulin responders and noninsulin-dependent diabetes mellitus patients. Phentolamine probably stimulates insulin secretion by a mechanism not involving alpha 2-adrenergic receptors directly.