Dose-response characteristics for glucose-stimulated insulin release in man and assessment of influence of glucose on arginine-stimulated insulin release

Glucose potentiates arginine-induced insulin release. We investigated the dose-response characteristics for both phases of glucose-induced insulin release in normal man, and studied the influence of hyperglycemia on arginine-induced insulin secretion. Dose-response curves of plasma C-peptide increments achieved during 60-minute hyperglycemia clamps (7, 11, 17, 24, and 32 mmol/L) with and without a primed continuous infusion of arginine (infusion rate, 15 mg/kg/min) were analyzed with a modified Michaelis-Menten equation. The ED50 (half-maximally stimulating blood glucose concentration) of first-phase insulin release (determined from plasma C-peptide increments at 5 minutes) was significantly lower than the ED50 for the second phase (60 minutes; 8.4 +/- 0.8 v 14.3 +/- 1.3 mmol/L, respectively, P less than .002). Combined glucose-arginine stimulation significantly increased insulin release. Vmax of both phases of glucose-arginine-stimulated insulin release were positively correlated (r = .75, P less than .05). The ED50 of the influence of glucose on first-phase arginine-induced insulin release was significantly lower than the ED50 for the second phase (9.0 +/- 1.1 v 12.7 +/- 1.0 mmol/L, respectively, P less than .02). For each insulin secretion phase separately, the ED50 for the influence of hyperglycemia on arginine-induced insulin release were not significantly different from the ED50 for glucose-induced insulin secretion (without arginine). When dose-response curves of plasma insulin increments were analyzed with the same equation, the ED50 of second-phase glucose-induced plasma insulin increments was significantly higher than the ED50 assessed from the plasma C-peptide increments (21.6 +/- 2.8 v 14.3 +/- 1.3 mmol/L, respectively, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormal B-cell function in rats with non-insulin-dependent diabetes induced by neonatal streptozotocin: effect of in vivo insulin, phlorizin, or vanadate treatments

Neonatal rats treated with streptozotocin on day 5 after birth (n5-STZ model) exhibited, when fully grown, a frank basal hyperglycemia (17.4 +/- 0.7 vs. 6.6 +/- 0.2 mmol/L in nondiabetic rats), a specific failure of glucose-induced insulin release, and hyperresponse to arginine. To investigate whether or not chronic correction of the hyperglycemia can improve the defects on insulin secretion, we tested diverse maneuvers, all of which aimed to lower chronically the hyperglycemia. Insulin secretion was studied with the isolated perfused pancreas preparation. A 16-day subcutaneous insulin therapy (approximately 10 U/kg/day) unevenly correcting the plasma glucose levels (10.8 +/- 1.6 mmol/L) did not improve the lack of insulin response to glucose while the arginine-induced insulin release returned to values close to normal. A 28-day intraperitoneal phlorizin infusion (50 mg/kg/day0 or a 20-day oral vanadate administration (40 mg/kg/day) caused near normalization of the basal plasma glucose level in the treated n5-STZ rats (7.8 +/- 0.5 and 8.2 +/- 0.5 mmol/L, respectively). Nevertheless, these treatments did not correct the insulin secretion in response to glucose nor the hyperresponsiveness to arginine. Furthermore, we investigated whether or not glucopenia in vitro could restore the glucose-induced insulin release in this diabetic model. After a 50 min glucose-free period, the insulin response to a subsequent glucose stimulation still did not materialize. These observations suggest that in the present n5-STZ diabetic model, (a) hyperresponsiveness to arginine cannot be solely regarded as a residual effect of hyperglycemia; (b) the return to normal values of insulin release in response to arginine after insulin therapy, despite a still prevailing mild hyperglycemia, suggests that exogenous insulin per se may regulate to some extent the diabetic B cells; and (c) near normalization of the basal glucose levels is not a sufficient condition to obtain improvement of the B-cell response to glucose, such a finding being consistent with the concept that stringent normalization of glycemia is a prerequisite.     

Pancreatic beta-cell defects in women at risk of type 2 diabetes

We evaluated insulin release and insulin sensitivity in women with basal and/or postprandial hyperglycemia but normal oral glucose tolerance test (OGTT) in previous pregnancy (GHG). These women were individually matched with females without previous hyperglycemia (NGT). Both groups consisted of normal glucose-tolerant women at the time of this study. They underwent OGTT (75 g; n=32 pairs) and hyperglycemic clamp experiments (10 mmoll(-1); n=27 pairs) with plasma glucose, insulin, and C-peptide measurements and calculation of insulinogenic index, first- and second-phase insulin release, and insulin sensitivity index (ISI). The GHG group showed higher glycosylated hemoglobin levels (6.2+/-0.6% versus 5.8+/-0.8%; P<0.05); lower insulinogenic index at 30 min (134.03+/-62.69 pmol mmol(-1) versus 181.59+/-70.26 pmol mmoll(-1); P<0.05) and diminished C-peptide response in relation to glucose (4.05+/-0.36 nmol mmol(-1) versus 4.23+/-0.36 nmol mmol(-1); P<0.05) at OGTT. Both groups did not show difference in insulin secretion and ISI by hyperglycemic clamp technique. We concluded that in up to 12 years from index pregnancy, women with previous GHG, presenting normal glucose tolerance and well-matched with their controls, showed beta-cell dysfunction without change in ISI. As women with previous GHG are at risk of type 2 diabetes, beta-cell dysfunction may be its primary defect.     

Short- and long-term gliclazide effects on pancreatic islet cell function and hepatic insulin extraction in non-insulin-dependent diabetes mellitus.

Nine non-obese males with non-insulin-dependent diabetes mellitus (NIDDM) were evaluated before and after 3 and 12 months (6 patients) treatment with the second generation hypoglycemic sulfonylurea: gliclazide. They underwent an oral glucose tolerance test, intravenous glucose and arginine tests measuring plasma insulin and C-peptide responses. Pre-hepatic insulin production and insulin delivery to peripheral tissues were calculated by deconvolution techniques and hepatic extraction of insulin estimated. An improvement was observed in the beta-cell function of the patients on gliclazide treatment: reduction of fasting plasma glucose associated with a progressive increase in C-peptide level but insulin levels decreased at 12 months, suggesting an increase in hepatic insulin extraction at this time. In the same way, while plasma glucose values after oral and i.v. glucose were greatly reduced at 3 and 12 months treatment, insulin did not change but C-peptide levels increased significantly at 12 month treatment. While the prehepatic insulin secretion rate increased progressively on gliclazide during all glucose challenges, the fractional hepatic insulin extraction fell after 3 and increased at 12 month treatment, with opposite changes in insulin delivered to peripheral tissues. Thus the insulinogenic effect of gliclazide could be masked during long-term administration by a concomitant effect of gliclazide which increases hepatic extraction of insulin. The maintenance of the responsiveness to the non-glucose secretagogue, arginine, as evaluated by the C-peptide levels, before and after correction of hyperglycemia, suggested improvement of beta-cell sensitivity to glucose after sulfonylurea treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diazoxide infusion at excess but not at basal hyperglycemia enhances beta-cell sensitivity to glucose in vitro in neonatally streptozotocin-diabetic rats.

The influence of chronic and moderate hyperglycemia vis-à-vis a 48-hour further elevation of blood glucose on beta-cell sensitivity to glucose was compared in an animal model of non-insulin-dependent diabetes. Neonatally streptozotocin-diabetic (n-STZ) rats infused with saline for 48 hours displayed moderate nonfasting hyperglycemia (mean, 11.5 +/- 1.5 mmol/L/48 h) and plasma insulin levels similar to those seen in normoglycemic, nondiabetic rats. In perfused pancreas, the insulin response to 27 mmol/L glucose was severely reduced to 1.60 +/- 0.45 pmol/min, ie, approximately 15% of the response in nondiabetic rats. A continuous infusion of diazoxide (5 mg/kg/h), which normally blocks glucose-induced insulin secretion, did not affect glucose and insulin levels in vivo, nor did it significantly affect the insulin response to glucose in vitro. In other experiments, "basal" hyperglycemia in n-STZ rats was doubled by glucose infusions for 48 hours to reach a mean of 23.8 +/- 0.6 mmol/L. Plasma insulin increased 3.2-fold. The in vitro insulin response to 27 mmol/L glucose was totally abolished, and the pancreatic insulin content was decreased by 81% relative to the content after saline. Addition of a diazoxide infusion inhibited the increase in plasma insulin by 93%. After the combined glucose and diazoxide infusion, the subsequent in vitro response to 27 mmol/L glucose was dramatically enhanced to 9.55 +/- 3.25 pmol/min, ie, the response was sixfold higher than after saline alone. This aftereffect of the diazoxide infusion was not significantly altered by an insulin infusion (2 U/d) added to the hyperglycemia plus diazoxide protocol to compensate for the insulin-lowering effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin and glucagon secretion are suppressed equally during both hyper- and euglycemia by moderate hyperinsulinemia in patients with diabetes mellitus

Hyper- and euglycemic clamp studies were performed in patients with noninsulin-dependent diabetes mellitus to examine the effects of exogenous insulin administration on insulin and glucagon secretion. Plasma glucose was kept at the fasting level [mean, 10.0 +/- 0.2 (+/- SE) mmol/L; hyperglycemic clamp], and graded doses of insulin (1, 3, and 10 mU/kg.min, each for 50 min) were infused. The plasma C-peptide level gradually decreased from 523 +/- 66 to 291 +/- 43 pmol/L (n = 13; P less than 0.005) by the end of the hyperglycemic clamp study. After 90 min of equilibration with euglycemia (5.4 +/- 0.1 mmol/L; euglycemic clamp), the same insulin infusion protocol caused a similar decrease in the plasma C-peptide level. With the same glucose clamp protocol, physiological hyperinsulinemia for 150 min (676 +/- 40 pmol/L), obtained by the infusion of 2 mU/kg.min insulin, caused suppression of the plasma C-peptide level from 536 +/- 119 to 273 +/- 65 pmol/L during hyperglycemia and from 268 +/- 41 to 151 +/- 23 pmol/L during euglycemia (n = 9; P less than 0.005 in each clamp). Plasma glucagon was suppressed to a similar degree in both glycemic states. These results demonstrate that 1) insulin secretion in non-insulin-dependent diabetes mellitus is suppressed by high physiological doses of exogenous insulin in both the hyper- and euglycemic states, the degree of inhibition being independent of the plasma glucose level; and 2) glucagon secretion is also inhibited by such doses of exogenous insulin.     

Influence of gliclazide on glucose-stimulated insulin release in man

Although sulfonylureas (SU) are widely used in the management of patients with non-insulin-dependent diabetes mellitus (NIDDM), there is still debate about their mechanism of action on the pancreatic beta cell. It is unclear whether the effect of SU on insulin release is additive to the effect of glucose, or whether SU act by increasing pancreatic beta-cell sensitivity to glucose (a shift in the dose-response curve of glucose-stimulated insulin release without a change in maximum release). To address this issue, we assessed the influence of the SU gliclazide on glucose-stimulated insulin release in eight healthy male volunteers. Sixty-minute hyperglycemic glucose clamps (blood glucose levels: 8 mmol/L, a submaximal stimulus; and 32 mmol/L, a maximally stimulating concentration) were performed with and without prior oral administration of gliclazide (80 mg) 30 minutes before the glucose clamp. Mean plasma C-peptide increment at 5 minutes (first-phase secretion) obtained during the 8-mmol/L hyperglycemic clamp, was higher on the gliclazide study day than on the control day (1.07 +/- 0.10 v 0.88 +/- 0.10 mmol/L, P less than .05), whereas no difference in plasma C-peptide response was observed during the 32-mmol/L hyperglycemic clamp. Mean plasma C-peptide increment obtained at the end 60 minutes; (second-phase secretion) of the 8-mmol/L hyperglycemic clamps was higher on the gliclazide study day than on the control day (1.36 +/- 0.13 v 1.09 +/- 0.09 mmol/L, P less than .02). No difference was observed in plasma C-peptide response at the end of the 32-mmol/L hyperglycemic glucose clamps.(ABSTRACT TRUNCATED AT 250 WORDS)     

Twenty-four-hour profile of plasma glucose and glucoregulatory hormones during normal living conditions in trained and untrained men

Compared with untrained (UT) subjects, in trained (T) subjects the increased insulin sensitivity and decreased glucose induced insulin secretion would tend to promote health by decreasing glucose levels and insulin secretion whereas the increased food intake would tend to increase these variables. To study the net effect of training, blood was sampled from seven T and eight UT young men [VO2max: 76 +/- 2 (T) vs. 48 +/- 1 (UT) mL.kg-1.min-1] for 24 h during ordinary living conditions. Athletes exercised 204 +/- 20 min and ate 50% more calories and 130% more carbohydrate than UT subjects (P less than 0.05). However, 24-h integrated plasma concentrations of glucose, C-peptide, glucagon, free fatty acids, and glycerol as well as glycosylated hemoglobin levels were identical in T and UT subjects. Mean insulin concentration was 41% lower in T than in UT but levels differed significantly (P less than 0.05) only late during the night. Urinary excretion of pancreatic peptides paralleled plasma concentrations. In conclusion, during training adaptations in pancreas- and insulin-sensitive tissues allow the necessary increase in food intake without harmful hyperglycemia and overloading of beta-cells, but sparing of insulin secretion and reductions in glucose levels are only relative to food intake. However, training may be wholesome by increasing hepatic insulin extraction and thereby decreasing arterial insulin levels. Training-induced beta-cell adaptation is not caused by diminished average glucose levels. Finally, renal handling of insulin, C-peptide, and glucagon is not influenced by training.     

Beta-cell hypersensitivity for glucose precedes loss of glucose-induced insulin secretion in 90% pancreatectomized rats

Summary Glucose-induced insulin secretion is impaired in the presence of chronic hyperglycaemia. Insulin secretion was studied in a diabetic rat model prior to the beta cells becoming non-responsive to glucose in order to map out the sequence of changes that accompany chronic hyperglycaemia. In vitro pancreas perfusions were carried out 1 and 2 weeks after a 90% pancreatectomy; controls underwent a sham pancreatectomy. One week post 90% pancreatectomy: (i) non-fasting plasma glucose values were 2–3 mmol/l above normal, (ii) the in vitro insulin response to 16.7 mmol/l glucose was 20 ± 4% of shams, a response that was appropriate for the surgical reduction in beta-cell mass, (iii) the beta-cell sensitivity for glucose was increased as reflected by left-shifted dose-response curves for glucose-induced insulin secretion (half maximal insulin output 5.7 mmol/l glucose vs 16.5 mmol/l glucose in shams) and glucose potentiation of arginine-induced insulin secretion (half maximal insulin output 3.5 mmol/l glucose vs 14.8 mmol/l glucose in shams). This heightened beta-cell sensitivity for glucose was not a result of the hyperglycaemia, because similarly reduced half-maximal insulin responses were found after a 60% pancreatectomy, a surgical procedure in which plasma glucose values remained normal. In summary, a rise in beta-cell sensitivity for glucose precedes the loss of glucose-induced insulin secretion in diabetic rats.     

Characterization of the influence of vildagliptin on model-assessed -cell function in patients with type 2 diabetes and mild hyperglycemia

OBJECTIVE: This study was conducted to characterize the effects of vildagliptin on beta-cell function in patients with type 2 diabetes and mild hyperglycemia. DESIGN: A 52-wk double-blind, randomized, parallel-group study comparing vildagliptin (50 mg every day) and placebo was conducted in 306 patients with mild hyperglycemia (glycosylated hemoglobin of 6.2-7.5%). Plasma glucose and C-peptide levels were measured during standard meal tests performed at baseline, wk 24 and 52, and after 4-wk washout. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution, and beta-cell function was quantified with a mathematical model that describes ISR as a function of absolute glucose levels (insulin secretory tone and glucose sensitivity), the glucose rate of change (rate sensitivity), and a potentiation factor. RESULTS: Vildagliptin significantly increased fasting insulin secretory tone [between-group difference in adjusted mean change from baseline to wk 52 (AM Delta) = +34.1 +/- 9.5 pmol.min(-1).m(-2), P < 0.001] glucose sensitivity (AM Delta = +20.7 +/- 5.2 pmol.min(-1).m(-2).mm(-1), P < 0.001), and rate sensitivity (AM Delta = +163.6 +/- 67.0 pmol.m(-2).mm(-1), P = 0.015), but total insulin secretion (ISR area under the curve at 0-2 h) and the potentiation factor excursion during meals were unchanged. These improvements in beta-cell function were accompanied by a decrease in the glucose area under the curve at 0-2 h (AM Delta = -1.7 +/- 0.5 mm/h, P = 0.002) and in glycosylated hemoglobin (AM Delta = -0.3 +/- 0.1%, P < 0.001). None of the effects of vildagliptin remained after 4-wk washout from study medication. CONCLUSIONS: Consistent with previous findings from shorter-term studies in patients with more severe hyperglycemia, in patients with mild hyperglycemia, improved beta-cell function is maintained throughout 52-wk treatment with vildagliptin and underlies a sustained improvement in glycemic control. However, no effects remain after washout.     

Prolonged mild hyperglycemia induces vagally mediated compensatory increase in C-Peptide secretion in humans

Experimentally induced prolonged hyperglycemia increases insulin release in humans, and in animals has been demonstrated to increase vagal efferent activity. The objective of the present experiment was to determine whether in humans, the compensatory increase in insulin release in response to short-term mild hyperglycemia is mediated by an induction of vagal efferent activity. Lean male subjects (n = 11; body mass index, 23.6 +/- 0.8 kg/m(2)) underwent a frequently sampled iv glucose tolerance test (FSIGT) to determine B cell function and insulin sensitivity. Subjects were then tested under four conditions over 4 months. Subjects were infused for 48 h with either glucose (15% dextrose at 200 mg/m(2).min) or saline (50 ml/h). Three hours after termination of the infusion, an FSIGT was administered in the presence of either saline or atropine (0.4 mg/m(2) bolus: 0.4 mg/m(2).h). Glucose (117 +/- 14 vs. 98 +/- 5 mg/dl) and insulin (49.5 +/- 10 vs. 23 +/- 5 muU/ml) levels were significantly elevated during the 48-h glucose infusion compared with those during saline treatment. Forty-eight-hour glucose infusions increased insulin and C-peptide levels during the FSIGT. When the FSIGT was conducted in the presence of atropine after glucose infusion, C-peptide levels were significantly attenuated during the period of endogenous insulin secretion (0-20 min; 31.8 +/- 13 vs. 39.2 +/- 11.9, atropine vs. no atropine) and exogenous insulin administration [20-40 min; 18.8 +/- 10.8 vs. 31.6 +/- 12.9., atropine vs. no atropine; F(3,9) = 4.99; P < 0.026]. A significant negative correlation was found between the repression of C-peptide by muscarinic blockade and the magnitude of the C-peptide response to the glucose infusion (r = 0.60; P < 0.045). Insulin AUC was not significantly altered by the presence of muscarinic blockade. In summary, we found that prolonged mild hyperglycemia results in a compensatory increase in C-peptide secretion, which is partially mediated by an induction in vagal efferent activity.     

Modulation of arginine-induced glucagon release by epinephrine and glucose levels in man

To assess how physiological epinephrine (EPI) elevations and EPI-induced hyperglycemia interact in the regulation of glucagon secretion, we measured acute glucagon responses (AGR) to arginine at controlled glucose levels during EPI infusions in man. With glucose levels matched at 166 +/- 5 mg/dl using glucose clamp techniques, the AGR (mean change at 2-5 min) to a 5-g iv arginine injection was greater in each subject during the infusion of 15 ng/kg . min EPI (low EPI) than during the control glucose infusion and was still greater during the infusion of 80 ng/kg . min EPI (high EPI; 69 +/- 15, 76 +/- 13, and 142 +/- 22 pg/ml, respectively; n = 8; P less than 0.003). With glucose levels matched at 256 +/- 5 mg/dl, a similar dose-related enhancement of AGR by EPI was seen (control, 53 +/- 12 pg/ml; low EPI, 63 +/- 5 pg/ml; high EPI, 130 +/- 20 pg/ml; P less than 0.008). During control infusions, raising the glucose level from 102 +/- 2 to 166 +/- 5 to 256 +/- 5 mg/dl suppressed AGR from 77 +/- 17 to 69 +/- 15 to 53 +/- 12 pg/ml (P less than 0.002). During low EPI, the same glycemic increments lowered GR from 108 +/- 19 to 76 +/- 13 to 63 +/- 5 pg/ml (P less than 0.02). This suppression of AGR by hyperglycemia was sufficient to obscure stimulation by EPI: at a glucose level of 102 +/- 2 mg/dl during control infusions, AGR was 77 +/- 17 pg/ml, compared to only 76 +/- 13 pg/ml during low EPI with the glucose level higher (166 +/- 5 mg/dl). Multiple linear regression analysis showed a highly significant dependence of AGR on both EPI and glucose levels, accounting for 80% of the within-subject variation in AGR (P less than 0.0001). These data show that 1) EPI is a dose-dependent amplifier of arginine-induced glucagon secretion in man, and 2) hyperglycemia suppresses arginine-induced glucagon secretion, potentially masking the stimulation caused by EPI. The findings suggest that the feedback effect of hyperglycemia on glucagon secretion may help regulate the level of hyperglycemia resulting from adrenergic stimulation.     

Effect of somatostatin and a glucagon-specific analog on glucose homeostasis during arginine infusion

The glucose response to arginine infusion in normal rats was studied during insulin and glucagon deficiency (somatostatin infusion, 1 mg/kg/hr) or selective glucagon deficiency ([D-Cys¹⁴]-somatostain infusion, 1 mg/kg/hr). In control studies, plasma glucose levels rose 14 mg/dl in response to arginine and returned to basal levels at the termination of the infusion. Insulin levels increased 136 ± 12 μU/ml and glucagon increased 76 ± 12 pg/ml during the infusion. Infusion of somatostatin resulted in supression of both arginine-induced insulin and arginine-induced glucagon release, and marked hyperglycemia ensued. The administration of [D-Cys¹⁴]-somatostatin during arginine infusion produced no associated hyperglycemia. It resulted in suppression of glucagon secretion and a modest rise in insulin release. These results demonstrate that the hyperglycemic effects of somatostatin in arginine-treated animals do not arise in animals treated with glucagon-specific somatostatin analogs.     

Studies of high and low insulin responders with the hyperglycemic clamp technique

We have investigated insulin responsiveness in relation to insulin sensitivity during sequential hyperglycemic clamping in low insulin responders (LIR), high insulin responders (HIR) and in women with a history of gestational diabetes (GD). Designation of HIR and LIR was done on the basis of mathematical modeling of the insulin response to a glucose infusion test. Insulin sensitivity was determined by a somatostatin-insulin-glucose infusion test (SIGIT) according to which LIR were subdivided into groups with higher or lesser sensitivity. Hyperglycemic clamping (60 min, 11 mmol/L of glucose) induced diphasic insulin and C-peptide responses in all groups. Insulin and C-peptide responses were significantly higher in HIR than in other groups. The ratio of first phase to total insulin response was higher in HIR v GD but did not differ between other groups. A second identical clamp was performed after a 60-minute rest period. Except in HIR, insulin levels attained were then moderately but significantly higher than during the first clamp. Conversely, the glucose utilization (mg/kg/min) to insulin (mU/L) = M/L ratio was markedly increased in LIR with high insulin sensitivity but not in other groups. We conclude that (1) large and consistent differences exist in glucose-induced insulin secretion from the pancreas between nondiabetic subjects; (2) time dynamics of insulin secretion and priming effects of glucose are similar in LIR with lesser and higher sensitivity; and (3) in the latter group a glucose stress affects insulin sensitivity more markedly than insulin responsiveness.     

beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis

The nature of the progressive beta-cell failure occurring as normal glucose tolerant (NGT) individuals progress to type 2 diabetes (T2DM) is incompletely understood. We measured insulin sensitivity (by a euglycemic insulin clamp) and insulin secretion rate (by deconvolution of plasma C-peptide levels during an oral glucose tolerance test) in 188 subjects [19 lean NGT (body mass index [BMI] 相似文献   

Contribution of insulin secretion and clearance to glucose-induced insulin concentration in african-american and caucasian children

Relative to Caucasians (C), African-American (AA) children and adults have lower indices of insulin sensitivity (S(i)) and a higher acute insulin response to glucose (AIR(g)). Among AA children, AIR(g) is greater than that which would be predicted based on lower S(i). The objectives of the present study were 1) to determine whether insulin secretory parameters differ in AA vs. C children and adolescents using C-peptide modeling, 2) to determine whether hepatic insulin extraction differs with ethnicity/race using the C-peptide to insulin molar ratio, and 3) to determine whether the relatively greater AIR(g) among African-Americans is due to greater insulin secretion or lesser clearance. Subjects (n = 76) were AA and C children (mean age, approximately 11 yr). A 3-h tolbutamide-modified iv glucose tolerance test and minimal modeling were used to determine S(i) and AIR(g). First phase C-peptide/insulin secretion and basal, first, and second phase beta-cell sensitivity to glucose were determined using C-peptide modeling with standard kinetic parameters developed in adults. The incremental C-peptide to insulin molar ratio over the 3-h test period, an index of hepatic insulin extraction, was calculated with the trapezoidal method. S(i) was lower and AIR(g) was higher in AA vs. C children. First phase C-peptide/insulin secretion and first phase beta-cell sensitivity to glucose were approximately 2-fold greater in AA vs. C children (P < 0.001); there were no between-group differences in basal or second phase beta-cell sensitivity to glucose. Hepatic insulin extraction was lower in AA vs. C (3.77 +/- 1.78% vs. 5.99 +/- 2.18%; P < 0.001). Multiple linear regression modeling indicated that first phase C-peptide/insulin secretion and hepatic insulin extraction contributed independently to AIR(g); however, it was only first phase C-peptide/insulin secretion that explained the significant independent contribution of ethnicity/race to AIR(g) after adjusting for S(i). The results of this study suggest that greater AIR(g) among AA is due to both greater insulin secretion and lesser hepatic insulin extraction, and that AIR(g) above that predicted based on lower S(i) is due to greater insulin secretion. The insulin secretion data await verification that the kinetic parameters used apply to children and AA.     

Glyburide enhances the responsiveness of the beta-cell to glucose but does not correct the abnormal patterns of insulin secretion in noninsulin-dependent diabetes mellitus

Eleven patients with noninsulin-dependent diabetes mellitus were studied before and after 6-10 weeks of glyburide therapy. Patients were studied during a 24-h period on a mixed diet comprising 30 Cal/kg divided into three meals. The following day a hyperglycemic clamp study was performed, with glucose levels clamped at 300 mg/dL (16.7 mmol/L) for a 3-h period. Insulin secretion rates were calculated by deconvolution of peripheral C-peptide concentrations using individual C-peptide clearance kinetics derived after bolus injection of biosynthetic human C-peptide. After 6-10 weeks on glyburide, the identical studies were repeated. In response to glyburide, the fasting plasma glucose level decreased from 12.3 +/- 1.2 to 6.8 +/- 0.9 mmol/L. Although the mean glucose over the 24 h of the meal study decreased from 12.7 +/- 1.4 to 10.8 +/- 1.2 mmol/L, postprandial hyperglycemia persisted on therapy, and after breakfast, glucose levels exceeded 10 mmol/L and did not return to fasting levels for the remainder of the day. Fasting serum insulin, plasma C-peptide, and the insulin secretion rate were not different before (152 +/- 48 pmol/L, 0.82 +/- 0.16 pmol/mL, and 196 +/- 34 pmol/min, respectively) and after (186 +/- 28 pmol/L, 0.91 +/- 0.11 pmol/mL, and 216 +/- 23 pmol/min, respectively) glyburide treatment despite lowering of the glucose level. However, average insulin and C-peptide concentrations over the 24-h period increased from 366 +/- 97 pmol/L and 1.35 +/- 0.19 pmol/mL to 434 +/- 76 pmol/L and 1.65 +/- 0.15 pmol/mL, respectively. The total amount of insulin secreted over the 24-h period rose from 447 +/- 58 nmol before therapy to 561 +/- 55 nmol while receiving glyburide. Insulin secretion was demonstrated to be pulsatile in all subjects, with periodicity ranging from 2-2.5 h. The number of insulin secretory pulses was not altered by glyburide, whereas pulse amplitude was enhanced after lunch and dinner, suggesting that the increased insulin secretion is characterized by increased amplitude of the individual pulses. In response to a hyperglycemic clamp at 300 mg/dL (16.7 mmol/L), insulin secretion rose more than 2-fold, from 47 +/- 9 nmol over the 3-h period before treatment to 103 +/- 21 nmol after glyburide therapy. We conclude that the predominant mechanism of action of glyburide in patients receiving therapy for 6-10 weeks is to increase the responsiveness of the beta-cell to glucose.(ABSTRACT TRUNCATED AT 400 WORDS)     

Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes

Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 +/- 1.2 vs 11.4 +/- 1.2 mmol/l, P less than 0.01) without enhancing mean day-time plasma insulin (43 +/- 4 vs 50 +/- 7 mU/l, NS) or C-peptide levels (1.26 +/- 0.12 vs 1.38 +/- 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 +/- 0.16 vs 1.44 +/- 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 +/- 0.11 vs 1.38 +/- 0.11 mmol/l, P less than 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 +/- 38 vs 313 +/- 33 mg.m-2.min-1, P less than 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 +/- 5.8 vs 50.6 +/- 2.8 ml.m-2.min-1, P less than 0.05), whereas basal hepatic glucose production was unchanged (81 +/- 6 vs 77 +/- 4 mg.m-2.min-1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Suppression of basal, but not of glucose-stimulated insulin secretion by human insulin in healthy and obese hyperinsulinemic subjects

To evaluate the suppressive effect of biosynthetic human insulin (BHI; 2.5 U/m2 . h) on basal and glucose-stimulated insulin secretion in healthy and obese hyperinsulinemic subjects, the plasma C-peptide response was measured during maintenance of euglycemia and hyperglycemia by means of the glucose clamp technique. In five healthy subjects in whom arterial insulin concentration was increased to 94 +/- 8 microU/mL, but euglycemia was maintained at the fasting level. C-peptide concentration fell from 1.3 +/- 1.0 ng/mL by 21 +/- 8% (P less than 0.05). When hyperglycemia of 7 mmol/L above basal was induced by a variable glucose infusion, the C-peptide response was similar in the control (5.0 +/- 0.6 ng/mL) and BHI experiments (4.7 +/- 0.6 ng/mL) and was paralleled by an identical increase in plasma insulin above the prevailing insulin concentration. In seven obese patients plasma C-peptide fell from 3.5 +/- 0.4 to 2.8 +/- 0.5 ng/mL (P less than 0.05) when BHI was infused at the same rate of euglycemia maintained as in the lean subjects. As in healthy subjects, however, the plasma C-peptide response to the hyperglycemic stimulus (8.7 +/- 0.9 ng/mL) was not altered by BHI (7.9 +/- 0.8 ng/mL). Glucose utilization as determined by the glucose infusion rate necessary to maintain the desired glucose level was reduced by half in the obese patients compared with that of normal subjects. From these data we conclude that in healthy as well as obese hyperinsulinemic subjects, insulin at concentrations capable of suppressing its basal secretion fails to suppress its glucose-stimulated secretion.     

Effects of galanin and calcitonin gene-related peptide on insulin and glucagon secretion in man.

To study the influence of the pancreatic neuropeptides, galanin and calcitonin gene-related peptide, on insulin and glucagon secretion in man, synthetic porcine galanin (80 pmol.kg-1.min-1; N = 6) or synthetic human calcitonin gen-related peptide (10 pmol.kg-1.min-1; N = 5) was infused intravenously in human volunteers. Following 5 min of infusion, arginine (5 g bolus + 10 mg.kg-1.min-1) was given. Galanin did not affect basal or arginine-stimulated insulin secretion judged from determinations of plasma insulin and C-peptide. Similarly, galanin did not affect arginine-stimulated glucagon secretion. Calcitonin gene-related peptide did not affect basal or arginine-stimulated insulin or glucagon secretion. However, calcitonin gene-related peptide slightly potentiated the arginine-induced hyperglycemia (p less than 0.01). Thus, in man, galanin has no influence on insulin or glucagon secretion when infused at 80 pmol.kg-1.min-1, whereas CGRP at 10 pmol.kg-1.min-1 induces slight hyperglycemia.