Effects of treadmill exercise to exhaustion on the insulin response to hyperglycemia in untrained men

The effects of a single bout of exercise to exhaustion on pancreatic insulin secretion were determined in seven untrained men by use of a 3-h hyperglycemic clamp with plasma glucose maintained at 180 mg/100 ml. Clamps were performed either 12 h after an intermittent treadmill run at approximately 77% maximum O2 consumption or without prior exercise. Arterialized blood samples for glucose, insulin, and C-peptide determination were obtained from a heated hand vein. The peak insulin response during the early phase (0-10 min) of the postexercise clamp was higher (81 +/- 8 vs. 59 +/- 9 microU/ml; P less than 0.05) than in the nonexercise clamp. Incremental areas under the insulin (376 +/- 33 vs. 245 +/- 51 microU.ml-1.min) and C-peptide (17 +/- 2 vs. 12 +/- 1 ng.ml-1.min) curves were also greater (P less than 0.05) during the early phase of the postexercise clamp. No differences were observed in either insulin concentrations or whole body glucose disposal during the late phase (15-180 min). Area under the C-peptide curve was greater during the late phase of the postexercise clamp (650 +/- 53 vs. 536 +/- 76 ng.ml-1.min, P less than 0.05). The exercise bout induced muscle soreness and caused an elevation in plasma creatine kinase activity (142 +/- 32 vs. 305 +/- 31 IU/l; P less than 0.05) before the postexercise clamp. We conclude that in untrained men a bout of running to exhaustion increased pancreatic beta-cell insulin secretion during the early phase of the hyperglycemic clamp. Increased insulin secretion during the late phase of the clamp appeared to be compensated by increased insulin clearance.     

Development of hyperinsulinemia and insulin resistance during the early stage of weight gain

Obesity is associated with insulin resistance and hyperinsulinemia, which is considered to be a core component in the pathophysiology of obesity-related comorbidities. As yet it is unknown whether insulin resistance and hyperinsulinemia already develop during weight gain within the normal range. In 10 healthy male subjects the effect of intentional weight gain by 2 BMI points was examined on insulin. C-peptide and glucose levels following a meal, 75 g of glucose, and a two-step hyperglycemic clamp increased plasma glucose by 1.38 and 2.75 mmol/l, respectively. Baseline insulin, C-peptide, and glucose concentrations were significantly higher after weight gain from 21.8 to 23.8 kg/m(2) BMI within 4(1/2) mo. Calculations of insulin secretion and clearance indicate that reduced insulin clearance contributes more to post-weight gain basal hyperinsulinemia than insulin secretion. Following oral or intravenous stimulation insulin concentrations were significantly higher post-weight gain during all three test conditions, whereas C-peptide and glucose levels did not differ. Calculations of insulin secretion and clearance demonstrated that higher stimulated insulin concentrations are entirely due to clearance but not secretion. Despite significantly higher insulin levels, the rate of intravenous glucose required to maintain the defined elevation of glucose levels was either identical (1.38 mmol/l) or even significantly lower (2.75 mmol/l) following weight gain. The present study demonstrates for the first time that insulin resistance already develops during weight gain within the normal range of body weight. The associated basal and stimulated hyperinsulinemia is the result of differentiated changes of insulin secretion and clearance, respectively.     

NEFA-glucose comodulation model of beta-cell insulin secretion in 24-h multiple-meal test

There is experimental evidence that a source of fatty acids (FAs) that is either exogenous or endogenous is necessary to support normal insulin secretion. Therefore, FAs comodulate the glucose-induced pancreatic insulin secretion. To assess the role of FAs, 16 morbidly obese nondiabetic patients and 6 healthy volunteers were studied. The controls and the obese subjects, before and after diet-induced weight loss, spent 24 h in a calorimetric chamber, where they consumed standardized meals. Hourly blood samples were drawn from a central venous catheter for the measurement of glucose, C-peptide, and nonesterified fatty acid (NEFA) concentrations. Insulin sensitivity was measured (as the M value) by euglycemic hyperinsulinemic clamp. In the present study, we propose a mathematical model in which insulin secretion rate (ISR) is expressed as a function of both plasma glucose and NEFA concentrations. Model parameters, obtained by fitting the individual experimental data of plasma C-peptide concentration, gave an estimated ISR comparable with that obtained by the deconvolution method. To evaluate the performance of the model in an experimental condition in which incretin effect was minimized, previous data on insulin secretion following a butter load and subsequent hyperglycemic clamp were reanalyzed. This model of nutrient-stimulated insulin secretion is the first attempt to represent in a simple way the interaction between glucose and NEFA in the regulation of insulin secretion in the beta-cell and explains, at least in part, the "potentiation factor" used in previous models to account for other control factors different from glucose after either an intravenous infusion of glucose or a mixed meal.     

Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

Elevated plasma FFA cause beta-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% (P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or DeltaC-peptide/Deltaglucose AUC (+177%, P = 0.02), an index of improved beta-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 +/- 5% (P < 0.04). First- (+19 +/- 6%, P = 0.1) and second-phase (+31 +/- 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 +/- 7 (P < 0.05) and 41 +/- 8% (P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR (r2 = 0.31, P < 0.02) and acute (2-4 min) glucose-induced insulin release after acipimox (r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.     

Gliclazide mainly affects insulin secretion in second phase of type 2 diabetes mellitus.

We studied the effect of the acute administration of gliclazide at 160 mg on insulin release during hyperglycaemic clamps in 12 type 2 diabetes patients, age 50 +/- 9.0 years, diabetes duration 5.5 +/- 4.8 years, fasting blood glucose 9.6 +/- 2.1 mmol/L (means +/- SD). After a 210 min of hyperinsulinaemic euglycaemic clamp (blood glucose 4.6 +/- 0.14mmol/L), gliclazide or placebo (randomised, double-blind, cross-over) was administered; 60 minutes later, a hyperglycaemic clamp (4hr) at 8mmol/L was started. Plasma C-peptide levels increased significantly after the administration of gliclazide (increment 0.17 +/- 0.15 vs. 0.04 +/- 0.07 nmol/L, p = 0.024) before the clamp. After the start of the hyperglycaemic clamp, the areas under the curve (AUC) for insulin and C-peptide did not differ from 0-10 min (first phase) with gliclazide. However, second-phase insulin release (30-240 min) was markedly enhanced by gliclazide. AUC plasma insulin (30 to 240 min) was statistically significantly higher after gliclazide (12.3 +/- 13.9 vs. -0.56 +/- 9.4 nmol/L x 210 min, p = 0.022); similarly, AUC plasma C-peptide (30 to 240 min) was also higher: 128 +/- 62 vs. 63 +/- 50 nmol/L x 210 min, p = 0.002). In conclusion, in long-standing type 2 diabetes the acute administration of gliclazide significantly enhances second phase insulin release at a moderately elevated blood glucose level. In contrast to previous findings in mildly diabetic subjects, these 12 type 2 diabetes patients who had an inconsiderable first phase insulin release on the placebo day, only showed an insignificant increase in first phase with gliclazide.     

Responses of plasma insulin C-peptide and proinsulin-like components to glucose and glucagon in the pig.

This study was undertaken to evaluate the relative contribution of insulin, proinsulin-like components (PLC) and C-peptide toward plasma levels of immuno reactive insulin (IRI) and C-peptide immunoreactivity (CPR) in the pig and to elucidate the mode of secretion of PLC in the early phase of insulin release. Following the intravenous glucose loads, the concomitant secretion of CPR with that of IRI occured rapidly and the maximum plasma level of IRI was observed at an earlier time than that of CPR. Following the intravenous glucagon injection, the maximum plasma levels of IRI and CPR were observed at the same time in the early phase. After the gel filtration of acid alcohol extracts of plasma in a fasted state, a very small amount of PLC and a small amount of C-peptide as well as a small amount of insulin were detected. The results obtained from the gel filtration of extracts revealed that the increased amounts in IRI and CPR after the injection of glucose or glucagon consisted mostly and respectively of insulin and C-peptide in the pig, because the concentration of PLC increased only slightly in the early phase. In fact, plasma levels of CPR and IRI were essentially and respectively paralleled to those of insulin and C-peptide which were assayed after the gel filtration of extracts. In addition, the slight elevation of PLC in the early phase after these stimulations indicated that PLC was elicited into blood circulation at the same time of the secretion of insulin and C-peptide.     

Metabolic Adaptations to Dexamethasone‐Induced Insulin Resistance in Healthy Volunteers

Objective : Insulin resistance is observed in individuals with normal glucose tolerance. This indicates that increased insulin secretion can compensate for insulin resistance and that additional defects are involved in impaired glucose tolerance or type 2 diabetes. The objective of this study was to evaluate a procedure aimed at assessing the compensatory mechanisms to insulin resistance. Research Methods and Procedures : Eight healthy nonobese female patients were studied on two occasions, before and after administration of 2 mg/d dexamethasone for 2 days during a two‐step hyperglycemic clamp. Insulin secretion was assessed from plasma insulin concentrations. Insulin sensitivity was assessed from the ratio of whole‐body glucose use (6, 6 ²H₂ glucose) to plasma insulin concentrations. This procedure is known to induce a reversible impairment of glucose tolerance and insulin resistance. Results : In all subjects, dexamethasone induced a decrease in insulin sensitivity and a proportionate increase in first‐phase insulin secretion and in insulin concentrations at both steps of glycemia. The resulting hyperinsulinemia allowed the restoration of normal whole‐body glucose uptake and the suppression of plasma free fatty acids and triglycerides. In contrast, the suppression of endogenous glucose production was impaired after dexamethasone (p < 0.01). Discussion : Increased insulin secretion fully compensates dexamethasone‐induced insulin resistance in skeletal muscle and adipose tissue but not in the liver. This suggests that failure to overcome hepatic insulin resistance can impair glucose tolerance. The compensatory insulin secretion in response to insulin resistance can be assessed by means of a hyperglycemic clamp after a dexamethasone challenge.     

Influence of lysine acetyl-salicylate on glucose and arginine stimulated insulin release in man

In order to determine the influence of acute inhibition of prostaglandin synthesis on insulin release in man, the influence of lysine acetyl-salicylate (0.9 g) on glucose- and arginine-stimulated insulin release was studied in eight volunteers. No significant differences were found in plasma C-peptide levels between the salicylate and the control study days during administration of arginine (0.5 g/kg; 30 min) nor during a hyperglycemic clamp (glucose level 17 mMol/L; 60 minutes). These studies indicate that acute administration of salicylate does not change insulin release in man.     

For debate: Starling's curve of the pancreas--overuse of a concept?

It is commonly accepted that insulin secretion follows the pattern of an inverted U, also termed 'Starling's curve of the pancreas' during the natural history of hyperglycemia in glucose intolerance and type 2 diabetes. This concept is based on the cross-sectional observation that insulin concentrations initially increase when insulin sensitivity declines (as a consequence of obesity, for example) and decrease when glucose tolerance deteriorates (impaired glucose tolerance or overt type 2 diabetes). The initial increase in insulin concentrations has been viewed as 'hypersecretion' of insulin, thought to indicate that beta cell dysfunction is not etiological but secondary in nature. However, this view is oblivious to the now well-established fact that assessment of insulin secretion must account for individual insulin sensitivity. Here, we revisit the concept of Starling's curve of the pancreas based on first-phase C-peptide concentrations (hyperglycemic clamp) from subjects with normal glucose tolerance (n=66), impaired glucose tolerance (n=19) and mild type 2 diabetes (n=9). In absolute terms, first-phase C-peptide concentrations plotted against increasing fasting glucose concentrations indeed followed an inverted U. However, adjusted for direct and indirect measures of insulin sensitivity (insulin sensitivity index from the hyperglycemic clamp, body mass index, age and sex), first-phase C-peptide concentrations of the same individuals tended to decrease steadily. In conclusion, while the Starling curve exists for insulin concentrations, and perhaps also for insulin secretion, it does not hold for beta-cell function if that term were to imply appropriateness of insulin secretion (based on a formal test of glucose-stimulated insulin secretion) for the degree of insulin resistance, as it should.     

Insulin secretion and glucose uptake in hypomagnesemic sheep fed a low magnesium, high potassium diet

Hyperglycemic and euglycemic clamp experiments were conducted to evaluate insulin secretion and glucose uptake in the hypomagnesemic sheep fed a low magnesium (Mg), high potassium (K) diet. Five mature sheep were fed a semipurified diet containing 0.24% Mg and 0.56% K (control diet) and five were fed 0.04% Mg and 3.78% K (low Mg/high K diet) for at least 2 weeks. In the hyperglycemic clamp experiment, plasma glucose concentrations were raised and maintained at a hyperglycemic steady-state (approximately 130 mg/100 ml) by variable rates of glucose infusion during the experimental period (120 minutes). The insulin response in the sheep fed the low Mg/high K diet (31.0 microU/ml) were significantly (P < 0.01) lower than those (111.7 microU/ml) of the sheep fed the control diet. In the euglycemic clamp experiment, insulin was infused at rates of 5, 10, 15, or 20 mU/kg/min, each followed by variable rates of glucose infusion to maintain a euglycemic steady-state (basal fasting levels). Hypomagnesemic sheep fed the low Mg/high K diet had significantly (P < 0.01) lower mean glucose disposal (3.72 mg/kg/min) across the insulin infusion rates compared with those of the sheep fed the control diet (5.37 mg/kg/min). These results suggest that glucose-induced insulin secretion and insulin-induced glucose uptake would be depressed in hypomagnesemic sheep and are caused by feeding the low Mg/high K diet.     

Positive correlation of galanin with glucose in healthy volunteers during an oral glucose tolerance test.

Galanin has been found in increased amounts in subjects with type 2 diabetes. The purpose of the present study was to determine the levels of galanin in healthy volunteers during an oral glucose tolerance test (OGTT). We enrolled 11 healthy volunteers, 4 males aged 48+/-3.56 years with BMI 27+/-0.5 kg/m (2) and 7 females aged 41.3+/-3.05 years with BMI 27.6+/-0.9 kg/m (2). All were in good health without cardiac, hepatic, renal or other chronic disease. None were taking any medication affecting glucose tolerance (beta-blockers, thiazide diuretics, and corticoids) and none had a first degree relative with type 2 diabetes. Glucose tolerance was determined by using the International Expert Committee criteria. Blood samples were collected at 0, 30, 60, 90, 120 and 180 minutes for the measurement of plasma glucose, insulin, C-peptide and human galanin (hGal). During the OGTT, hGal exhibited a significant increase from time 0 to 90 minutes (p < 0.001) and returned to the basal values at 180 minutes, while a positive correlation of blood glucose with hGal was observed during the time scale of OGTT. A significant increase was detected both in insulin and C-peptide from the early beginning of the test at 30 minutes, which remained steady until 90 minutes, and returned gradually to the basal values at 180 minutes. No relationship was found either between hGal and serum insulin, or between hGal and serum C-peptide among the healthy subjects, during the OGTT.     

Acute lowering of circulating fatty acids improves insulin secretion in a subset of type 2 diabetes subjects

We tested the effects of acute perturbations of elevated fatty acids (FA) on insulin secretion in type 2 diabetes. Twenty-one type 2 diabetes subjects with hypertriglyceridemia (triacylglycerol >2.2 mmol/l) and 10 age-matched nondiabetic subjects participated. Glucose-stimulated insulin secretion was monitored during hyperglycemic clamps for 120 min. An infusion of Intralipid and heparin was added during minutes 60-120. In one of two tests, the subjects ingested 250 mg of Acipimox 60 min before the hyperglycemic clamp. A third test (also with Acipimox) was performed in 17 of the diabetic subjects after 3 days of a low-fat diet. Acipimox lowered FA levels and enhanced insulin sensitivity in nondiabetic and diabetic subjects alike. Acipimox administration failed to affect insulin secretion rates in nondiabetic subjects and in the group of diabetic subjects as a whole. However, in the diabetic subjects, Acipimox increased integrated insulin secretion rates during minutes 60-120 in the 50% having the lowest levels of hemoglobin A(1c) (379 +/- 34 vs. 326 +/- 30 pmol x kg(-1) x min(-1) without Acipimox, P < 0.05). A 3-day dietary intervention diminished energy from fat from 39 to 23% without affecting FA levels and without improving the insulin response during clamps. Elevated FA levels may tonically inhibit stimulated insulin secretion in a subset of type 2 diabetic subjects.     

Pharmacological doses of oxytocin affect plasma hormone levels modulating glucose homeostasis in normal man

Pharmacological doses of oxytocin administered in basal conditions evoked a rapid surge in plasma glucose and glucagon levels followed by a later increase in plasma insulin and adrenaline levels. The effects of oxytocin on plasma glucagon and adrenaline levels were potentiated by hypoglycemia. When the endogenous pancreas secretion was suppressed by cyclic somatostatin (150 micrograms/h) and exogenous glucagon (3.5 micrograms/h) and insulin (0.2 mU/kg.min) were both replaced, oxytocin (0.2 U/min) evoked a transient but significant increase in plasma glucose levels suppressing the glucose infusion rate (GIR) in the first 60 min. On the contrary at higher insulin infusion rate (0.6 mU/kg.min) plasma glucose levels and GIR remained unaffected throughout the study. Oxytocin seems also to potentiate glucose-induced insulin secretion as evidenced by hyperglycemic glucose clamp. In conclusion, pharmacological doses of oxytocin seem to exert a prevalent hyperglycemic effect by a combined action at the liver site (as glycogenolytic agent) and at the endocrine pancreas (as a stimulatory agent of A cell secretion).     

A novel use of the hyperinsulinemic-euglycemic clamp technique to estimate insulin sensitivity of systemic lipolysis.

The aim of the present study was to assess whether a standard hyperinsulinemic-euglycemic clamp can provide an estimate for the antilipolytic insulin sensitivity. For this purpose, we infused 9 non-obese, healthy volunteers with [2H5]glycerol and used the glycerol rate of appearance (Ra) in plasma as an index for systemic lipolysis during a standard (1 mU/kg x min, 120 min) and a 3-step (0.1, 0.25, 1.0 mU/kg x min) hyperinsulinemic-euglycemic clamp. The insulin concentration, which half-maximally suppressed lipolysis (EC50) in the three-step clamp, was considered to be the gold standard for the antilipolytic insulin sensitivity. Glycerol Ra decreased from 1.53+/-0.11 micromol/kg x min to 0.60+/-0.09 micromol/kg x min (p <0.001) during the standard clamp. The decrease in Ra at most time points during the standard clamp significantly correlated with the EC50. The highest correlation for the % decrease of glycerol Ra from baseline was found at 60 min (r = 0.96, p < 0.001) making this parameter a useful index for the antilipoytic insulin sensitivity. Neither plasma glycerol nor plasma free fatty acid (FFA) concentrations were significantly correlated with the EC50. In conclusion, the standard hyperinsulinemic-euglycemic clamp in combination with isotopic determination of glycerol Ra provides a reasonable estimate for the antilipolytic insulin sensitivity. In healthy subjects, the parameter best suited to estimate the insulin EC50 (by linear correlation) was the percentage decrease of glycerol Ra at 60 min.     

Insulin secretion and sensitivity in hyperthyroidism

To examine the effect of hyperthyroidism on carbohydrate metabolism, we studied glucose-stimulated insulin secretion and glucose utilization in 8 subjects with Graves' disease before and after treatment for hyperthyroidism and 8 age-, sex- and weight-matched normal subjects. Subjects with Graves' disease had significant elevated serum levels of thyroxine (24.81 +/- 2.44 micrograms/dl, mean +/- SEM) and triiodothyronine (459 +/- 5.5 ng/dl, mean +/- SEM). Simultaneous measurement of plasma glucose, serum insulin and C-peptide levels during fasting and every 30 minutes up to 180 minutes after 75 g oral glucose loading was determined. In addition, plasma glucose, serum insulin and serum C-peptide were measured during euglycemic glucose clamp with insulin infusion of 40 mU/m2 min-1. Mean fasting plasma glucose (P less than 0.05, serum insulin (P less than 0.005) and serum C-peptide (P less than 0.005) levels were significantly higher in the hyperthyroid patients. After glucose loading, the plasma glucose (P less than 0.05), serum insulin (P less than 0.05) and C-peptide (P less than 0.05) responses were significantly higher in hyperthyroid patients at all times up to 180 minutes. During euglycemic clamp studies, the steady-state serum insulin levels were identical in the two groups. The glucose disposal rate was lower in hyperthyroid patients before treatment (P less than 0.01) than in normal subjects. After thyroid function had been normalized for 2 to 4 weeks, the glucose disposal rate increased significantly (P less than 0.05), but was still significantly lower than those of normal subjects (P less than 0.05). Our data show that patients with Graves' hyperthyroidism manifest glucose intolerance, hyperinsulinemia and insulin resistance.     

Insulin secretion in the conscious mouse is biphasic and pulsatile

Islets in most species respond to increased glucose with biphasic insulin secretion, marked by a sharp first-phase peak and a slowly rising second phase. Mouse islets in vitro, however, lack a robust second phase. To date, this observation has not been extended in vivo. We thus compared insulin secretion from conscious mice with isolated mouse islets in vitro. The arterial plasma insulin response to a hyperglycemic clamp was measured in conscious mice 1 wk after surgical implantation of carotid artery and jugular vein catheters. Mice were transfused using clamps with blood from a donor mouse to maintain blood volume, allowing frequent arterial sampling. When plasma glucose in vivo was raised from approximately 5 to approximately 13 mM, insulin rose to a first-phase peak of 403+/-73% above basal secretion (n=5), followed by a rising second phase of mean 289+/- 41%. In contrast, perifused mouse islets ( approximately 75 islets/trial) responded with a similar first phase of 508+/- 94% (n=4) but a smaller and virtually flat second phase of 169+/- 9% (n=4, P<0.05). Furthermore, the slope of the second-phase response differed significantly from zero in mice (2.63+/-0.39%/min, P<0.01), in contrast to perifused islets (0.18+/- 0.14%/min, P>0.30). Mice also displayed pulsatile patterns in insulin concentration (period: 4.2+/- 0.4 min, n=8). Conscious mice thus responded to increased glucose with biphasic and pulsatile insulin secretion, as in other species. The robust second phase observed in vivo suggests that the processes needed to generate second-phase insulin secretion may be abrogated by islet isolation.     

Comparison of the effect of semisynthetic human insulin and porcine insulin on glucose kinetics, plasma free fatty acid and amino acid levels in man

The effect of semisynthetic human insulin on hepatic glucose output, peripheral glucose clearance, plasma levels of C-Peptide, free fatty acids and amino acids was compared with purified pork insulin using the glucose clamp technique. 8 normal overnight-fasted subjects received intravenous infusions of either human or porcine insulin at 20 mU/m2.min(-1) during 120 min achieving plasma insulin levels of approximately equal to 50 mU/l. Plasma glucose levels were maintained at euglycaemia by variable rates of glucose infusion. Hepatic glucose production measured by continuous infusion of 3-(3) H-glucose was similarly suppressed by both insulins to rates near zero. The metabolic clearance rate of glucose increased during infusion of human insulin by 120%, C-peptide levels decreased by 41% and plasma FFA concentrations fell by 74%. The respective changes during infusion of pork insulin were similar, 118%, 48% and 72%. Both insulins decreased the plasma levels of branched-chain amino acids, tyrosine, phenylalanine, methionine, serine and histidine similarly. Thus, the results demonstrate that semisynthetic human and porcine insulin are aequipotent with respect to suppression of hepatic glucose output, stimulation of glucose clearance, inhibition of insulin secretion, lipolysis and proteolysis.     

Normal inhibition by somatostatin of glucose-stimulated B cell secretion in the obese subjects

Aim of the present study was to evaluate whether the inhibitory effect of somatostatin on pancreatic B-cell secretion is normal in nondiabetic obese subjects. For this purpose plasma C-peptide concentrations were measured in 10 nondiabetic obese subjects and 10 nonobese healthy controls during a 4-h hyperglycemic (11 mmol/l) glucose clamp. Somatostatin was infused (2.5 nmol/min) during the third hour of the study period in order to inhibit glucose-stimulated B-cell secretion. Fasting C-peptide averaged 0.46 +/- 0.04 nmol/l (mean +/- SEM) in nonobese subjects, and 0.85 +/- 0.08 nmol/l in obese patients (P less than 0.001). In the period 0-120 min the area under the plasma C-peptide curve was significantly higher in obese than in nonobese subjects (292 +/- 23 vs. 230 +/- 17 nmol/l x 120 min, P less than 0.05), however, in the last 20 min of the glucose infusion period without somatostatin (100-120 min) plasma C-peptide was not significantly different in the two groups (2.94 +/- 0.32 nmol/l in nonobese subjects and 3.21 +/- 0.19 nmol/l in obese patients, p = NS). During somatostatin infusion while maintaining hyperglycemia, plasma C-peptide decreased in both groups, and in the period 160-180 min it averaged 0.89 +/- 0.12 nmol/l in control subjects and 0.93 +/- 0.08 nmol/l in obese patients (P = NS), with a percent reduction similar in the two groups (70 +/- 2% in controls and 71 +/- 2% in obese patients). After discontinuing somatostatin infusion, plasma C-peptide increased to concentrations which were higher in obese than in nonobese subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Immunoreactive dog C-peptide level in the pancreatic vein

C-peptide immunoreactivity (CPR) levels were measured in dog superior pancreaticoduodenal vein using synthetic dog C-peptide and its antiserum. The basal CPR level was approximately twice as high as the basal immunoreactive insulin (IRI) level on a molar basis. Glucose (10 mg/kg/min) or arginine (250 mg/kg/min) infusion for 5 min into the superior pancreaticoduodenal artery caused a prompt, parallel increase in IRI and CPR. IRI and CPR were closely equimolar at peak secretions. One bolus administration of synthetic neurotensin (10 microgram/kg) into the same artery produced a mild hyperglycemic response and biphasic IRI and CPR responses at 30 min in the vein. The IRI and CPR increases were closely equimolar during the first phase of secretion, but during the second peak a larger increase was found in CPR than IRI. Upon infusion of synthetic substance P (50 ng/kg/min) for 30 min, IRI and CPR concentrations showed a parallel and closely equimolar fall. These results indicate that insulin and C-peptide were released from beta cells in equimolar concentrations.