Effects of nonglucose nutrients on insulin secretion and action in people with pre-diabetes

To determine whether nonglucose nutrient-induced insulin secretion is impaired in pre-diabetes, subjects with impaired or normal fasting glucose were studied after ingesting either a mixed meal containing 75 g glucose or 75 g glucose alone. Despite comparable glucose areas above basal, glucose-induced insulin secretion was higher (P < 0.05) and insulin action lower (P < 0.05) during the meal than the oral glucose tolerance test (OGTT) in all subgroups regardless of whether they had abnormal or normal glucose tolerance (NGT). However, the nutrient-induced delta (meal minus OGTT) in insulin secretion and glucagon concentrations did not differ among groups. Furthermore, the decrease in insulin action after meal ingestion was compensated in all groups by an appropriate increase in insulin secretion resulting in disposition indexes during meals that were equal to or greater than those present during the OGTT. In contrast, disposition indexes were reduced (P < 0.01) during the OGTT in the impaired glucose tolerance groups, indicating that reduced glucose induced insulin secretion. We conclude that, whereas glucose-induced insulin secretion is impaired in people with abnormal glucose tolerance, nonglucose nutrient-induced secretion is intact, suggesting that a glucose-specific defect in the insulin secretory pathway is an early event in the evolution of type 2 diabetes.     

Ultradian oscillations of insulin secretion in humans

Ultradian rhythmicity appears to be characteristic of several endocrine systems. As described for other hormones, insulin release is a multioscillatory process with rapid pulses of about 10 min and slower ultradian oscillations (50--120 min). The mechanisms underlying the ultradian circhoral oscillations of insulin secretion rate (ISR), which arise in part from a rhythmic amplification of the rapid pulses, are not fully understood. In humans, included in the same period range is the alternation of rapid eye movement (REM) and non-REM (NREM) sleep cycles and the associated opposite oscillations in sympathovagal balance. During sleep, the glucose and ISR oscillations were amplified by about 150%, but the REM-NREM sleep cycles did not entrain the glucose and ISR ultradian oscillations. Also, the latter were not related to either the ultradian oscillations in sympathoagal balance, as inferred from spectral analysis of cardiac R-R intervals, or the plasma fluctuations of glucagon-like peptide-1 (GLP-1), an incretin hormone known to potentiate glucose-stimulated insulin. Other rhythmic physiological processes are currently being examined in relation to ultradian insulin release.     

Effect of acute hyperglycemia on insulin secretion in humans

First-phase insulin response to intravenous glucose is impaired both in type 2 diabetic patients and in subjects at risk for the disease. Hyperglycemia can modify beta-cell response by either inhibiting or potentiating both first- and second-phase insulin release. In normal subjects, the effect of acute hyperglycemia on insulin secretion is controversial. We measured (in 13 healthy volunteers) insulin secretion (by deconvolution of plasma C-peptide concentrations) during three consecutive 30-min hyperglycemic steps (2.8, 2.8, and 5.6 mmol/l), followed by an intravenous arginine bolus. First-phase insulin secretion in response to the first hyperglycemic step (456 +/- 83 pmol.min(-1).m(-2)) was significantly larger than that in response to the second step (311 +/- 37 pmol.min(-1).m(-2), P < 0.01); the subsequent increase in glycemia failed to stimulate first-phase secretion any further (377 +/- 60 pmol.min(-1).m(-2), NS vs. the previous value). This inhibition was also evident when insulin release rates were corrected for the respective increments (absolute or percentage) in plasma glucose levels and was not due to beta-cell exhaustion because the arginine bolus still elicited a large peak of insulin secretion (4,790 +/- 2,330 pmol.min(-1).m(-2)). In contrast, second-phase insulin secretion was related to the prevailing glucose levels across the three hyperglycemic steps in a direct quasilinear manner. We conclude that first-phase insulin secretion is inhibited by short-term modest hyperglycemia, whereas the second-phase insulin secretion increases linearly with hyperglycemia.     

Insulin action and insulin secretion in identical twins with MODY. Evidence for defects in both insulin action and secretion

To evaluate the pathogenetic mechanisms responsible for development of diabetes in the genetically inherited disease maturity-onset diabetes of the young (MODY), we have investigated a pair of identical twins (19 yr old) from a MODY family. One twin had nondiabetic fasting plasma glucose values but impaired glucose tolerance (IGT), whereas the other suffered from frank diabetes (fasting plasma glucose 12.5 mM). Differences in insulin secretion pattern and/or insulin action between the twins is supposed to be responsible for development of hyperglycemia in MODY. On the other hand, identical defects in insulin secretion and action in the twins may point to the primary genetic defect in MODY. Therefore, our aim was to investigate insulin secretion and insulin action in the twins to find these differences and similarities. We found that fasting plasma insulin and C-peptide values were slightly increased in the twins, whereas the responses of insulin and C-peptide to oral glucose tolerance tests (OGTT) and meals were similar in the twins and within normal range. The insulin responses to OGTT were, however, lower than expected from the glucose values, indicating a beta-cell defect. Despite elevated plasma insulin levels, basal hepatic glucose output (HGO) was normal in the IGT twin but increased by 75% in the diabetic twin. The maximally inhibitory effect of insulin on HGO, when estimated at euglycemia, was normal in the IGT twin but reduced by 60% in the diabetic twin. Furthermore, the maximal insulin-mediated glucose uptake in peripheral tissues was reduced by 40% in the diabetic twin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of age and diet on insulin secretion and insulin action in the rat

The effects of aging on various aspects of insulin secretion and action were studied in male Sprague-Dawley rats, maintained from 1 1/2 to 12 mo of age on conventional rat chow, sucrose-rich, or calorie-restricted diets. In chow-fed rats, islet volume increased as the animals grew from 1 1/2 to 12 mo of age, but glucose-stimulated insulin secretion (per volume islet) declined over the same interval. In addition, in vivo insulin-stimulated glucose utilization fell in these rats. However, the plasma insulin response to an oral glucose challenge was sufficient to prevent frank decompensation of glucose tolerance (presumably due to an increase in total pancreatic endocrine cell mass). All these changes, with the exception of the decline in glucose-stimulated insulin secretion per volume islet, were accentuated by feeding sucrose. Thus, 12-mo-old sucrose-fed rats had larger islets and higher plasma insulin levels in response to an oral glucose challenge, and the rats were more insulin-resistant than chow-fed rats. However, glucose-stimulated insulin release per volume islet was similar in 12-mo-old chow-fed and sucrose-fed rats. In contrast, calorie restriction led to an amelioration in all but one of the age-related changes, i.e., islets from calorie-restricted rats were comparable in size to those of 2-mo-old rats, the animals had lower plasma insulin levels in response to an oral glucose load, and they were less insulin resistant than the other two groups of 12-mo-old rats. On the other hand, glucose-stimulated insulin secretion per volume islet was similar to that of the other 12-mo-old rats. These results suggest that aging leads to marked changes in both insulin secretion and insulin action. The decline in glucose-stimulated insulin secretion per unit endocrine pancreas appears to be an inevitable consequence of the aging process. In contrast, the age-related changes in islet size, insulin response to a glucose load, and in vivo insulin-stimulated glucose uptake are extremely responsive to variations in amount and kind of calories. DIABETES 32:175-180, February 1983.     

The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus

We have studied the effects of 3 wk of continuous subcutaneous insulin infusion (CSII) on endogenous insulin secretion and action in a group of 14 type II diabetic subjects with a mean (+/-SEM) fasting glucose level of 286 +/- 17 mg/dl. Normal basal and postprandial glucose levels were achieved during insulin therapy at the expense of marked peripheral hyperinsulinemia. During the week of posttreatment evaluation, the subjects maintained a mean fasting glucose level of 155 +/- 11 mg/dl off insulin therapy, indicating a persistent improvement in carbohydrate homeostasis. Adipocyte insulin binding and in vivo insulin dose-response curves for glucose disposal using the euglycemic clamp technique were measured before and after therapy to assess the effect on receptor and postreceptor insulin action. Adipocyte insulin binding did not change. The insulin dose-response curve for overall glucose disposal remained right-shifted compared with age-matched controls, but the mean maximal glucose disposal rate increased by 74% from 160 +/- 14 to 278 +/- 18 mg/m2/min (P less than 0.0005). The effect of insulin treatment on basal hepatic glucose output was also assessed; the mean rate was initially elevated at 159 +/- 8 mg/m2/min but fell to 90 +/- 5 mg/m2/min in the posttreatment period (P less than 0.001), a value similar to that in control subjects. Endogenous insulin secretion was assessed in detail and found to be improved after exogenous insulin therapy. Mean 24-h integrated serum insulin and C-peptide concentrations were increased from 21,377 +/- 2766 to 35,584 +/- 4549 microU/ml/min (P less than 0.01) and from 1653 +/- 215 to 2112 +/- 188 pmol/ml/min (P less than 0.05), respectively, despite lower glycemia. Second-phase insulin response to an intravenous (i.v.) glucose challenge was enhanced from 170 +/- 53 to 1022 +/- 376 microU/ml/min (P less than 0.025), although first-phase response remained minimal. Finally, the mean insulin and C-peptide responses to an i.v. glucagon pulse were unchanged in the posttreatment period, but when glucose levels were increased by exogenous glucose infusion to approximate the levels observed before therapy and the glucagon pulse repeated, responses were markedly enhanced. Simple and multivariate correlation analysis showed that only measures of basal hepatic glucose output and the magnitude of the postbinding defect in the untreated state could be related to the respective fasting glucose levels in individual subjects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of aging on insulin secretion

Aging is associated with hyperinsulinemia, but reports vary on the contributions of altered insulin clearance versus insulin secretion to this phenomenon. To elucidate the role of insulin secretion in the hyperinsulinemia of aging, 10 elderly (age 66 +/- 4 yr, body mass index 25 +/- kg/m2) and 8 young (age 30 +/- 5 yr, body mass index 24 +/- 3 kg/m2) subjects were studied to determine rates of insulin secretion in response to fasting, mixed meals, and intravenous glucose administration. Insulin secretion was determined with a two-compartment model based on individual C-peptide kinetic parameters derived after bolus injection of biosynthetic human C-peptide. Basal insulin secretion rates were increased in elderly subjects (82.5 +/- 9.0 vs. 62.8 +/- 6.1 pmol.min-1.m-2; P less than .05). This was reflected in elevated serum insulin levels in elderly subjects (62.8 +/- 10.1 vs. 41.1 +/- 5.0 pM, P less than .05). During a 24-h mixed-meal profile, elderly subjects had an increase in their glucose response (P less than .01 by analysis of variance [ANOVA]) and total insulin secretion (261 +/- 28 vs. 195 +/- 22 nmol.24 h-1.m-2; P less than .05) compared with young subjects. However, the relative total increases in both glycemia and insulin secretion, calculated as a function of basal levels, were similar between the groups (both NS). To experimentally control for differences in glycemia, both groups underwent a 16.8-mM hyperglycemic clamp and a stepped intravenous glucose infusion to match glycemia. Under these steady-state and dynamic conditions, insulin secretion profiles were nearly identical (NS by ANOVA).(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose homeostasis and insulin secretion during isoflurane anesthesia in humans

The effect of isoflurane-air anesthesia on glucose tolerance in humans was investigated using two successive intravenous glucose tolerance tests (IVGTT). After a first IVGTT while awake, patients received a second IVGTT either while awake (group I), during anesthesia with isoflurane-air and pancuronium without surgical stimulation (group II), or during the same anesthetic technique but combined with surgery (group III). Isoflurane seemed to induce glucose intolerance (glucose disappearance rate K10-60 min = 1.628 +/- 0.462% min-1 [control] versus 1.086 +/- 0.920% min-1 [anesthesia], P less than 0.05) partly due to a decreased glucose induced insulin response. Growth hormone and norepinephrine levels were also increased during anesthesia. Epinephrine levels were lowered by isoflurane anesthesia. Although glucose intolerance was marked during surgery (K10-60 min = 0.892 +/- 0.286% min-1), the glucose-induced insulin response remained similar to that observed in patients in group II, while growth hormone, cortisol, epinephrine, and norepinephrine concentrations increased significantly. These known stress factors thus seemed to enhance glucose intolerance through a diminished response to insulin action and/or an enhanced hepatic glucose output, rather than by further impairing pancreatic insulin secretion.     

Calpains play a role in insulin secretion and action

Studies of the genetic basis of type 2 diabetes suggest that variation in the calpain-10 gene affects susceptibility to this common disorder, raising the possibility that calpain-sensitive pathways may play a role in regulating insulin secretion and/or action. Calpains are ubiquitously expressed cysteine proteases that are thought to regulate a variety of normal cellular functions. Here, we report that short-term (4-h) exposure to the cell-permeable calpain inhibitors calpain inhibitor II and E-64-d increases the insulin secretory response to glucose in mouse pancreatic islets. This dose-dependent effect is observed at glucose concentrations above 8 mmol/l. This effect was also seen with other calpain inhibitors with different mechanisms of action but not with cathepsin inhibitors or other protease inhibitors. Enhancement of insulin secretion with short-term exposure to calpain inhibitors is not mediated by increased responses in intracellular Ca2+ or increased glucose metabolism in islets but by accelerated exocytosis of insulin granules. In muscle strips and adipocytes, exposure to both calpain inhibitor II and E-64-d reduced insulin-mediated glucose transport. Incorporation of glucose into glycogen in muscle also was reduced. These results are consistent with a role for calpains in the regulation of insulin secretion and insulin action.     

Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans

In health, insulin is secreted in discrete pulses into the portal vein, and the regulation of the rate of insulin secretion is accomplished by modulation of insulin pulse mass. Several lines of evidence suggest that the pattern of insulin delivery by the pancreas determines hepatic insulin clearance. In previous large animal studies, the amplitude of insulin pulses was related to the extent of insulin clearance. In humans (and in large animals), the amplitude of insulin oscillations is approximately 100-fold higher in the portal vein than in the systemic circulation, despite only a fivefold dilution, implying preferential hepatic extraction of insulin pulses. In the present study, by direct hepatic vein sampling in healthy humans, we sought to establish the extent of first-pass hepatic insulin extraction and to determine whether the pattern of insulin secretion (insulin pulse mass and amplitude) dictates the hepatic insulin clearance and thereby delivery of insulin to extrahepatic insulin-responsive tissues. Five nondiabetic subjects (two men and three women, mean age 32 years [range 25-39], BMI 24.9 kg/m(2) [21.2-27.1]) participated. Insulin and C-peptide delivery from the splanchnic bed was measured in basal overnight-fasted state and during a glucose infusion of 2 mg . kg(-1) . min(-1) by simultaneous sampling from the hepatic vein and an arterialized vein along with direct estimation of splanchnic blood flow. Fractional insulin extraction was calculated from the difference between the C-peptide and insulin delivery rates from the liver. The time patterns of insulin concentrations and hepatic insulin clearance were analyzed by deconvolution and Cluster analysis, respectively. Cross-correlation analysis was used to relate C-peptide secretion and insulin clearance. Glucose infusion increased peripheral glucose concentrations from 5.4 +/- 0.1 to 6.4 +/- 0.4 mmol/l (P < 0.05). Likewise, insulin and C-peptide concentrations increased during glucose infusion (P < 0.05). Hepatic insulin clearance increased with glucose infusion (1.06 +/- 0.18 vs. 2.55 +/- 0.38 pmol . kg(-1) . min(-1); P < 0.01), but fractional hepatic insulin clearance was stable (78.2 +/- 4.4 vs. 84 0. +/- 3.9%, respectively; P = 0.18). Insulin secretory-burst mass rose during glucose infusion (P < 0.05), whereas the interburst interval remained unchanged (4.4 +/- 0.2 vs. 4.5 +/- 0.3 min; P = 0.36). Cluster analysis identified an oscillatory pattern in insulin clearance, with peaks occurring approximately every 5 min. Cross-correlation analysis between prehepatic C-peptide secretion and hepatic insulin clearance demonstrated a significant positive association without detectable (<1 min) time lag. Insulin secretory-burst mass strongly predicted insulin clearance (r = 0.81, P = 0.0043). In conclusion, in humans, approximately 80% of insulin is extracted during the first liver passage. The liver rapidly responds to fluctuations in insulin secretion, preferentially extracting insulin delivered in pulses. The mass (and therefore amplitude) of insulin pulses traversing the liver is the predominant determinant of hepatic insulin clearance. Therefore, through this means, the pulse mass of insulin release dictates both hepatic (directly) as well as extra-hepatic (indirectly) insulin delivery. These findings emphasize the dual role of the liver and pancreas and their relationship mediated through magnitude of insulin pulse mass in regulating the quantity and pattern of systemic insulin delivery.     

Effects of age and sex on postprandial glucose metabolism: differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction

To determine the effects of age and sex on the regulation of postprandial glucose metabolism, glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction were concurrently measured in 145 healthy elderly (aged 70 +/- 1 years) and in 58 young (aged 28 +/- 1 years) men and women before and after ingestion of a mixed meal containing [1-(13)C]glucose. At the time of meal ingestion, [6-(3)H]glucose and [6,6-(2)H(2)]glucose were infused intravenously to enable concurrent measurement of the rates of postprandial endogenous glucose production (EGP), meal appearance, and glucose disappearance. Fasting and postprandial glucose concentrations were higher (P < 0.001) in both elderly women and elderly men compared with young individuals of the same sex. The higher postprandial glucose concentrations in the elderly than young women were caused by higher rates of meal appearance (P < 0.01) and slightly lower (P < 0.05) rates of glucose disappearance immediately after eating. In contrast, higher glucose concentrations in the elderly than young men were solely due to decreased (P < 0.001) glucose disappearance. Although postprandial glucose concentrations did not differ in elderly women and elderly men, rates of meal appearance and glucose disappearance rates both were higher (P < 0.001) in the women. Fasting EGP was higher (P < 0.05) in elderly than young subjects of both sexes and in women than men regardless of age. On the other hand, postprandial suppression of EGP was rapid all groups. Insulin action and secretion were lower (P < 0.001) in the elderly than young men but did not differ in the elderly and young women. This resulted in lower (P < 0.001) meal disposition indexes in elderly than young men but no difference in elderly and young women. Total meal disposition indexes were lower (P < 0.05) in elderly men than elderly women, indicating impaired insulin secretion, whereas disposition indexes were higher (P < 0.05) in young men than young women. Hepatic insulin clearance was greater (P < 0.001) in the elderly than young subjects of both sexes but did not differ between men and women regardless of age. In contrast, the ability of glucose to facilitate its own uptake (glucose effectiveness) was higher (P < 0.001) in women than men but did not differ in elderly and young subjects. Thus, age and sex impact on insulin secretion, insulin action, hepatic insulin extraction, and glucose effectiveness, resulting in substantial differences in the regulation of postprandial glucose metabolism in men and women and in elderly and young subjects.     

Decrease in glucose-stimulated insulin secretion with aging is independent of insulin action

While the incidence of diabetes increases with age, a decrease in beta-cell function independent of age-related insulin resistance has not been conclusively determined. We studied insulin secretion (by hyperglycemic clamp) in 3-, 9-, and 20-month-old chronically catheterized, awake, Sprague Dawley (SD) rats (n = 78). Insulin action was modulated in a group of old rats by caloric restriction (CR) or by surgical removal of visceral fat (VF-). During the first 2 h of the clamp (11 mmol/l glucose), insulin secretion and insulin resistance (S(i hyper clamp)) demonstrated the characteristic hyperbolic relationship. However, after hyperglycemia for an additional 2 h, the ability to maintain insulin secretion, commensurate with the degree of insulin resistance, was decreased in all aging rats (P < 0.05). Increasing plasma glucose levels to 18 mmol/l glucose, after clamp at 11 mmol/l, increased insulin secretion by approximately threefold in young rats, but failed to induce similar magnitude of response in the aging rats ( approximately 50%). However, elevation of plasma free fatty acid (FFA) levels by twofold (by intralipid infusion during 11 mmol/l glucose clamp) resulted in a robust, approximate twofold response in both young and old rats. Thus, prolonged stimulation by hyperglycemia unveiled a functional defect in insulin secretion with aging. This age-related defect is independent of insulin action and is specific to glucose and not FFAs. We suggest that prolonged hyperglycemic stimulation can be a tool to identify functional defects in insulin secretion, particularly in the context of the hyperbolic relationship with insulin action, in elderly subjects or those at risk for type 2 diabetes.     

Endothelin limits insulin action in obese/insulin-resistant humans

The normal action of insulin to vasodilate and redistribute blood flow in support of skeletal muscle metabolism is impaired in insulin-resistant states. Increased endogenous endothelin contributes to endothelial dysfunction in obesity and diabetes. Here, we test the hypothesis that increased endogenous endothelin action also contributes to skeletal muscle insulin resistance via impairments in insulin-stimulated vasodilation. We studied nine lean and seven obese humans, measuring the metabolic and hemodynamic effects of insulin (300 mU . m(-2) . min(-1)) alone and during femoral artery infusion of BQ123 (an antagonist of type A endothelin receptors, 1 micromol/min). Endothelin antagonism augmented skeletal muscle responses to insulin in obese subjects through changes in both leg blood flow (LBF) and glucose extraction. Insulin-stimulated LBF was significantly increased in obese subjects only. These changes, combined with differential effects on glucose extraction, resulted in augmented insulin-stimulated leg glucose uptake in obese subjects (54.7 +/- 5.7 vs. 107.4 +/- 18.9 mg/min with BQ123), with no change in lean subjects (103.7 +/- 11.4 vs. 88.9 +/- 16.3, P = 0.04 comparing BQ123 across groups). BQ123 allowed augmented leg glucose extraction in obese subjects even in the face of NOS antagonism. These findings suggest that increased endogenous endothelin action contributes to insulin resistance in skeletal muscle of obese humans, likely through both vascular and tissue effects.     

Insulin augmentation of glucose-stimulated insulin secretion is impaired in insulin-resistant humans

Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell dysfunction, the latter possibly caused by a defect in insulin signaling in β-cells. We hypothesized that insulin's effect to potentiate glucose-stimulated insulin secretion (GSIS) would be diminished in insulin-resistant persons. To evaluate the effect of insulin to modulate GSIS in insulin-resistant compared with insulin-sensitive subjects, 10 participants with impaired glucose tolerance (IGT), 11 with T2D, and 8 healthy control subjects were studied on two occasions. The insulin secretory response was assessed by the administration of dextrose for 80 min following a 4-h clamp with either saline infusion (sham) or an isoglycemic-hyperinsulinemic clamp using B28-Asp-insulin (which can be distinguished immunologically from endogenous insulin) that raised insulin concentrations to high physiologic concentrations. Pre-exposure to insulin augmented GSIS in healthy persons. This effect was attenuated in insulin-resistant cohorts, both those with IGT and those with T2D. Insulin potentiates glucose-stimulated insulin secretion in insulin-resistant subjects to a lesser degree than in normal subjects. This is consistent with an effect of insulin to regulate β-cell function in humans in vivo with therapeutic implications.     

Validation of methods for measurement of insulin secretion in humans in vivo

To detect and understand the changes in beta-cell function in the pathogenesis of type 2 diabetes, an accurate and precise estimation of prehepatic insulin secretion rate (ISR) is essential. There are two common methods to assess ISR, the deconvolution method (by Eaton and Polonsky)-considered the "gold standard"-and the combined model (by V?lund et al.). The deconvolution method is a 2-day method, which generally requires separate assessment of C-peptide kinetics, whereas the combined model is a single-day method that uses insulin and C-peptide data from a single test of interest. The validity of these mathematical techniques for quantification of insulin secretion have been tested in dogs, but not in humans. In the present studies, we examined the validity of both methods to recover the known infusion rates of insulin and C-peptide mimicking ISR during an oral glucose tolerance test. ISR from both the combined model and the deconvolution method were accurate, i.e., recovery of true ISR was not significantly different from 100%. Furthermore, both maximal and total ISRs from the combined model were strongly correlated to those obtained by the deconvolution method (r = 0.89 and r = 0.82, respectively). These results indicate that both approaches provide accurate assessment of prehepatic ISRs in type 2 diabetic patients and control subjects. A simplified version of the deconvolution method based on standard kinetic parameters for C-peptide (Van Cauter et al.) was compared with the 2-day deconvolution method, and a close agreement was found for the results of an oral glucose tolerance test. We also studied whether C-peptide kinetics are influenced by somatostatin infusion. The decay curves after bolus injection of exogenous biosynthetic human C-peptide, the kinetic parameters, and the metabolic clearance rate were similar whether measured during constant peripheral somatostatin infusion or without somatostatin infusion. Assessment of C-peptide kinetics can be performed without infusion of somatostatin, because the endogenous insulin concentration remains constant. Assessment of C-peptide kinetics with and without infusion of somatostatin results in nearly identical secretion rates for insulin during an oral glucose tolerance test.     

Glucose-induced insulin secretion in uremia: effects of aminophylline infusion and glucose loads

To explain mechanisms responsible for derangement of insulin release in uremia, we investigated glucose metabolism through three different tests in 14 patients with end-stage chronic renal failure. These tests were: intravenous glucose tolerance test with 0.33 g/kg of glucose solution (IVGTT); IVGTT with 0.5 g/kg of glucose solution (IVGTT2); IVGTT during aminophylline infusion (IVGTT + A). Twelve of the patients had IVGTT repeated after two to four months of thrice-weekly regular hemodialysis (IVGTT3). In each test we measured plasma glucose (G), immunoreactive insulin (IRI) and C-peptide. We also calculated glucose constant decay (K), insulin production (IRI area), insulinogenic index (IGI), and insulin resistance index (RI). Twenty-nine healthy volunteers formed the normal controls for IVGTT. As compared to controls, during IVGTT uremic patients showed significantly lower values in K, IRI area and IGI, and showed a significant RI value increase. During IVGTT2, IRI are values were higher than during IVGTT but IGI and K values were unchanged. During IVGTT + A both IRI area and IGI values were higher than during IVGTT. After hemodialysis treatment (IVGTT3) K, IRI areas and IGI increased significantly as compared to the predialysis period. K increase after hemodialysis correlated directly to IGI increase and inversely to RI changes. IGI increase during IVGTT3 was directly correlated to IGI rise during IVGTT + A. From these data we infer that defective insulin release in uremia is due to a decrease of beta-cell glucose sensitivity rather than to their functional exhaustion. An impaired adenyl cyclase-cAMP system may have an important role in the pathogenesis of this abnormality.     

Beta-endorphin-induced inhibition and stimulation of insulin secretion in normal humans is glucose dependent

This study evaluated the effect of human beta-endorphin on pancreatic hormone levels and their responses to nutrient challenges in normal subjects. Infusion of 0.5 mg/h beta-endorphin caused a significant rise in plasma glucose concentrations preceded by a significant increase in peripheral glucagon levels. No changes occurred in the plasma concentrations of insulin and C-peptide. Acute insulin and C-peptide responses to intravenous pulses of different glucose amounts (0.33 g/kg and 5 g) and arginine (3 g) were significantly reduced by beta-endorphin infusion (P less than .01). This effect was associated with a significant reduction of the glucose disappearance rates, suggesting that the inhibition of insulin was of biological relevance. beta-Endorphin also inhibited glucose suppression of glucagon levels and augmented the glucagon response to arginine. To verify whether the modification of prestimulus glucose level could be important in these hormonal responses to beta-endorphin, basal plasma glucose concentrations were raised by a primed (0.5 g/kg) continuous (20 mg kg-1.min-1) glucose infusion. After stabilization of plasma glucose levels (350 +/- 34 mg/dl, t = 120 min), beta-endorphin infusion caused an immediate and marked increase in plasma insulin level (peak response 61 +/- 9 microU/ml, P less than .01), which remained elevated even after the discontinuation of opioid infusion. Moreover, the acute insulin response to a glucose pulse (0.33 g/kg i.v.) given during beta-endorphin infusion during hyperglycemia was significantly higher than the response obtained during euglycemia (171 +/- 32 vs. 41 +/- 7 microU/ml, P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)