The pharmacokinetics of porcine C-peptide after intraperitoneal injection.

BACKGROUND: Previously, we have demonstrated that there were very low C-Peptide concentrations and normal blood glucose levels when we transplanted encapsulated islets in the abdominal cavity of diabetic nude mice. In addition, the C-peptide concentration in the ascites fluid of the peritoneal cavity was 40 times higher than in the peripheral blood. In this study, we investigated the pharmacokinetics of intraperitoneal porcine C-peptide. METHODS: To assess the pharmacokinetics of porcine C-peptide, a synthesized porcine C-peptide solution was injected into the peripheral circulation through the tail vein or into the peritoneal cavity in rats at low or high doses of either 200 or 2000 pmol/kg, respectively. Arterial blood samples were collected at time intervals of 1-120 minutes after injection to calculate the terminal elimination half-life (t1/2 ) and area under the time-concentration curve (AUC0-t ). RESULTS: After intraperitoneal C-peptide injection, the highest porcine C-peptide concentration in peripheral blood was only one-fortieth compared to after intravenous injection. The AUC0-t for the intraperitoneal injection was 78% at the low dose and only 39% at the high dose compared to the intravenous injection. This finding indicates that C-peptide remains in the abdominal cavity when intraperitoneally transplanted islets release C-peptide via high glucose stimulation. CONCLUSIONS: Porcine C-peptide injected into a peritoneal cavity slowly and incompletely entered peripheral circulation, which resulted in very low concentration in peripheral blood.

C-Peptide replacement therapy in type 1 diabetes: are we in the trough of disillusionment?

Type 1 diabetes is associated with such complications as blindness, kidney failure, and nerve damage. Replacing C-peptide, a hormone normally co-secreted with insulin, has been shown to reduce diabetes-related complications. Interestingly, after nearly 30 years of positive research results, C-peptide is still not being co-administered with insulin to diabetic patients. The following review discusses the potential of C-peptide as an auxilliary replacement therapy and why it's not currently being used as a therapeutic.

Effect of gestational age and blood glucose on C-peptide excretion rate and clearance in neonates.

AIMS: The aim of this study was to measure urinary C-peptide concentrations, and then calculate C-peptide clearance (Cl), and excretion rate (UER) in neonates. In addition, the effect of gestational age (GA) and blood glucose levels (BGL) on C-peptide UER were investigated. METHODS: Insulin concentrations in plasma and C-peptide concentrations were measured in plasma and urine, in 20 neonates. Chemiluminescent immunoassays were used for insulin and C-peptide measurements, with urine diluted to 40% with bovine serum albumin 1% in phosphate buffered saline. Urine volume and time of collection were recorded and used to calculate UER and Cl. RESULTS: The mean Cl of C-peptide was 0.309 ± 0.329 mL/min/kg, and UER was 0.0329 ± 0.0342 pmol/min/kg. Correlations between Cl or UER and GA were not significant (P > 0.05). No significant correlation was shown between Cl or UER and BGL (P > 0.05). CONCLUSIONS: Both Cl and UER were highly variable in neonates, but were not correlated with GA. Additionally, BGL did not appear to affect C-peptide UER and Cl. As GA and BGL did not appear to affect Cl and UER, urinary C-peptide may provide a non-invasive method of measuring insulin production in neonates.

A 9-Month Toxicity and Toxicokinetic Assessment of Subcutaneous Pegylated Human C-peptide (CBX129801) in Cynomolgus Monkeys.

C-peptide is formed in the biosynthesis of insulin and is therefore deficient in patients with type 1 diabetes mellitus. A pegylated form of human synthetic C-peptide (CBX129801) has been developed to extend the half-life of the native peptide and is undergoing clinical investigation as replacement therapy to treat diabetic peripheral neuropathy. This monkey study was conducted to evaluate the toxicity of CBX129801 with weekly subcutaneous dosing for 39 weeks at dose levels of 0 (vehicle), 0.4, 1.33, and 4.0 mg/kg/wk. No systemic adverse effects were observed at any dose with maximal CBX129801 plasma concentrations of 735 to 1050 nmol/L during the dosing period (physiological range is 1-3 nmol/L). CBX129801-related effects were limited to minimal macrophagic vacuolization at the injection sites and in the associated draining (axillary) lymph nodes; these local effects largely resolved by the end of a 7-week recovery period. No systemic macrophagic vacuolization was observed. Additionally, there was no histological evidence for plaque formation in the major arteries of these nondiabetic animals.

Insulin enhances glucose-stimulated insulin secretion in healthy humans.

Islet beta-cells express both insulin receptors and insulin-signaling proteins. Recent evidence from rodents in vivo and from islets isolated from rodents or humans suggests that the insulin signaling pathway is physiologically important for glucose sensing. We evaluated whether insulin regulates beta-cell function in healthy humans in vivo. Glucose-induced insulin secretion was assessed in healthy humans following 4-h saline (low insulin/sham clamp) or isoglycemic-hyperinsulinemic (high insulin) clamps using B28-Asp insulin that could be immunologically distinguished from endogenous insulin. Insulin and C-peptide clearance were evaluated to understand the impact of hyperinsulinemia on estimates of beta-cell function. Preexposure to exogenous insulin increased the endogenous insulin secretory response to glucose by approximately 40%. C-peptide response also increased, although not to the level predicted by insulin. Insulin clearance was not saturated at hyperinsulinemia, but metabolic clearance of C-peptide, assessed by infusion of stable isotope-labeled C-peptide, increased modestly during hyperinsulinemic clamp. These studies demonstrate that insulin potentiates glucose-stimulated insulin secretion in vivo in healthy humans. In addition, hyperinsulinemia increases C-peptide clearance, which may lead to modest underestimation of beta-cell secretory response when using these methods during prolonged dynamic testing.

In vivo biodistribution and pharmacokinetics of (18)F-labeled human C-peptide: evaluation in monkeys using positron emission tomography.

The recently observed beneficial effects exerted by C-peptide in insulin-dependent diabetes patients (IDDM) have instigated research into the mechanisms of C-peptide action as well as the location for it. Here we report in vivo biodistribution studies performed in monkeys using positron emission tomography (PET) and C-peptide labeled in the N-terminal with fluorine-18. Following iv injection of the radiotracer, dynamic decay data were collected over the chest and/or abdomens of the monkeys. The radioactivity distributed mainly to the kidneys, less to the heart and to some extent to the liver. Excretion of radioactivity into the urinary bladder was observed. Brain uptake was not detected in a static emission scan of the head performed at late times. Accumulation of radioactivity in the skeleton as a result of in vivo defluorination was not observed. Pharmacokinetic modeling of the regional concentrations of radioactivity over time resulted, for most organs, in two-compartment models. The organs with the highest radioactivity concentrations have been identified, enabling dose estimations for studies in humans with low or no C-peptide.

Quantification of beta-cell function during IVGTT in Type II and non-diabetic subjects: assessment of insulin secretion by mathematical methods.

AIMS/HYPOTHESIS: We compared four methods to assess their accuracy in measuring insulin secretion during an intravenous glucose tolerance test in patients with Type II (non-insulin-dependent) diabetes mellitus and with varying beta-cell function and matched control subjects. METHODS: Eight control subjects and eight Type II diabetic patients underwent an intravenous glucose tolerance test with tolbutamide and an intravenous bolus injection of C-peptide to assess C-peptide kinetics. Insulin secretion rates were determined by the Eaton deconvolution (reference method), the Insulin SECretion method (ISEC) based on population kinetic parameters as well as one-compartment and two-compartment versions of the combined model of insulin and C-peptide kinetics. To allow a comparison of the accuracy of the four methods, fasting rates and amounts of insulin secreted during the first phase (0-10 min) and the second phase (10-180 min) were calculated. RESULTS: All secretion responses from the ISEC method were strongly correlated to those obtained by the Eaton deconvolution method (r = 0.83-0.92). The one-compartment combined model, however, showed a high correlation to the reference method only for the first-phase insulin response (r = 0.78). The two-compartment combined model failed to provide reliable estimates of insulin secretion in three of the control subjects and in two patients with Type II diabetes. The four methods were accurate with respect to mean basal and first-phase secretion response. The one-compartment and two-compartment combined models were less accurate in measuring the second-phase response. CONCLUSION/INTERPRETATION: The ISEC method can be applied to normal, obese or Type II diabetic patients. In patients with deviating kinetics of C-peptide the Eaton deconvolution method is the method of choice while the one-compartment combined model is suitable for measuring only the first-phase insulin secretion.

C-Peptide determinations in islet xenotransplantation: A study in the pig-to-mouse model.

Assays of C-peptide are used to monitor allogeneic islet graft function. However, it is not known whether xenogeneic C-peptide is metabolized and excreted in a fashion similar to endogenous and allogeneic C-peptide. In this study, injection of 10 times the physiological amount of porcine C-peptide into mice did not result in the excretion of the C-peptide in the urine. In contrast, when a physiological amount of porcine C-peptide was injected into athymic mice, urinary excretion of porcine C-peptide was readily detected. After injection of radioactively labeled porcine C-peptide into mice, the radioactive uptake in tissues belonging to the mononuclear phagocytic system was significantly increased in mice immunized towards the xenogeneic C-peptide. These results may reflect an immunological reactivity towards the C-peptide. Antibodies against porcine C-peptide could not be detected in the serum of any of the mice. However, porcine C-peptide was found to be glycosylated. Thus, a possible explanation to the lack of porcine C-peptide in the urine is that xenoreactive antibodies had bound to carbohydrate structures on the peptide and that the antibody-C-peptide complex had been cleared from the circulation by the mononuclear phagocytic system. Thus, the urinary excretion of xenogeneic C-peptide seems to be different from that of endogenous and allogeneic C-peptide. Consequently, determinations of donor-specific C-peptide may not properly reflect islet xenograft function. In fact, islet xenograft function may be underestimated.

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 Vølund 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.

High chromium yeast supplementation improves glucose tolerance in pigs by decreasing hepatic extraction of insulin.

Twenty Landrace x Yorkshire cross pigs (body wt, 47.9+/-2.9 kg) were used to evaluate effects of dietary high chromium (Cr) yeast supplementation on plasma kinetics of glucose, insulin and C-peptide. Pigs were provided free access to either a control diet (C) containing 204 microg Cr/kg or a diet supplemented with an additional 200 microg Cr/kg as high Cr yeast (CR) for between 23 and 30 d. After overnight food deprivation, dextrose (500 g/L) was infused through a jugular vein catheter at a dose of 0.5 g glucose/kg body weight with an infusion rate of 10 g glucose/min within 6 min. High Cr yeast supplementation did not affect body weight gain or food intake. There were no differences in fasting plasma concentrations of either glucose or C-peptide, although basal plasma concentration of insulin tended to be higher in pigs fed CR (P<0.10). Plasma glucose concentrations were lower (P<0.01) at postinfusion times 5, 10, 15 and 20 min in pigs fed CR. Plasma insulin concentrations in pigs fed CR were higher (P<0.05) at 2 and 0 min before the completion of dextrose infusion. However, the increase in plasma insulin concentrations was not accompanied by a comparable elevation in plasma C-peptide concentrations. The 30-min (postinfusion) area of plasma glucose concentrations tended to be lower (P<0.10) in pigs fed CR, but there were no differences in 30-min areas of either plasma insulin or plasma C-peptide concentrations between treatments. Plasma clearance rates of glucose, insulin and C-peptide were higher and their half-lives shorter (P<0.05) in pigs fed CR. In conclusion, dietary high Cr yeast supplementation improved glucose tolerance, possibly through a decrease in hepatic extraction of insulin.

Beta-cell function during insulin-modified intravenous glucose tolerance test successfully assessed by the C-peptide minimal model.

The insulin-modified intravenous glucose tolerance test (IM-IVGTT) is increasingly used to measure insulin sensitivity. However, the assessment of beta-cell secretion is usually made using rough indices. The aim here is to evaluate the ability of the minimal model of C-peptide secretion and kinetics recently proposed for the standard IVGTT (S-IVGTT) to also assess beta-cell function during the IM-IVGTT. C-peptide and glucose data from the IM-IVGTT in 15 normal humans were analyzed. The results show that the same rich beta-cell picture from the S-IVGTT can be obtained during an IM-IVGTT. In particular, in each individual, the time course of beta-cell secretion can be reconstructed and the functional indices of glucose control on first-phase (phi1), second-phase (phi2), and basal (phi(b)) insulin secretion can be estimated (phi1 = 191 +/- 29, phi2 = 10.9 +/- 1.4 x 10(-9) x min(-1), and phi(b) = 5.7 +/- 1.0 x 10(-9) x min(-1), mean +/- SE). Finally, the comparison between IM-IVGTT and S-IVGTT phi1, phi2, and phi(b) values suggest they are not affected by insulin administration.

Lack of insulin feedback inhibition in non-obese and obese men.

The existence of insulin feedback inhibition is a controversial issue. The present study adopted a novel approach to determine whether insulin feedback inhibition exists in vivo during physiologic hyperinsulinemia and if it could contribute to enhanced insulin secretion in obesity. Serial plasma insulin and C-peptide levels were determined during a basal state and a hyperinsulinemic clamp (287 pmol/min/m2) and following discontinuation of the insulin infusion under euglycemic conditions. Insulin secretion rates were derived from plasma C-peptide levels and individual C-peptide kinetics using a two-compartment model. Eight non-obese and nine obese men were recruited for the studies, which were performed in random order. Men with significant variations in glucose levels during hyperinsulinemia were excluded from the analysis. Plasma glucose levels were similar between the non-obese and obese groups during all phases of the study, and similar plasma insulin levels were achieved in both groups during euglycemic hyperinsulinemia. In obese men, C-peptide levels were significantly greater compared with non-obese men during euglycemic hyperinsulinemia (P < .05). However, neither the non-obese nor the obese group demonstrated significant suppression of insulin secretion rates during euglycemic hyperinsulinemia. Expressing the data in absolute terms or as a percent of basal did not alter the results. Moreover, there was no significant change between the non-obese and the obese group during the rapid onset and cessation of hyperinsulinemia. Under euglycemic conditions, physiologic hyperinsulinemia does not induce suppression of endogenous insulin secretion in non-obese or obese men.

Relationship of insulin secretory pulses to sex hormone-binding globulin in normal men.

Insulin has emerged as a regulator of sex hormone-binding globulin (SHBG) production in vitro and in vivo. A role for insulin in regulating SHBG exists in insulin resistant states such as obesity and polycystic ovary syndrome. The relationship of in vivo insulin secretion rates to SHBG levels in healthy normal men is less well documented. Hepatic synthesis of SHBG may be influenced by quantitative insulin exposure as well as qualitative characteristics such as frequency and amplitude of insulin secretory pulses. The present study was undertaken to assess these relationships in 10 normal men. Adiposity was determined by the body mass index and fat distribution by the waist hip ratio. Peripheral insulin sensitivity was determined by the euglycemic clamp technique at an insulin infusion rate of 287 pmol/min.m2. SHBG levels were determined in the fasting state by RIA. Arterialized venous samples for C-peptide were obtained every 2 min for 90 min in the basal state. Individual C-peptide kinetics were derived after a bolus injection of biosynthetic human C-peptide and a previously validated two compartmental model. Insulin secretion rates at each time point were calculated using the plasma C-peptide values and the C-peptide kinetics. Insulin secretion rates were unrelated to SHBG concentrations (r = -0.29, P > 0.05). The insulin secretory pulse interval had a significant positive association with SHBG levels (r = 0.86, P < 0.05). Insulin secretory pulse amplitude, body mass index, waist hip ratio, and peripheral insulin sensitivity were not associated with SHBG concentrations in a regression analysis. We postulate that insulin secretory pulse frequency may be an important determinant of SHBG synthesis in normal man.

Beta-cell hypersecretion and not reduced hepatic insulin extraction is the main cause of hyperinsulinemia in obese nondiabetic subjects.

Obesity is characterized by peripheral hyperinsulinemia, for which either beta-cell hypersecretion, diminished hepatic insulin extraction, or both may be responsible. To clarify this issue, we investigated insulin secretion and hormone hepatic extraction in 18 nondiabetic obese patients (body mass index [BMI], 39 +/- 1.3 kg/m2) and 18 healthy, lean control subjects (BMI, 21.3 +/- 0.7 kg/m2). Body fat distribution was calculated by measuring the waist to hip ratio (WHR). A highly reduced tissue insulin sensitivity (2.4 +/- 0.5 v 9.5 +/- 1.5 10(4).min-1/[microU/mL], P > .0005) and glucose effectiveness, ie, glucose's ability to stimulate its own disappearance at basal insulin (16 +/- 2 v 30 +/- 3 10(3).min-1, P > .005), were found in the overweight subjects compared with the controls. The basal (76 +/- 14 v 37 +/- 4 pmol/L/min) and total (377,848 +/- 5,562 v 16,864 +/- 1,850 pmol/L) prehepatic insulin secretion and the basal (15 +/- 2 v 7 +/- 0.7 pmol/L/min) and total (8,286 +/- 2,009 v 2,840 +/- 210 pmol/L) posthepatic insulin delivery were significantly higher in the overweight subjects compared with the controls (P < .005), whereas the mean hepatic insulin extraction did not differ (77.8% +/- 2.6% v 79.5% +/- 2.6%). A significant inverse correlation was found between the hepatic insulin extraction and the WHR (r = .5, P > .04), signifying the importance of fat distribution in insulin metabolism. The obese patients were subdivided into two subgroups according to their glucose tolerance; eight patients exhibited a normal tolerance and the remaining 10 were intolerant.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty-four hour C-peptide and insulin secretion rates and diurnal profiles of glucose, lipids and intermediary metabolites in cirrhosis.

1. To examine the contributions of hypersecretion and decreased insulin clearance to the hyperinsulinaemia of cirrhosis, insulin secretion was calculated over the day from serum C-peptide concentrations and C-peptide metabolic clearance rate. The latter was measured during infusions of recombinant human C-peptide. In cirrhotic patients (n = 9) insulin secretion rate was twice that of normal control subjects (n = 10), both in the basal state [02.00-07.00 hours, 15.7 +/- 2.1 (mean +/- SEM) nmol/h (2.6 +/- 0.4 units/h) versus 7.0 +/- 0.9 nmol/h (1.2 +/- 0.2 units/h), P < 0.002] and over 24 h [787 +/- 93 nmol (132 +/- 16 units) versus 346 +/- 34 nmol (58 +/- 6 units), P < 0.001]. However, the area under the serum insulin concentration curve was approximately six times greater in the cirrhotic patients (24 h basal, 6.3 +/- 1.0 versus 1.1 +/- 0.3 nmol l-1 h, P < 0.001; 24 h total, 21.7 +/- 3.2 versus 3.7 +/- 0.7 nmol l-1 h, P < 0.001). Thus, despite impairment of insulin clearance there is continuing hypersecretion of insulin in cirrhosis. 2. The relationship of carbohydrate and lipid metabolism with insulin secretion was assessed. In cirrhotic patients, 24 h blood glucose profiles showed a worsening of glucose tolerance over breakfast, despite greater insulin secretion compared with other meals, suggesting that the insulin insensitivity of cirrhosis is worse at this time. 3. Cirrhotic patients showed impaired suppression of blood glycerol levels after meals but normal suppression of serum non-esterified fatty acid concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal and splanchnic exchange of human biosynthetic C-peptide in type 1 (insulin-dependent) diabetes mellitus.

Biosynthetic human C-peptide or NaCl (154 mmol.l-1) was given intravenously to 13 Type 1 (insulin-dependent) diabetic patients to determine the renal and splanchnic exchange of C-peptide. Catheters were inserted percutaneously into an artery and a renal and hepatic vein. Infusions of C-peptide were given for 60 min at two dose levels (5 and 30 pmol.kg-1.min-1). Insulin was infused throughout the study (0.5 mU.kg-1.min-1) and plasma glucose was kept constant by a variable glucose infusion. The regional blood flows were measured by indicator dilution techniques. In 11 of the 13 patients basal C-peptide levels were not detectable. The arterial steady-state C-peptide concentration was 0.81 +/- 0.10 nmol.l-1 and 2.33 +/- 0.30 nmol.l-1 at the low and high rate infusions, respectively. Renal uptake was 124 +/- 18 pmol.min-1 at the low infusion corresponding to 39% of the infused amount. At the higher dose C-peptide infusion renal uptake increased to 155 +/- 21 pmol.min-1 (p less than 0.05). Urinary excretion of C-peptide was 7 +/- 2 pmol.min-1 at the low dose infusion and increased to 34 +/- 6 pmol.min-1 at the high dose infusion (p less than 0.01). The proportions of infused amount excreted were fairly constant and between 2% and 3%. No net exchange of C-peptide was found across the splanchnic vascular bed. The rate of glucose infusion had to be increased by 35% during the low dose C-peptide, but not during NaCl infusion in order to maintain a constant plasma glucose concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of weight loss and reduced hyperglycemia on the kinetics of insulin secretion in obese non-insulin dependent diabetes mellitus.

Impairment in pancreatic production of insulin, a cardinal feature of noninsulin dependent diabetes mellitus (NIDDM), was quantified and the kinetics of insulin secretion characterized in six obese individuals with NIDDM before and after weight loss (18.0 +/- 3.0 kg, mean +/- SEM) using a validated mathematical model that employs C-peptide as a marker of the in vivo rate of insulin secretion. The metabolic clearance of C-peptide, assessed by decay analysis after bolus injection of biosynthetic human C-peptide, was not changed by weight loss (0.143 +/- 0.009 L/min.m2 vs. 0.137 +/- 0.010 L/min.m2). Kinetic parameters from each individual's decay curve before and after weight loss were used to derive accurate rates of secretion during the basal (postabsorptive) state, an oral glucose tolerance test and two hyperglycemic clamps. Basal rates of insulin secretion declined 20 +/- 5 pmol/min.m2 (96 +/- 15 to 76 +/- 15 pmol/min.m2, P less than 0.05) concomitant with decreases of 6.9 +/- 0.9 mmol/L in fasting serum glucose (13.7 +/- 1.0 to 6.8 +/- 0.7 mmol/L, P less than 0.05), 60 +/- 14 pmol/L in serum insulin (134 +/- 30 to 74 +/- 15 pmol/L, P less than 0.05), and 0.15 +/- 0.03 pmol/ml in plasma C-peptide (0.67 +/- 0.11 to 0.52 +/- 0.08 pmol/ml, P less than 0.05) concentrations. As expected, weight loss resulted in improved glucose tolerance as measured by the glycemic profiles during the oral glucose tolerance test (P less than 0.05 analysis of variance). The insulin secretory response before weight loss showed a markedly reduced ability to respond appropriately to an increase in the ambient serum glucose. After weight loss, the pancreatic response was more dynamic (P less than 0.05, analysis of variance) and parralleled the moment-to-moment changes in glycemia. Insulin production above basal doubled (11.2 +/- 3.2 to 24.5 +/- 5.8 nmol/6h.m2, P less than 0.05) and peak rates of insulin secretion above basal tripled (55 +/- 16 to 157 +/- 32 pmol/min/m2, P less than 0.05). To assess the beta-cell response to glucose per se and the changes associated with weight reduction, two hyperglycemic clamps were performed at steady state glucose levels in the range characteristic of individuals with severe NIDDM. At a fixed glycemia of 20 mmol/L, average rates of insulin secretion increased almost 2-fold with treatment (161 +/- 41 to 277 +/- 60 pmol/min.m2, P less than 0.05). At an increment of 6 mmol/L glucose above prevailing fasting glucose levels, the average rate of insulin secretion increased 53% (120 +/- 21 to 183 +/- 39 pmol/min.m2, P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Oscillations in insulin secretion during constant glucose infusion in normal man: relationship to changes in plasma glucose.

Peripheral plasma or serum concentrations of glucose, insulin, C-peptide, glucagon, and cortisol and insulin secretory rates (ISR) were determined at 15-min intervals in eight normal subjects during a constant iv infusion of 4.5 mg glucose/kg.min for a 24-h period. During each sampling interval, the secretory rate of insulin was calculated by deconvolution of the peripheral plasma C-peptide concentration using C-peptide kinetic parameters derived after bolus injections of C-peptide in individual subjects. Periodogram analysis of the individual glucose curves demonstrated a circadian rhythm in all subjects, with a major nocturnal acrophase occurring at an average clock time of 0228 h (range, 0045-0350 h). In five of the eight subjects, a minor acrophase occurred at an average time of 1774 h (range, 1530-2045 h). This diurnal variation in plasma glucose levels was not paralleled by a similar pattern in insulin secretion. Although glucose was infused at a constant rate, significant pulses were found in glucose, insulin, and C-peptide levels and ISR; the pulse durations of these parameters were 182 +/- 30 (+/- SE), 89 +/- 5, 100 +/- 8, and 85 +/- 5 min, respectively, and their periodicities were 208 +/- 33, 106 +/- 7, 114 +/- 10, and 106 +/- 7 min. The durations and frequencies for pulses of insulin, C-peptide, and ISR were not significantly different, whereas glucose pulses had a longer duration and were less frequent (P less than 0.05, by analysis of variance). On the average, 54 +/- 9% of the C-peptide pulses and 47 +/- 8% of the ISR pulses were concomitant with a pulse in glucose levels. Moreover, approximately half of the C-peptide and ISR pulses that were not concomitant with a glucose pulse occurred in synchrony with a shoulder on the up-stroke or down-stroke of glucose pulses. Analysis of glucagon and cortisol profiles revealed no significant associations with the insulin and glucose oscillations. In conclusion, during a constant glucose infusion in normal subjects, regular oscillations of insulin secretion occur at 80- to 120-min intervals. Their tight coupling with glucose oscillations and the lack of association with fluctuations of glucagon and cortisol suggest that these oscillations represent a dynamic property of the insulin-glucose feedback loop.