Insulin Secretion Rate Research Articles

Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients

To quantitate the separate impact of obesity and hyperglycemia on the incretin effect (i.e., the gain in beta-cell function after oral glucose versus intravenous glucose). Isoglycemic oral (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20-61 kg/m(2)). C-peptide deconvolution was used to reconstruct insulin secretion rates, and beta-cell glucose sensitivity (slope of the insulin secretion/glucose concentration dose-response curve) was determined by mathematical modeling. The incretin effect was defined as the oral-to-intravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique. The incretin effect on total insulin secretion and beta-cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P <or= 0.05). The results were similar when subjects were stratified by BMI tertile (P <or= 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r = 0.27-0.59, P <or= 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r = 0.53, P < 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients. Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another.

Glucose Intolerance Associated to Insulin Resistance and Increased Insulin Secretion in Rats Depleted in Long-chain ω3 Fatty Acids

An intragastric D-glucose tolerance test was performed, after overnight starvation, in female rats depleted in long-chain polyunsaturated omega3 fatty acids (omega3D rats) and control rats of same age and gender. The plasma D-glucose and insulin concentrations, insulinogenic index, and HOMA for insulin resistance were all higher, after overnight starvation, in omega3D rats than in control animals. Over the 120-minute period following the intragastric administration of D-glucose, the area under the curve for the same four variables was also higher in omega3D rats than in control animals. In addition to visceral obesity, liver steatosis, hypertension, and cardiac hypertrophy, the omega3D rats thus display further features of the metabolic syndrome, namely glucose intolerance and insulin resistance, despite hyperinsulinemia.

Effects of the Dipeptidyl Peptidase-IV Inhibitor Vildagliptin on Incretin Hormones, Islet Function, and Postprandial Glycemia in Subjects With Impaired Glucose Tolerance

This study was conducted to determine the effects of vildagliptin on incretin hormone levels, islet function, and postprandial glucose control in subjects with impaired glucose tolerance (IGT). A 12-week, double-blind, randomized, parallel-group study comparing vildagliptin (50 mg q.d.) and placebo was conducted in 179 subjects with IGT (2-h glucose 9.1 mmol/l, A1C 5.9%). Plasma levels of intact glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), glucose, insulin, C-peptide, and glucagon were measured during standard meal tests performed at baseline and at week 12. Insulin secretory rate (ISR) was estimated by C-peptide deconvolution. The between-group differences (vildagliptin - placebo) in the adjusted mean changes from baseline to end point in the total and incremental (Delta) area under the curve (AUC)(0-2 h) for these analytes were assessed by ANCOVA; glucose AUC(0-2 h) was the primary outcome variable. Relative to placebo, vildagliptin increased GLP-1 (DeltaAUC, +6.0 +/- 1.2 pmol x l(-1) x h(-1), P < 0.001) and GIP (DeltaAUC, +46.8 +/- 5.4 pmol . l(-1) x h(-1), P < 0.001) and decreased glucagon (DeltaAUC, -3.0 +/- 1.0 pmol x l(-1) x h(-1), P = 0.003). Although postprandial insulin levels were unaffected (DeltaAUC, +20.8 +/- 35.7 pmol x l(-1) x h(-1), P = 0.561), prandial glucose excursions were reduced (DeltaAUC, -1.0 +/- 0.3 mmol x l(-1) x h(-1), P < 0.001), representing an approximately 30% decrease relative to placebo. Beta-cell function as assessed by the ISR AUC(0-2 h)/glucose AUC(0-2 h) was significantly increased (+6.4 +/- 2.0 pmol x min(-1) x m(-2) x mmol x l(-1), P = 0.002). Adverse event profiles were similar in the two treatment groups, and no hypoglycemia was reported. The known effects of vildagliptin on incretin levels and islet function in type 2 diabetes were reproduced in subjects with IGT, with a 32% reduction in postprandial glucose excursions and no evidence of hypoglycemia or weight gain.

Characterization of the Influence of Vildagliptin on Model-Assessed β-Cell Function in Patients with Type 2 Diabetes and Mild Hyperglycemia

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

Comparison of the effect of multiple short-duration with single long-duration exercise sessions on glucose homeostasis in type 2 diabetes mellitus

We evaluated and compared the effects on glycaemic control of two different exercise protocols in elderly men with type 2 diabetes mellitus. Eighteen patients with type 2 diabetes mellitus carried out home-based bicycle training for 5 weeks. Patients were randomly assigned to one of two training programmes at 60% of maximal oxygen uptake: three 10 min sessions per day (3 x 10) or one 30 min session per day (1 x 30). Plasma insulin, C-peptide and glucose concentrations were measured during a 3 h oral glucose tolerance test (OGTT). Insulin sensitivity index (ISI(composite)), pre-hepatic insulin secretion rates (ISR) and change in insulin secretion per unit change in glucose concentrations (B(total)) were calculated. Cardiorespiratory fitness increased in response to training in both groups. In group 3 x 10 (n = 9) fasting plasma glucose (p = 0.01), 120 min glucose OGTT (p = 0.04) and plasma glucose concentration areas under the curve at 120 min (p < 0.04) and 180 min (p = 0.07) decreased. These parameters remained unchanged in group 1 x 30 (n = 9). No significant changes were found in ISI(composite), ISR and B(total) in either of the exercise groups. In a matched time-control group (n = 10), glycaemic control did not change. Moderate to high-intensity training performed at 3 x 10 min/day is preferable to 1 x 30 min/day with regard to effects on glycaemic control. This is in spite of the fact that cardiorespiratory fitness increased similarly in both exercise groups. A possible explanation is that the energy expenditure associated with multiple short daily sessions may be greater than that in a single daily session.

The DPP‐4 inhibitor vildagliptin: robust glycaemic control in type 2 diabetes and beyond

Vildagliptin is a potent selective inhibitor of dipeptidyl peptidase-4 (DPP-4) that improves glycaemic control by increasing islet alpha-cell and beta-cell responsiveness to glucose. In patients with type 2 diabetes mellitus (T2DM), vildagliptin improves beta-cell function, measured as insulin secretory rate relative to glucose level, and reduces glucagon secretion and endogenous glucose production in the postprandial period, resulting in reduced glucose levels. In clinical trials in T2DM, vildagliptin 100 mg/day monotherapy is effective in reducing haemoglobin A1c (HbA1c) across the spectrum of hyperglycaemia and has maintained efficacy over long-term treatment with neutral effects on body weight and lipids. Vildagliptin is associated with a low risk of hypoglycaemia, and has an adverse event profile comparable to placebo, including a reduced rate of gastrointestinal adverse effects compared with metformin and a reduced rate of oedema compared with rosiglitazone. As add-on combination therapy, vildagliptin produces significant further reductions in HbA1c in patients receiving metformin, pioglitazone, glimepiride and insulin, and has been found to reduce frequency of hypoglycaemia as an add-on to insulin. Preliminary findings indicate that the improved islet cell function underlying the efficacy of vildagliptin in T2DM is also observed in patients with impaired glucose tolerance, with vildagliptin treatment resulting in reduced glycaemic excursions. The overall profile of vildagliptin and the preliminary evidence of beneficial effects in the prediabetic state suggest that DPP-4 inhibition could be an effective strategy to prevent or delay progression from the prediabetic state to overt T2DM.

Symptomatic hypoglycemia during imatinib mesylate in a non-diabetic female patient with gastrointestinal stromal tumor

Imatinib mesylate is a selective competitive inhibitor of the bcr-abl tyrosine kinase and c-KIT. Other kinases, such as phosphatidylinositol- 3'-kinase (PI-3K) involved in insulin signaling, have also been shown to be indirectly affected by imatinib. A recent report described a lowering of blood glucose levels in Type 2 diabetic patients treated with imatinib resulting in a reduction of oral antidiabetic medication or insulin dosage. We present a female non-diabetic patient with a resected gastrointestinal stromal tumor with an increased insulin response following an oral glucose challenge and hypoglycemic episodes following imatinib therapy. In addition to a rise in insulin sensitivity, the patient showed inappropriately high insulin secretion rates in relation to the actual blood glucose concentrations during and after the completion of imatinib treatment. The symptoms suggestive of hypoglycemia such as dizziness and shivering formerly observed in patients treated with imatinib may be related to hypoglycemic glucose concentrations. Physicians treating patients with imatinib should be aware of the possible occurrence of hypoglycemic episodes in non-diabetic patients.

An adenylate kinase is involved in KATP channel regulation of mouse pancreatic beta cells

In a previous study, we demonstrated that a creatine kinase (CK) modulates K(ATP) channel activity in pancreatic beta cells. To explore phosphotransfer signalling pathways in more detail, we examined whether K(ATP) channel regulation in beta cells is determined by a metabolic interaction between adenylate kinase (AK) and CK. Single channel activity was measured with the patch-clamp technique in the inside-out (i/o) and open-cell attached (oca) configuration. The ATP sensitivity of K(ATP) channels was higher in i/o patches than in permeabilised beta cells (oca). One reason for this observation could be that the local ATP:ADP ratio in the proximity of the channels is determined by factors not active in i/o patches. AMP (0.1 mmol/l) clearly increased open channel probability in the presence of ATP (0.125 mmol/l) in permeabilised cells but not in excised patches. This suggests that AK-catalysed ADP production in the vicinity of the channels is involved in K(ATP) channel regulation. The observation that the stimulatory effect of AMP on K(ATP) channels was prevented by the AK inhibitor P (1),P (5)-di(adenosine-5')pentaphosphate (Ap(5)A; 20 micromol/l) and abolished in the presence of the non-metabolisable ATP analogue adenosine 5'-(beta,gamma-imido)triphosphate tetralithium salt (AMP-PNP; 0.12 mmol/l) strengthens this idea. In beta cells from AK1 knockout mice, the effect of AMP was less pronounced, though not completely suppressed. The increase in K(ATP) channel activity induced by AMP in the presence of ATP was outweighed by phosphocreatine (1 mmol/l). We suggest that this is due to an elevation of the ATP concentration by CK. We propose that phosphotransfer events mediated by AK and CK play an important role in determining the effective concentrations of ATP and ADP in the microenvironment of pancreatic beta cell K(ATP) channels. Thus, these enzymes determine the open probability of K(ATP) channels and eventually the actual rate of insulin secretion.

Pancreatic Insulin Secretion in Rats Fed a Soy Protein High Fat Diet Depends on the Interaction between the Amino Acid Pattern and Isoflavones

Obesity is frequently associated with the consumption of high carbohydrate/fat diets leading to hyperinsulinemia. We have demonstrated that soy protein (SP) reduces hyperinsulinemia, but it is unclear by which mechanism. Thus, the purpose of the present work was to establish whether SP stimulates insulin secretion to a lower extent and/or reduces insulin resistance, and to understand its molecular mechanism of action in pancreatic islets of rats with diet-induced obesity. Long-term consumption of SP in a high fat (HF) diet significantly decreased serum glucose, free fatty acids, leptin, and the insulin:glucagon ratio compared with animals fed a casein HF diet. Hyperglycemic clamps indicated that SP stimulated insulin secretion to a lower extent despite HF consumption. Furthermore, there was lower pancreatic islet area and insulin, SREBP-1, PPARgamma, and GLUT-2 mRNA abundance in comparison with rats fed the casein HF diet. Euglycemic-hyperinsulinemic clamps showed that the SP diet prevented insulin resistance despite consumption of a HF diet. Incubation of pancreatic islets with isoflavones reduced insulin secretion and expression of PPARgamma. Addition of amino acids resembling the plasma concentration of rats fed casein stimulated insulin secretion; a response that was reduced by the presence of isoflavones, whereas the amino acid pattern resembling the plasma concentration of rats fed SP barely stimulated insulin release. Infusion of isoflavones during the hyperglycemic clamps did not stimulate insulin secretion. Therefore, isoflavones as well as the amino acid pattern seen after SP consumption stimulated insulin secretion to a lower extent, decreasing PPARgamma, GLUT-2, and SREBP-1 expression, and ameliorating hyperinsulinemia observed during obesity.

A matlab framework for estimation of NLME models using stochastic differential equations

The non-linear mixed-effects model based on stochastic differential equations (SDEs) provides an attractive residual error model, that is able to handle serially correlated residuals typically arising from structural mis-specification of the true underlying model. The use of SDEs also opens up for new tools for model development and easily allows for tracking of unknown inputs and parameters over time. An algorithm for maximum likelihood estimation of the model has earlier been proposed, and the present paper presents the first general implementation of this algorithm. The implementation is done in Matlab and also demonstrates the use of parallel computing for improved estimation times. The use of the implementation is illustrated by two examples of application which focus on the ability of the model to estimate unknown inputs facilitated by the extension to SDEs. The first application is a deconvolution-type estimation of the insulin secretion rate based on a linear two-compartment model for C-peptide measurements. In the second application the model is extended to also give an estimate of the time varying liver extraction based on both C-peptide and insulin measurements.

Impaired proinsulin secretion before and during oral glucose stimulation in HIV-infected patients who display fat redistribution

The beta-cell function of HIV-infected patients on highly active antiretroviral therapy who display lipodystrophy may be impaired. An early defect in beta-cell function may be characterized by an increase in secretion of 32-33 split proinsulin (SP) and intact proinsulin (IP). To address this issue, the secretion patterns of SP and IP of 16 HIV-infected men with lipodystrophy (LIPO) and 15 HIV-infected men without lipodystrophy (NONLIPO) were studied during an oral glucose tolerance test (OGTT). All patients received highly active antiretroviral therapy. Insulin secretion rates were determined by deconvolution of plasma C-peptide concentrations. More LIPO than NONLIPO patients displayed diabetes mellitus and impaired glucose tolerance than normal glucose tolerance (LIPO 2/8/6 vs NONLIPO 1/2/12, P = .05). LIPO patients had increased fasting levels of SP and IP, ratio of SP/IP, and area under the curve of SP and IP during the early phase (0, 10, and 20 minutes) and during the late phase (45, 75, and 105 minutes) of the OGTT compared with NONLIPO patients ( Ps < .05). LIPO patients exhibited significantly increased fasting SP/IP ratio, fasting SP/insulin ratio, and total proinsulin to C-peptide ratio during the OGTT. LIPO patients displayed increased incremental secretion of IP during the first 10 minutes of the OGTT ( P < .05), although the incremental insulin secretion during this period did not differ between LIPO and NONLIPO patients. These data suggest that HIV-infected patients with lipodystrophy display major perturbations of proinsulin secretion in the fasting state and during an OGTT, which is compatible with the notion of a beta-cell dysfunction of such patients.

Effects of supraphysiologic concentration glucose on pancreatic duodenal homeobox-1 expression and insulin secretion in rats

Effects of supraphysiologic concentration glucose on pancreatic duodenal homeobox-1 expression and insulin secretion in rats

Glucose-Dependent Modulation of Insulin Secretion and Intracellular Calcium Ions by GKA50, a Glucokinase Activator

Because glucokinase is a metabolic sensor involved in the regulated release of insulin, we have investigated the acute actions of novel glucokinase activator compound 50 (GKA50) on islet function. Insulin secretion was determined by enzyme-linked immunosorbent assay, and microfluorimetry with fura-2 was used to examine intracellular Ca(2+) homeostasis ([Ca(2+)](i)) in isolated mouse, rat, and human islets of Langerhans and in the MIN6 insulin-secreting mouse cell line. In rodent islets and MIN6 cells, 1 micromol/l GKA50 was found to stimulate insulin secretion and raise [Ca(2+)](i) in the presence of glucose (2-10 mmol/l). Similar effects on insulin release were also seen in isolated human islets. GKA50 (1 micromol/l) caused a leftward shift in the glucose-concentration response profiles, and the half-maximal effective concentration (EC(50)) values for glucose were shifted by 3 mmol/l in rat islets and approximately 10 mmol/l in MIN6 cells. There was no significant effect of GKA50 on the maximal rates of glucose-stimulated insulin secretion. In the absence of glucose, GKA50 failed to elevate [Ca(2+)](i) (1 micromol/l GKA50) or to stimulate insulin release (30 nmol/l-10 micromol/l GKA50). At 5 mmol/l glucose, the EC(50) for GKA50 in MIN6 cells was approximately 0.3 micromol/l. Inhibition of glucokinase with mannoheptulose or 5-thioglucose selectively inhibited the action of GKA50 on insulin release but not the effects of tolbutamide. Similarly, 3-methoxyglucose prevented GKA50-induced rises in [Ca(2+)](i) but not the actions of tolbutamide. Finally, the ATP-sensitive K(+) channel agonist diazoxide (200 micromol/l) inhibited GKA50-induced insulin release and its elevation of [Ca(2+)](i.) We show that GKA50 is a glucose-like activator of beta-cell metabolism in rodent and human islets and a Ca(2+)-dependent modulator of insulin secretion.

NEFA-glucose comodulation model of β-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.

Human Insulin Vesicle Dynamics During Pulsatile Secretion

In healthy individuals, plasma insulin levels oscillate in both fasting and fed states. Numerous studies of isolated pancreata and pancreatic islets support the hypothesis that insulin oscillations arise because the underlying rate of insulin secretion also oscillates; yet, insulin secretion has never been observed to oscillate in individual pancreatic beta-cells. Using expressed fluorescent vesicle cargo proteins and total internal reflection fluorescence (TIRF) microscopy, we demonstrate that glucose stimulates human pancreatic beta-cells to secrete insulin vesicles in short, coordinated bursts of approximately 70 vesicles each. Randomization tests and spectral analysis confirmed that the temporal patterns of secretion were not random, instead exhibiting alternating periods of secretion and rest, recurring with statistically significant periods of 15-45 s. Although fluorescent vesicles arrived at the plasma membrane before, during, and after stimulation, their rate of arrival was significantly slower than their rate of secretion, so that their density near the plasma membrane dropped significantly during the cell's response. To study in greater detail the vesicle dynamics during cyclical bursts of secretion, we applied trains of depolarizations once a minute and performed simultaneous membrane capacitance measurements and TIRF imaging. Surprisingly, young fluorescent insulin vesicles contributed at least half of the vesicles secreted in response to a first train, even though young vesicles were vastly outnumbered by older, nonfluorescent vesicles. For subsequent trains, young insulin vesicles contributed progressively less to total secretion, whereas capacitance measurements revealed that total stimulated secretion did not decrease. These results suggest that in human pancreatic beta-cells, young vesicles are secreted first, and only then are older vesicles recruited for secretion.

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.

Protein restriction during lactation alters the autonomic nervous system control on glucose-induced insulin secretion in adult rats

Involvement of autonomic nervous system (ANS) neurotransmitters on insulin secretion in rats submitted to protein malnutrition during lactation was studied. During the first 2/3 of lactation, mothers received a 4% protein diet (LP). Control group received normal diet (23% protein) (NP). After protein restriction, mothers received normal diets. At 81 days rats were submitted to intravenous glucose tolerance tests (ivGTT). Plasma glucose and insulin concentration (PIC) were measured. Glucose-induced insulin secretion (GIIS) was tested in pancreatic islets. Fasting normoglycemia and hypoinsulinemia were observed in LP rats. Glucose intolerance and low PIC in LP group were detected during ivGTT. Acetylcholine (Ach) or blockage of α-adrenoceptors induced high PIC increment in LP rats; atropine or stimulation of α-adrenoceptors did not change PIC. Insulin secretion of LP rat islets showed low glucose and carbachol responses. Epinephrine-inhibited GIIS in both islet groups. Hypoinsulinemia observed in lactation-malnourished rats might be caused by alterations in GIIS regulation, including ANS modulation.

The Dipeptidyl Peptidase IV Inhibitor Vildagliptin Suppresses Endogenous Glucose Production and Enhances Islet Function after Single-Dose Administration in Type 2 Diabetic Patients

Vildagliptin is a selective dipeptidyl peptidase IV inhibitor that augments meal-stimulated levels of biologically active glucagon-like peptide-1. Chronic vildagliptin treatment decreases postprandial glucose levels and reduces hemoglobin A1c in type 2 diabetic patients. However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration. Sixteen patients with type 2 diabetes (age, 48+/-3 yr; body mass index, 34.4+/-1.7 kg/m2; hemoglobin A1c, 9.0+/-0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-(3)H-glucose iv and 1-(14)C-glucose orally). After vildagliptin, suppression of endogenous glucose production (EGP) during 6-h MTT was greater than with placebo (1.02+/-0.06 vs. 0.74+/-0.06 mg.kg-1.min-1; P=0.004), and insulin secretion rate increased by 21% (P=0.003) despite significant reduction in mean plasma glucose (213+/-4 vs. 230+/-4 mg/dl; P=0.006). Consequently, insulin secretion rate (area under the curve) divided by plasma glucose (area under the curve) increased by 29% (P=0.01). Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin (P<0.02). The decline in EGP was positively correlated (r=0.55; P<0.03) with the decrease in fasting plasma glucose (change=-14 mg/dl). During MTT, vildagliptin augments insulin secretion and inhibits glucagon release, leading to enhanced suppression of EGP. During the postprandial period, a single dose of vildagliptin reduced plasma glucose levels by enhancing suppression of EGP.

C-peptide: a redundant relative of insulin?

Historically, focus on C-peptide has been relegated to the exploitation of its peculiar pharmacokinetics (i.e. distribution and elimination) to derive accurate assessment of beta cell secretion, whereas, more recently, greater interest has been placed on its pharmacodynamics (i.e. the biological actions it exerts). In the present paper we will address the latter subject, but to put things in perspective—and because it is well known that kinetics and the time course of dynamics are intimately linked—we will begin with a brief overview of the kinetic properties of C-peptide. C-peptide is stored together with insulin in the mature granules within the beta cell. It is secreted intraportally with insulin, on an equimolar basis, and shows the characteristic biphasic shape in response to i.v. challenges [1, 2]. Whereas newly secreted insulin undergoes a large (∼50%) hepatic extraction [3], the rate of which probably varies, all of the released C-peptide reaches the peripheral circulation without appreciable extraction by the liver. For this reason, C-peptide has proven to be a fundamental tool for accurate quantification of beta cell secretion. In fact, with the aid of kinetic modelling and deconvolution (the so-called Eaton– Polonsky approach [4, 5]), C-peptide levels can be used to provide a reliable measure of the insulin secretory rate. To estimate C-peptide secretion by deconvolution, knowledge of C-peptide kinetics is required. C-peptide kinetics are usually determined by analysing the C-peptide decay curve following a bolus injection of biosynthetic C-peptide. Polonsky described the kinetics of peripherally administered biosynthetic human C-peptide in terms of a linear, two-compartment model. The half-life of C-peptide has been shown to be relatively slow (approximately 35 min), and glomerular filtration is the major route of its removal. The slow metabolism of C-peptide is consistent with the hypothesis that C-peptide diffuses into the extracellular space, but is not integrated into cell membranes. In contrast, insulin is rapidly removed from the circulation (half-life approximately 5 min) via insulin receptor-mediated uptake followed by lysosomal degradation. In terms of its biological action, C-peptide has been long believed to be biologically inert, a sort of useless byproduct of insulin. In recent years, several intracellular effects of C-peptide have been described in vitro, and some in vivo studies have shown that C-peptide has an effect on clinical manifestations of diabetes complications (mainly in the short term). Such biological effects have been reviewed in the companion paper by Wahren et al. [6]. The key point of our argument is not whether C-peptide does or does not have a biological effect (this has been already proven beyond any reasonable doubt), but whether such a biological effect is actually relevant and can be profitably exploited to improve the health of diabetic patients by fending off the complications associated with diabetes. The crucial question is: Are the in vitro and in vivo data sufficient to consider C-peptide an endogenous molecule with a distinct physiology that makes it a suitable addition to the arsenal of therapeutic agents available to the clinician? In our opinion, this is not the case. We believe that C-peptide is neither the ‘shavings of the carpenter’s Diabetologia (2007) 50:500–502 DOI 10.1007/s00125-006-0576-x

A dominant role for glucose in β cell compensation of insulin resistance

Increased insulin secretion and expansion of pancreatic beta cell mass work together to maintain normal glucose levels when insulin resistance develops. Changes in glucose concentration have long been known to have profound effects upon the rates of insulin secretion and beta cell mass, but various other agents can also cause changes, raising questions about which mechanisms are dominant. Evidence favoring a dominant role for glucose is provided by Terauchi et al. in this issue of the JCI (see the related article beginning on page 246). Mice haploinsufficient for beta cell glucokinase (Gck) were unable to increase their beta cell mass in response to insulin resistance produced by high-fat feeding. Gck is known to be the glucose sensor for glucose metabolism in beta cells. The study also provides strong evidence that insulin receptor substrate 2 (Irs2), which is known to have major effects on beta cell growth and survival, is a key downstream mediator of the effects of glucose found in this study.