Changes In Glucose-stimulated Insulin Secretion Research Articles

Metallothionein 1 negatively regulates glucose-stimulated insulin secretion and is differentially expressed in conditions of beta cell compensation and failure in mice and humans.

The mechanisms responsible for beta cell compensation in obesity and for beta cell failure in type 2 diabetes are poorly defined. The mRNA levels of several metallothionein (MT) genes are upregulated in islets from individuals with type 2 diabetes, but their role in beta cells is not clear. Here we examined: (1) the temporal changes of islet Mt1 and Mt2 gene expression in mouse models of beta cell compensation and failure; and (2) the role of Mt1 and Mt2 in beta cell function and glucose homeostasis in mice. Mt1 and Mt2 expression was assessed in islets from: (1) control lean (chow diet-fed) and diet-induced obese (high-fat diet-fed for 6weeks) mice; (2) mouse models of diabetes (db/db mice) at 6weeks old (prediabetes) and 16weeks old (after diabetes onset) and age-matched db/+ (control) mice; and (3) obese non-diabetic ob/ob mice (16-week-old) and age-matched ob/+ (control) mice. MT1E, MT1X and MT2A expression was assessed in islets from humans with and without type 2 diabetes. Mt1-Mt2 double-knockout (KO) mice, transgenic mice overexpressing Mt1 under the control of its natural promoter (Tg-Mt1) and corresponding control mice were also studied. In MIN6 cells, MT1 and MT2 were inhibited by small interfering RNAs. mRNA levels were assessed by real-time RT-PCR, plasma insulin and islet MT levels by ELISA, glucose tolerance by i.p. glucose tolerance tests and overnight fasting-1h refeeding tests, insulin tolerance by i.p. insulin tolerance tests, insulin secretion by RIA, cytosolic free Ca2+ concentration with Fura-2 leakage resistant (Fura-2 LR), cytosolic free Zn2+ concentration with Fluozin-3, and NAD(P)H by autofluorescence. Mt1 and Mt2 mRNA levels were reduced in islets of murine models of beta cell compensation, whereas they were increased in diabetic db/db mice. In humans, MT1X mRNA levels were significantly upregulated in islets from individuals with type 2 diabetes in comparison with non-diabetic donors, while MT1E and MT2A mRNA levels were unchanged. Ex vivo, islet Mt1 and Mt2 mRNA and MT1 and MT2 protein levels were downregulated after culture with glucose at 10-30mmol/l vs 2-5mmol/l, in association with increased insulin secretion. In human islets, mRNA levels of MT1E, MT1X and MT2A were downregulated by stimulation with physiological and supraphysiological levels of glucose. In comparison with wild-type (WT) mice, Mt1-Mt2 double-KO mice displayed improved glucose tolerance in association with increased insulin levels and enhanced insulin release from isolated islets. In contrast, isolated islets from Tg-Mt1 mice displayed impaired glucose-stimulated insulin secretion (GSIS). In both Mt1-Mt2 double-KO and Tg-Mt1 models, the changes in GSIS occurred despite similar islet insulin content, rises in cytosolic free Ca2+ concentration and NAD(P)H levels, or intracellular Zn2+ concentration vs WT mice. In MIN6 cells, knockdown of MT1 but not MT2 potentiated GSIS, suggesting that Mt1 rather than Mt2 affects beta cell function. These findings implicate Mt1 as a negative regulator of insulin secretion. The downregulation of Mt1 is associated with beta cell compensation in obesity, whereas increased Mt1 accompanies beta cell failure and type 2 diabetes.

Exercise Intensity Modulates Glucose-Stimulated Insulin Secretion when Adjusted for Adipose, Liver and Skeletal Muscle Insulin Resistance.

Little is known about the effects of exercise intensity on compensatory changes in glucose-stimulated insulin secretion (GSIS) when adjusted for adipose, liver and skeletal muscle insulin resistance (IR). Fifteen participants (8F, Age: 49.9±3.6yr; BMI: 31.0±1.5kg/m2; VO2peak: 23.2±1.2mg/kg/min) with prediabetes (ADA criteria, 75g OGTT and/or HbA1c) underwent a time-course matched Control, and isocaloric (200kcal) exercise at moderate (MIE; at lactate threshold (LT)), and high-intensity (HIE; 75% of difference between LT and VO2peak). A 75g OGTT was conducted 1 hour post-exercise/Control, and plasma glucose, insulin, C-peptide and free fatty acids were determined for calculations of skeletal muscle (1/Oral Minimal Model; SMIR), hepatic (HOMAIR), and adipose (ADIPOSEIR) IR. Insulin secretion rates were determined by deconvolution modeling for GSIS, and disposition index (DI; GSIS/IR; DISMIR, DIHOMAIR, DIADIPOSEIR) calculations. Compared to Control, exercise lowered SMIR independent of intensity (P<0.05), with HIE raising HOMAIR and ADIPOSEIR compared with Control (P<0.05). GSIS was not reduced following exercise, but DIHOMAIR and DIADIPOSEIR were lowered more following HIE compared with Control (P<0.05). However, DISMIR increased in an intensity based manner relative to Control (P<0.05), which corresponded with lower post-prandial blood glucose levels. Taken together, pancreatic insulin secretion adjusts in an exercise intensity dependent manner to match the level of insulin resistance in skeletal muscle, liver and adipose tissue. Further work is warranted to understand the mechanism by which exercise influences the cross-talk between tissues that regulate blood glucose in people with prediabetes.

Acute but not chronic activation of brain glucagon-like peptide-1 receptors enhances glucose-stimulated insulin secretion in mice.

To investigate the role of brain glucagon-like peptide-1 (GLP-1) in pancreatic β-cell function. To determine the role of brain GLP-1 receptor (GLP-1R) on β-cell function, we administered intracerebroventricular (i.c.v.) infusions of GLP-1 or the specific GLP-1 antagonist exendin-9 (Ex-9), in both an acute and a chronic setting. We observed that acute i.c.v. GLP-1 infusion potentiates glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance, whereas central GLP-1R blockade with Ex-9 impaired glucose excursion after a glucose load. Sustained activation of central nervous system GLP-1R, however, did not produce any effect on either GSIS or glucose tolerance. Similarly, ex vivo GSIS performed in islets from mice chronically infused with i.c.v. GLP-1 resulted in no differences compared with controls. In addition, in mice fed a high-fat diet we observed that acute i.c.v. GLP-1 infusion improved glucose tolerance without changes in GSIS, while chronic GLP-1R activation had no effect on glucose homeostasis. Our results indicate that, under non-clamped conditions, brain GLP-1 plays a functional neuroendocrine role in the acute regulation of glucose homeostasis in both lean and obese rodents.

Longitudinal changes in insulin sensitivity, insulin secretion, beta cell function and glucose effectiveness during development of non-diabetic hyperglycemia in a Japanese population.

Since there had been no previous studies of alterations in insulin sensitivity, glucose-stimulated insulin secretion, beta cell function and glucose effectiveness during the development of non-diabetic hyperglycemia in Asian populations, we conducted a longitudinal study of such changes in 244 Japanese adults with normal glucose tolerance (median BMI 23.3 kg/m2 and age 51 yrs). The median follow-up period was 3.3 yrs. One hundred and eighty-two subjects maintained normal glucose tolerance (nonprogressors). After excluding the 3 subjects who progressed to diabetes, we analyzed the 59 who developed non-diabetic hyperglycemia (progressors), of which 31 progressed to impaired fasting glucose and 28 to impaired glucose tolerance. Whole body insulin sensitivity was estimated by ISIMatsuda, glucose-stimulated insulin secretion by [δIRI0-30/δPG0-30] and Stumvoll indices, hepatic insulin sensitivity by quantitative insulin sensitivity check index (QUICKI) and 1/fasting IRI, beta cell function by oral disposition index (DIO) ([δIRI0-30/δPG0-30]∙[ISIMatsuda]), and glucose effectiveness by an OGTT-derived index (SgIO). ISIMatsuda (p <0.05), [δIRI0-30/δPG0-30], DIO and SgIO (both p <0.01), but not QUICKI, 1/fasting IRI, or Stumvoll-1st and -2nd phases, were lower in the progressors at baseline. This group was also characterized by the following: 1) ISIMatsuda, DIO and SgIO were reduced by 34%, 32% and 11%, respectively (all p <0.01); 2) QUICKI and 1/fasting IRI diminished by 21% and 5%, respectively (both p <0.01); and 3) no significant changes were found in [δIRI0-30/δPG0-30], Stumvoll-1st and -2nd phases or BMI during the follow-up. In the nonprogressors, no indices changed significantly during the follow-up. Our study concluded that during the transition from normal glucose tolerance to non-diabetic hyperglycemia in this non-obese population, whole body insulin sensitivity, hepatic insulin sensitivity, beta cell function, and glucose effectiveness were all attenuated, but no significant changes in glucose-stimulated insulin secretion occurred. Also of note is the fact that the transition took place without any accompanying increase in BMI.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-252) contains supplementary material, which is available to authorized users.

Pancreatic β-cell Function Is a Stronger Predictor of Changes in Glycemic Control After an Aerobic Exercise Intervention Than Insulin Sensitivity

Understanding intersubject variability in glycemic control following exercise training will help individualize treatment. Our aim was to determine whether this variability is related to training-induced changes in insulin sensitivity or pancreatic β-cell function. We conducted an observational clinical study of 105 subjects with impaired glucose tolerance or type 2 diabetes. Individual subject changes in fitness (VO2max), glycemia (glycosylated hemoglobin, fasting glucose, oral glucose tolerance test), insulin sensitivity (hyperinsulinemic-euglycemic clamp), oral glucose-stimulated insulin secretion (GSIS), and disposition index (DI) were measured following 12 to 16 weeks of aerobic exercise training. Regression analyses were used to identify relationships between variables. After training, 86% of subjects increased VO2max and lost weight. Glycosylated hemoglobin, fasting glucose, and 2-hour oral glucose tolerance test were reduced in 69%, 62%, and 68% of subjects, respectively, while insulin sensitivity improved in 90% of the participants. Changes in glycemic control were congruent with changes in GSIS such that 66% of subjects had a reduction in first-phase GSIS, and 46% had reduced second-phase GSIS. Training increased first- and second-phase DI in 83% and 74% of subjects. Training-induced changes in glycemic control were related to changes in GSIS (P < .05), but not insulin sensitivity or DI, and training-induced improvements in glycemic control were largest in subjects with greater pretraining GSIS. Intersubject variability in restoring glycemic control following exercise is explained primarily by changes in insulin secretion. Thus, baseline and training-induced changes in β-cell function may be a key determinant of training-induced improvements in glycemic control.

Identifying novel plasma biomarkers of pancreatic beta‐cell function using acute and chronic models of hyperglycemia.

Beta‐cell function is impaired in type 2 diabetes. Identifying related plasma metabolites related to insulin secretion may help identify novel treatment targets. Intravenous glucose‐stimulated insulin secretion (GSIS) was measured in healthy subjects before and after acute 24‐hour experimental‐elevation of plasma glucose (+5 mM). GSIS was also measured in age/BMI‐matched type 2 diabetic (T2D) patients. The plasma metabolite profile (358 compounds) was determined using LC/GC‐MS and correlated with group differences in GSIS and with hyperglycemia‐induced changes in GSIS. GSIS was lower in T2D compared to controls (6.8±0.8 vs. 10.1±0.9 pmol/kg/min; P&lt;0.05), but elevated following experimental hyperglycemia in healthy controls (13.1±0.8). Hexadecanedioate, octadecanedioate and 3‐aminoisobutyrate were significantly correlated with GSIS (r= −0.66,−0.61,−0.56; P&lt;0.05) showing the same direction of change in both acute and chronic models of hyperglycemia. These plasma metabolites are biomarkers of beta‐cell function in humans and may reveal novel therapeutic targets. The effect of these compounds on GSIS in perifused pancreatic islets is currently being determined.

Peroxisome Proliferator–Activated Receptor-α and Glucocorticoids Interactively Regulate Insulin Secretion During Pregnancy

We evaluated the impact of peroxisome proliferator-activated receptor (PPAR)alpha activation and dexamethasone treatment on islet adaptations to the distinct metabolic challenges of fasting and pregnancy, situations where lipid handling is modified to conserve glucose. PPARalpha activation (24 h) in vivo did not affect glucose-stimulated insulin secretion (GSIS) in nonpregnant female rats in the fasted state, although fasting suppressed GSIS. Dexamethasone treatment (5 days) of nonpregnant rats lowered the glucose threshold and augmented GSIS at high glucose; the former effect was selectively opposed by PPARalpha activation. Pregnancy-induced changes in GSIS were opposed by PPARalpha activation at day 19 of pregnancy. Dexamethasone treatment from day 14 to 19 of pregnancy did not modify the GSIS profile of perifused islets from 19-day pregnant rats but rendered the islet GSIS profile refractory to PPARalpha activation. During sustained hyperglycemia in vivo, dexamethasone treatment augmented GSIS in nonpregnant rats but limited further modification of GSIS by pregnancy. We propose that the effect of PPARalpha activation to oppose lowering of the glucose threshold for GSIS by glucocorticoids is important as part of the fasting adaptation, and modulation of the islet GSIS profile by glucocorticoids toward term facilitates the transition of maternal islet function from the metabolic demands of pregnancy to those imposed after parturition.

Muscle Lipid Metabolism and Insulin Secretion Are Altered in Insulin-Resistant Rats Fed a High Sucrose Diet

Feeding rats a sucrose rich diet (SRD) induces hypertriglyceridemia and insulin resistance. The purposes of this study were to determine the time course of changes in lipid and glucose metabolism in the gastrocnemius muscle, both in the basal state and after the euglycemic hyperinsulinemic clamp, in rats fed a SRD for 3, 15 or 30 wk, and to analyze the changes in glucose-stimulated insulin secretion from perifused isolated islets from SRD-fed rats and their relationships to peripheral insulin insensitivity. A control group of rats was fed a control diet (CD) for the same period of time. After 3 wk of consuming the SRD, long-chain acyl CoA (LCACoA) levels in muscle were greater than in rats fed the CD, an early indication of the disturbance of lipid metabolism. Neither glycogen storage nor glucose oxidation were impaired at this time. Moreover, the biphasic patterns of glucose-stimulated insulin secretion showed a marked increase in the first peak, which helped maintain normoglycemia in SRD-fed rats. After 15 or 30 wk of consuming the SRD, triglyceride and LCACoA levels in muscles were greater than in rats fed the CD. Glucose oxidation as well as insulin-stimulated glycogen synthase activity and glycogen storage were lower than in rats fed the CD. Moreover, the altered pattern of insulin secretion further deteriorated. This was accompanied by peripheral insulin resistance and moderate hyperglycemia. Our results indicate that the dyslipemia present in rats chronically fed a SRD may play an important role in the progressive deterioration of insulin secretion and sensitivity in this animal model.

Differential expression of rat pancreatic islet beta-cell glucose transporter (GLUT 2), proinsulin and islet amyloid polypeptide genes after prolonged fasting, insulin-induced hypoglycaemia and dexamethasone treatment.

The question posed by these studies was whether chronic adaptive changes in glucose-stimulated insulin secretion are accompanied by comparable changes in islet Beta-cell glucose transporter (GLUT 2) gene expression. Control, fasted (3-day), insulin-injected hypoglycaemic (5-day), and dexamethasone-treated (4-day) rats (n = 5 for each condition), were studied. After fasting significant decrements in proinsulin mRNA/microgram RNA (-32%, p < 0.05) and islet amyloid polypeptide mRNA/microgram RNA (-44%, p < 0.05) were observed, while there was no change in GLUT 2 mRNA/microgram RNA (-13%, p > 0.05). After insulin-induced hypoglycaemia, decrements in proinsulin mRNA/microgram RNA (-49%, p < 0.01) and islet amyloid polypeptide mRNA/microgram RNA (-44%, p < 0.01) were also observed, with no change in islet GLUT 2 mRNA/microgram RNA (-18%, p > 0.05). Dexamethasone treatment resulted in a marked stimulatory effect on proinsulin mRNA/microgram RNA (+236%, p < 0.001) and islet amyloid polypeptide mRNA/microgram RNA (+221%, p < 0.01), while again there was no change in islet GLUT 2 mRNA/microgram RNA (+0.3%, p > 0.05). Quantitative immunoblot analysis with a GLUT 2 specific antibody revealed no change in islet GLUT 2 protein with fasting, but a small decrease (-39 +/- 11%) in islet GLUT 2/microgram protein after insulin-induced hypoglycaemia. These results do not support the hypothesis that chronic changes in glucose-stimulated insulin secretion are accompanied by changes in GLUT 2 expression. In contrast to the lack of correlation with GLUT 2, there was a striking correlation between proinsulin and islet amyloid polypeptide mRNAs for all experimental conditions (r = 0.974, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)