Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro3) GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-diabetes.

Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R) action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro3)GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P <0.05) in (Pro3)GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P <0.05) and insulin (1.5-fold; P <0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P <0.05) insulin sensitivity in the (Pro3)GIP-treated group. Daily injection of (Pro3)GIP reduced pancreatic insulin content (1.3-fold; P <0.05) and partially corrected the obesity-related islet hypertrophy and ß-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro3)GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes.

Decision rules, energy metabolism and vigour of hermit-crab fights

Aggressive interactions between animals are often settled by the use of repeated signals that reduce the risk of injury from combat but are expected to be costly. The accumulation of lactic acid and the depletion of energy stores may constrain activity rates during and after fights and thus represent significant costs of signalling. We tested this by analysing the concentrations of lactate and glucose in the haemolymph of hermit crabs following agonistic interactions over the ownership of the gastropod shells that they inhabit. Attackers and defenders play distinct roles of sender and receiver that are fixed for the course of the encounter. Attackers perform bouts of 'shell rapping', which vary in vigour between attackers and during the course of the encounter, and are a key predictor of victory. In contrast to the agonistic behaviour of other species, we can quantify the vigour of fighting. We demonstrate, to our knowledge for the first time, an association between the vigour of aggressive activity and a proximate cost of signalling. We show that the lactate concentration in attackers increases with the amount of shell rapping, and that this appears to constrain the vigour of subsequent rapping. Furthermore, attackers, but not defenders, give up when the concentration of lactate is high. Glucose levels in attackers also increase with the amount of rapping they perform, but do not appear to influence their decision to give up. Defenders are more likely to lose when they have particularly low levels of glucose. We conclude that the two roles use different decision rules during these encounters.

Direct and indirect effects of obestatin peptides on food intake and the regulation of glucose homeostasis and insulin secretion in mice

Obestatin is a recently discovered peptide hormone that appears to be involved in reducing food intake, gut motility and body weight. Obestatin is a product of the preproghrelin gene and appears to oppose several physiological actions of ghrelin. This study investigated the acute effects of obestatin (1-23) and the truncated form, obestatin (11-23), on feeding activity, glucose homeostasis or insulin secretion. Mice received either intraperitoneal obestatin (1-23) or (11-23) (1 mu mol/kg) 4 h prior to an allowed 15 min period of feeding. Glucose excursions and insulin responses were lowered by 64-77% and 39-41%, respectively, compared with saline controls. However this was accompanied by 43% and 53% reductions in food intake, respectively. The effects of obestatin peptides were examined under either basal or glucose (18 mmol/kg) challenge conditions to establish whether effects were independent of changes in feeding. No alterations in plasma glucose or insulin responses were observed. In addition, obestatin peptides had no effect on insulin sensitivity as revealed by hypoglycaemic response when co-administered with insulin. Our observations support a role for obestatin in regulating metabolism through changes of appetite, but indicate no direct actions on glucose homeostasis or insulin secretion. (c) 2007 Elsevier Inc. All rights reserved.

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro(3))GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

Aims/hypothesis Ablation of gastric inhibitory polypeptide ( GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro(3)) GIP is able to counter the development of genetic obesity-related diabetes.

Degradation, cyclic adenosine monophosphate production, insulin secretion, and glycemic effects of two novel N-terminal Ala(2)-substituted analogs of glucose-dependent insulinotropic polypeptide with preserved biological activity in vivo

Glucose-dependent insulinotropic polypeptide (GIP) has significant potential in diabetes therapy due to its ability to serve as a glucose-dependent activator of insulin secretion. However, its biological activity is severely compromised by the ubiquitous enzyme dipeptidylpeptidase IV (DPP IV), which removes the N-terminal Tyr(1)-Ala(2) dipeptide from GIP. Therefore, 2 novel N-terminal Ala(2)-substituted analogs of GIP, with Ala substituted by 2-aminobutyric acid (Abu) or sarcosine (Sar), were synthesized and tested for metabolic stability and biological activity both in vitro and in vivo. Incubation with DPP IV gave half-lives for degradation of native GIP, (Abu(2))GIP, and (Sar(2))GIP to be 2.3, 1.9, and 1.6 hours, respectively, while in human plasma, the half-lives were 6.2, 7.6, and 5.4 hours, respectively. In Chinese hamster lung (CHL) cells expressing the cloned human GIP receptor, native GIP, (Abu(2))GIP, and (Sar(2))GIP dose-dependently stimulated cyclic adenosine monophosphate (camp) production with EC50 values of 18.2, 38.5, and 54.6 nmol/L, respectively. In BRIN-BD11 cells, both (Abu(2))GIP and (Sar(2))GIP (10(-13) to 10(-8) mol/L) dose-dependently stimulated insulin secretion with significantly enhanced effects at 16.7 mmol/L compared with 5.6 mmol/L glucose. In obese diabetic (ob/ob) mice, GIP and (Sar(2))GIP significantly increased (1.4-fold to 1.5-fold; P <.05) plasma insulin concentrations, whereas (Abu(2))GIP exerted only minor effects. Changes in plasma glucose were small reflecting the severe insulin resistance of this mutant. The present data show that substitution of the penultimate N-terminal Ala(2) in GIP by Abu or Sar results in analogs with moderately reduced metabolic stability and biological activity in vitro, but with preserved biological activity in vivo. (C) 2003 Elsevier Inc. All rights reserved.

Acute exercise and impaired glucose tolerance in obese humans

BACKGROUND: Individuals with impaired glucose tolerance (IGT) have a greater risk of developing diabetes and cardiovascular disease compared with those with normal glycemic control. The aim of this study was to examine the effects of acute aerobic exercise on glycemia, regional arterial stiffness, and oxidative stress in obese subjects with IGT.

Effect of pioglitazone on endothelial function in impaired glucose tolerance

Aim: Flow-mediated dilation (FMD) is a surrogate marker of endothelial function, which has been proposed as a barometer of vascular health. Impaired microvascular response to reactive hyperaemia is thought to be the mechanism behind reduced shear stress and subsequently impaired FMD, which has been associated with cardiovascular events. This study aims to assess the effect of pioglitazone on the vasculature of patients with impaired glucose tolerance (IGT).

Materials and Methods: Forty IGT patients with no cardiovascular disease were compared with 24 healthy age- and sex-matched controls. Endothelial function was assessed using FMD of the brachial artery. Adiponectin (ADN) levels were measured and insulin sensitivity was calculated using homeostasis model assessment of insulin resistance (HOMA-IR). A randomised double-blind placebo-controlled trial of the IGT subjects was then performed, with subjects receiving either pioglitazone 30 mg od or matched placebo for 12 weeks before the measurements were repeated.

Results: The IGT subjects had a significantly impaired FMD compared with the controls (p < 0.001). Diastolic shear stress (DSS) was also significantly reduced in IGT (p = 0.04). High molecular weight (HMW) ADN was significantly lower in the IGT group than in controls (p = 0.03). On analysis of the IGT group after 12 weeks treatment, FMD was significantly increased in the pioglitazone group compared with placebo (p = 0.03) as was endothelium-independent dilation (EID) (p = 0.03). A significant increase in total ADN (p < 0.001), HMW ADN (p < 0.001) and HMW/total ratio (p = 0.001) occurred in the pioglitazone group compared with placebo.

Conclusions: Pioglitazone improved endothelial function in IGT. Treatment with pioglitazone may reduce the risk of cardiovascular disease in this patient group.

Maternal Glucose at 28 Weeks of Gestation Is Not Associated With Obesity in 2-Year-Old Offspring:The Belfast Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Family Study

OBJECTIVE:Diabetes during pregnancy is a strong risk factor for obesity in the offspring, but the age at which this association becomes apparent is unknown. The purpose of this study was to examine the relation of glycemia during pregnancy with anthropometry in offspring of nondiabetic pregnant women from the Belfast U.K. center of the multinational Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study.
RESEARCH DESIGN AND METHODS: Women from the HAPO Study were invited to participate in follow-up of their offspring aged 2 years. Measurements included height, weight, and thickness of triceps, subscapular, and suprailiac skinfolds. RESULTS: A total of 1,165 offspring (73% of eligible children; 598 boys and 567 girls) were seen from ages 22-30 completed months. The only association that reached statistical significance was between categories of maternal 1-h glucose and BMI Z score =85th percentile at 2 years (P = 0.017). Overall the correlations between maternal glucose during pregnancy and BMI Z score at age 2 years were weak (fasting glucose r = 0.05, P = 0.08; 1-h glucose r = 0.04, P = 0.22; 2-h glucose r = 0.03, P = 0.36; and area under the curve for glucose r = 0.04, P = 0.18).
CONCLUSIONS: This study found little association between maternal glucose during pregnancy and obesity in the offspring at this young age. These findings are not unexpected given that study results for young offspring whose mothers had diabetes during pregnancy were indistinguishable from those for normal offspring at this age. It will be interesting to see whether, as these children age, maternal glucose during pregnancy in the ranges included in the HAPO Study will be associated with obesity in their children. © 2010 by the American Diabetes Association.

Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation

Background: Nateglinide restores early-phase insulin secretion to feeding and reduces postprandial hyperglycaemia in type 2 diabetes. This study evaluated the effects of nateglinide on dipeptidyl peptidase-IV (DPP-IV) activity and glucose-dependent insulinotropic polypeptide (GIP) degradation

Effects of nateglinide on the secretion of glycated insulin and glucose tolerance in type 2 diabetes

Aims: Glycation of insulin has been demonstrated within pancreatic beta-cells and the resulting impaired bioactivity may contribute to insulin resistance in diabetes. We used a novel radioimmunoassay to evaluate the effect of nateglinide on plasma concentrations of glycated insulin and glucose tolerance in type 2 diabetes. Methods. Ten patients (5 M/5 F, age 57.8 +/- 1.9 years, HbA(1c), 7.6 +/- 0.5%,, fasting plasma glucose 9.4 +/- 1.2 mmol/l, creatinine 81.6 +/- 4.5 mumol/l) received oral nateglinide 120 mg or placebo, 10 min prior to 75 g oral glucose in a random, single blind, crossover design, 1 week apart. Blood samples were taken for glycated insulin, glucose, insulin and C-peptide over 225 min. Results: Plasma glucose and glycated insulin responses were reduced by 9% (P = 0.005) and 38% (P = 0.047), respectively, following nateglinide compared with placebo. Corresponding AUC measures for insulin and C-peptide were enhanced by 36% (P = 0.005) and 25% (P = 0.007) by nateglinide. Conclusions: Glycated insulin in type 2 diabetes is reduced in response to the insulin secretagogue nateglinide, resulting in preferential release of native insulin. Since glycated insulin exhibits impaired biological activity, reduced glycated insulin release may contribute to the anti hyperglycaemic action of nateglinide. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Vitamin C supplementation decreases insulin glycation and improves glucose homeostasis in obese hyperglycemic (ob/ob) mice

The effects of dietary vitamin C supplementation on glucose homeostasis and insulin glycation were examined in adult lean and obese hyperglycemic (ob/ob) mice. In lean mice, supplementation of the drinking water with vitamin C (25 g/L) for 14 days did not affect food intake, fluid intake, glycated hemoglobin, plasma glucose, or plasma insulin concentrations. Total pancreatic insulin content and the percentage of glycated pancreatic insulin were also similar to control lean mice. In ob/ob mice, vitamin C supplementation caused significant reductions by 26% to 48% in food intake and fluid intake, glycated hemoglobin, plasma glucose, and insulin concentrations compared with untreated control ob/ob mice. The total insulin content and the extent of insulin glycation in the pancreas of ob/ob mice were also significantly decreased by 42% to 45% after vitamin C supplementation. This change was accompanied by a significant 80% decrease in the percentage of glycated insulin in the circulation of vitamin C- supplemented ob/ob mice. These data demonstrate that vitamin C supplementation can decrease insulin glycation and ameliorate aspects of the obesity-diabetes syndrome in ob/ob mice. Copyright 2002, Elsevier Science (USA). All rights reserved.

Glucose lowers the threshold for human aortic vascular smooth muscle cell migration: inhibition by protein phosphatase-2A

AIMS/HYPOTHESIS: Atherosclerosis, which occurs prematurely in individuals with diabetes, incorporates vascular smooth muscle cell (VSMC) chemotaxis. Glucose, through protein kinase C-beta(II) signalling, increases chemotaxis to low concentrations of platelet-derived growth factor (PDGF)-BB. In VSMC, a biphasic response in PDGF-beta receptor (PDGF-betaR) level occurs as PDGF-BB concentrations increase. The purpose of this study was to determine whether increased concentrations of PDGF-BB and raised glucose level had a modulatory effect on the mitogen-activated protein kinase/extracellular-regulated protein kinase pathway, control of PDGF-betaR level and chemotaxis.

METHODS: Cultured aortic VSMC, exposed to normal glucose (NG) (5 mmol/l) or high glucose (HG) (25 mmol/l) in the presence of PDGF-BB, were assessed for migration (chemotaxis chamber) or else extracted and immunoblotted.

RESULTS: At concentrations of PDGF-BB <540 pmol/l, HG caused an increase in the level of PDGF-betaR in VSMC (immunoblotting) versus NG, an effect that was abrogated by inhibition of aldose reductase or protein kinase C-beta(II). At higher concentrations of PDGF-BB (>540 pmol/l) in HG, receptor level was reduced but in the presence of aldose reductase or protein kinase C-beta(II) inhibitors the receptor levels increased. It is known that phosphatases may be activated at high concentrations of growth factors. At high concentrations of PDGF-BB, the protein phosphatase (PP)2A inhibitor, endothall, caused an increase in PDGF-betaR levels and a loss of biphasicity in receptor levels in HG. At higher concentrations of PDGF-BB in HG, the chemoattractant effect of PDGF-BB was lost (chemotaxis chamber). Under these conditions inhibition of PP2A was associated with a restoration of chemotaxis to high concentrations of PDGF-BB.

CONCLUSION/INTERPRETATION: The biphasic response in PDGF-betaR level and in chemotaxis to PDGF-BB in HG is due to PP2A activation.

Glucose-induced oxidative stress in vascular contractile cells - Comparison of aortic smooth muscle cells and retinal pericytes

Free radical-mediated damage to vascular cells may be involved in the pathogenesis of diabetic vasculopathy. The aim of this study was to compare the extent of glucose-induced oxidative stress in both vascular smooth muscle cells (VSMCs) and pericytes and the effect on antioxidant enzyme gene expression and activities. Porcine aortic VSMC and retinal pericytes were cultured in either 5 or 25 mmol/l glucose for 10 days. Intracellular malondialdehyde (MDA) was measured as a marker of peroxidative damage, and mRNA expression of CuZn-SOD, MnSOD, catalase, and glutathione peroxidase (GPX) were measured by Northern analysis. Glutathione (GSH) was also measured. There was a significant increase in MDA in VSMCs in 25 mmol/l glucose (1.34 +/- 0.11 vs. 1.88 +/- 0.24 nmol/mg protein, 5 vs. 25 mmol/l D-glucose, mean +/- SE, n = 15, P