Glucose regulation of islet stress responses and β‐cell failure in type 2 diabetes

Abstract

Pancreatic β-cells exposed to high glucose concentrations display altered gene expression, function, survival and growth that may contribute to the slow deterioration of the functional β-cell mass in type 2 diabetes. These glucotoxic alterations may result from various types of stress imposed by the hyperglycaemic environment, including oxidative stress, endoplasmic reticulum stress, cytokine-induced apoptosis and hypoxia. The glucose regulation of oxidative stress-response and integrated stress-response genes in cultured rat islets follows an asymmetric V-shaped profile parallel to that of β-cell apoptosis, with a large increase at low glucose and a moderate increase at high vs. intermediate glucose concentrations. These observations suggest that both types of stress could play a role in the alteration of the functional β-cell mass under states of prolonged hypoglycaemia and hyperglycaemia. In addition, β-cell demise under glucotoxic conditions may also result from β-cell hypoxia and, in vivo, from their exposure to inflammatory cytokines released locally by non-endocrine islet cells. A better understanding of the relative contribution of each type of stress to β-cell glucotoxicity and of their pathophysiological cause in vivo may lead to new therapeutic strategies to prevent the slow deterioration of the functional β-cell mass in glucose intolerant and type 2 diabetic patients.

Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

“…1,18,27). In this study, acute pharmacological GK activation increased the glucose sensitivity of control islets but failed at restoring ␤-cell glucose responsiveness in rat islets cultured for 1 wk at nonstimulating or very high vs. intermediate glucose concentration.…”

“…We first tested the effects of two chemically unrelated GKAs, Ro and Compound A, during overnight culture at increasing glucose concentrations, on insulin secretion, on the islet mRNA levels of metallothionein 1a (Mt1a), a sensitive indicator of oxidative stress in rat islets (18), and on the mRNA levels of thioredoxininteracting protein (Txnip), a sensitive marker of ␤-cell glucotoxicity (5). The strong regulation of these genes and of insulin secretion over different parts of the glucose concentrationresponse curve (2) should provide an optimal system to compare the intensity of the effects of GKAs and glucose in rat islets.…”

“…apoptosis; glucotoxicity; insulin secretion; pancreatic ␤-cell GLUCOSE STIMULATION OF INSULIN SECRETION (GSIS) by endocrine pancreatic ␤-cells depends on the acceleration of glucose metabolism through glycolysis and the TCA cycle, with enhanced production of metabolic coupling factors (25,39,41). Besides these rapid effects, glucose exerts complex long-term effects on the ␤-cell phenotype (2,10,16,18,27,45). During long-term culture of rodent islets, ␤-cell gene expression, survival, and glucose responsiveness are optimally preserved in the presence of 10 mM glucose (G10), whereas they are markedly altered by culture at either nonstimulating (G5) or very high (G30) glucose concentrations.…”

Anti-apoptotic effects of silk fibroin hydrolysate in RIN5F cell on high glucose condition

“…Also, hyperglycemia induces the generation of ROS and triggers pancreatic β-cell apoptosis (Robertson et al 2003;Kim et al 2005;Ortega-Camarillo et al 2006;Jonas et al 2009). Therefore, prevention of pancreatic β-cell apoptosis induced by hyperglycemia is an important therapeutic issue for diabetic and metabolic disease patients.…”

“…We subsequently asked how SFH maintains pancreatic β-cell mass under hyperglycemic conditions. Exposure to high glucose conditions reduces pancreatic β-cell viability (Kim et al 2005;Robertson et al 2003;Jonas et al 2009). Thus, the effects of SFH on high glucose conditions were investigated in RIN5F cells.…”