Glucose regulation of islet stress responses and beta-cell failure in type 2 diabetes

Diabetes Obes Metab. 2009 Nov;11 Suppl 4:65-81. doi: 10.1111/j.1463-1326.2009.01112.x.

Abstract

Pancreatic beta-cells exposed to high glucose concentrations display altered gene expression, function, survival and growth that may contribute to the slow deterioration of the functional beta-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 beta-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 beta-cell mass under states of prolonged hypoglycaemia and hyperglycaemia. In addition, beta-cell demise under glucotoxic conditions may also result from beta-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 beta-cell glucotoxicity and of their pathophysiological cause in vivo may lead to new therapeutic strategies to prevent the slow deterioration of the functional beta-cell mass in glucose intolerant and type 2 diabetic patients.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cell Hypoxia / physiology
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Disease Progression
  • Endoplasmic Reticulum / physiology*
  • Gene Expression
  • Glucose / metabolism*
  • Humans
  • Hyperglycemia / physiopathology
  • Hypoglycemia / physiopathology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology*
  • Oxidative Stress / physiology*
  • Rats

Substances

  • Glucose