Glucose regulation of islet stress responses and beta-cell failure in type 2 diabetes.
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.
Jonas
J C
JC
Université catholique de Louvain, Brussels, Belgium. jean-christophe.jonas@uclouvain.be
Bensellam
M
M
Duprez
J
J
Elouil
H
H
Guiot
Y
Y
Pascal
S M A
SM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000502:physiology*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D007003:Hypoglycemia / Q000503:physiopathology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats
D005947:Glucose