Glucotoxicity and beta-cell failure in type 2 diabetes mellitus.
Type 2 diabetes mellitus is increasing worldwide with a trend of declining age of onset. It is characterized by insulin resistance and a progressive loss of beta-cell function. The ability to secrete adequate amounts of insulin is determined by the functional integrity of beta-cells and their overall mass. Glucose, the main regulator of insulin secretion and production, exerts negative effects on beta-cell function when present in excessive amounts over a prolonged period. The multiple metabolic aberrations induced by chronic hyperglycemia in the beta-cell include increased sensitivity to glucose, increased basal insulin release, reduced response to stimulus to secrete insulin, and a gradual depletion of insulin stores. Inadequate insulin production during chronic hyperglycemia results from decreased insulin gene transcription due to hyperglycemia-induced changes in the activity of beta-cell specific transcription factors. Hyperglycemia may negatively affect beta-cell mass by inducing apoptosis without a compensatory increase in beta-cell proliferation and neogenesis. The detrimental effect of excessive glucose concentrations is referred to as 'glucotoxicity'. The present review discusses the role of glucotoxicity in beta-cell dysfunction in type 2 diabetes mellitus.
Kaiser
Nurit
N
Endocrinology and Metabolism Service, Department of Medicine and The Hadassah Diabetes Center, Hebrew University-Hadassah Medical Center, Jerusalem, Israel. kaiser@md.huji.ac.il
Leibowitz
Gil
G
Nesher
Rafael
R
D000818:Animals; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000503:physiopathology*; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology*; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000503:physiopathology*
D007328:Insulin