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In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic [beta] cells, causing impaired insulin secretion. IL-1[beta] is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1[beta] inhibits [beta] cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-[kappa]B. Recently, we have shown that increased glucose concentrations also induce Fas expression and [beta] cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1[beta] may mediate the deleterious effects of high glucose on human [beta] cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1[beta], followed by NF-[kappa]B activation, Fas upregulation, DNA fragmentation, and impaired [beta] cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. [beta] cells themselves were identified as the islet cellular source of glucose-induced IL-1[beta]. In vivo, IL-1[beta]-producing [beta] cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1[beta] was induced in [beta] cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented [beta] cell expression of IL-1[beta]. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1[beta]/NF-[kappa]B pathway as a target to preserve [beta] cell mass and function in this condition.

Copyright (C) 2002 The American Society for Clinical Investigation, Inc.