Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets

Abstract

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