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Biotech / Medical : Indications -- diabetes -- Ignore unavailable to you. Want to Upgrade?

To: Miljenko Zuanic who wrote (40)	9/16/2002 10:04:21 PM
From: Miljenko Zuanic	Respond to of 278

J. Clin. Invest. 110:851-860 (2002). doi:10.1172/JCI200215318. Copyright ©2002 by the American Society for Clinical Investigation -------------------------------------------------------------------------------- Article Glucose-induced ß cell production of IL-1ß contributes to glucotoxicity in human pancreatic islets Kathrin Maedler1, Pavel Sergeev1, Frédéric Ris2,3, José Oberholzer3, Helen I. Joller-Jemelka4, Giatgen A. Spinas1, Nurit Kaiser5, Philippe A. Halban2 and Marc Y. Donath1 1 Division of Endocrinology and Diabetes, University Hospital, Zurich, Switzerland 2 Louis-Jeantet Research Laboratories, University of Geneva Medical Center, Geneva, Switzerland 3 Division of Surgical Research, Department of Surgery, University of Geneva Medical Center, Geneva, Switzerland 4 Division of Clinical Immunology, University Hospital, Zurich, Switzerland 5 Department of Endocrinology and Metabolism, Hebrew University — Hadassah Medical Center, Jerusalem, Israel Address correspondence to: Marc Y. Donath, Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland. Phone: 41-1-255-3625; Fax: 41-1-255-4447; E-mail: marc.donath@dim.usz.ch. Received for publication February 20, 2002, and accepted in revised form July 16, 2002. In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic ß cells, causing impaired insulin secretion. IL-1ß is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1ß inhibits ß cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-B. Recently, we have shown that increased glucose concentrations also induce Fas expression and ß cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1ß may mediate the deleterious effects of high glucose on human ß cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1ß, followed by NF-B activation, Fas upregulation, DNA fragmentation, and impaired ß cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. ß cells themselves were identified as the islet cellular source of glucose-induced IL-1ß. In vivo, IL-1ß–producing ß cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1ß was induced in ß cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented ß cell expression of IL-1ß. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1ß/NF-B pathway as a target to preserve ß cell mass and function in this condition.