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B and Endoplasmic Reticulum Stress
Laboratory of Experimental Medicine (I.K., L.L., A.K.C., Z.D., M.C., D.L.E.) and Division of Endocrinology (M.C.), Erasmus Hospital, Université Libre de Bruxelles, B-1070 Brussels, Belgium
Address all correspondence and requests for reprints to: Décio L. Eizirik, Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808 CP 618, B-1070 Brussels, Belgium. E-mail: deizirik{at}ulb.ac.be.
Apoptosis is probably the main form of ß-cell death in both type 1 diabetes mellitus (T1DM) and T2DM. In T1DM, cytokines contribute to ß-cell destruction through nuclear factor-
B (NF-B) activation. Previous studies suggested that in T2DM high glucose and free fatty acids (FFAs) are ß-cell toxic also via NF-B activation. The aims of this study were to clarify whether common mechanisms are involved in FFA- and cytokine-induced ß-cell apoptosis and determine whether TNF
, an adipocyte-derived cytokine, potentiates FFA toxicity through enhanced NF-B activation. Apoptosis was induced in insulinoma (INS)-1E cells, rat islets, and fluorescence-activated cell sorting-purified ß-cells by oleate, palmitate, and/or cytokines (IL-1ß, interferon-
, TNF). Palmitate and IL-1ß induced a similar percentage of apoptosis in INS-1E cells, whereas oleate was less toxic. TNF did not potentiate FFA toxicity in primary ß-cells. The NF-B-dependent genes inducible nitric oxide synthase and monocyte chemoattractant protein-1 were induced by IL-1ß but not by FFAs. Cytokines activated NF-B in INS-1E and ß-cells, but FFAs did not. Moreover, FFAs did not enhance NF-B activation by TNF. Palmitate and oleate induced C/EBP homologous protein, activating transcription factor-4, and immunoglobulin heavy chain binding protein mRNAs, X-box binding protein-1 alternative splicing, and activation of the activating transcription factor-6 promoter in INS-1E cells, suggesting that FFAs trigger an endoplasmic reticulum (ER) stress response. We conclude that apoptosis is the main mode of FFA- and cytokine-induced ß-cell death but the mechanisms involved are different. Whereas cytokines induce NF-B activation and ER stress (secondary to nitric oxide formation), FFAs activate an ER stress response via an NF-B- and nitric oxide-independent mechanism. Our results argue against a unifying hypothesis for the mechanisms of ß-cell death in T1DM and T2DM.
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