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Glucose and leptin induce apoptosis in human β-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases

Kathrin Maedler^*,1, Fabienne T. Schulthess^*, Christelle Bielman, Thierry Berney, Christophe Bonny, Marc Prentki, Marc Y. Donath^|| and Raphael Roduit^,¶

^* Larry L. Hillblom Islet Research Center, University of California, Los Angeles, California, USA;

Medical Genetic Service, Centre Hospitalier Universitarie Vaudois Lausanne, Lausanne, France;

Department of Surgery, University Medical Center, Geneva, Switzerland;

Molecular Nutrition Unit and the Montreal Diabetes Research Center, Centre de Recherche du CHUM, and Department of Nutrition and Biochemistry, Université de Montréal, Montréal, Quebec, Canada;

^|| Division of Endocrinology and Diabetes, University Hospital Zurich, University of Zurich, Switzerland; and

^¶ Institut de Recherche en Ophtalmologie, Sion, Switzerland

¹Correspondence: Centre for Biomolecular Interactions Bremen, University of Bremen, NW2, Box 33 04 40, D-28334 Bremen, Germany. E-mail: kmaedler{at}uni-bremen.de

c-Jun N-terminal kinases (SAPK/JNKs) are activated by inflammatory cytokines, and JNK signaling is involved in insulin resistance and β-cell secretory function and survival. Chronic high glucose concentrations and leptin induce interleukin-1β (IL-1β) secretion from pancreatic islets, an event that is possibly causal in promoting β-cell dysfunction and death. The present study provides evidence that chronically elevated concentrations of leptin and glucose induce β-cell apoptosis through activation of the JNK pathway in human islets and in insulinoma (INS 832/13) cells. JNK inhibition by the dominant inhibitor JNK-binding domain of IB1/JIP-1 (JNKi) reduced JNK activity and apoptosis induced by leptin and glucose. Exposure of human islets to leptin and high glucose concentrations leads to a decrease of glucose-induced insulin secretion, which was partly restored by JNKi. We detected an interplay between the JNK cascade and the caspase 1/IL-1β-converting enzyme in human islets. The caspase 1 gene, which contains a potential activating protein-1 binding site, was up-regulated in pancreatic sections and in isolated islets from type 2 diabetic patients. Similarly, cultured human islets exposed to high glucose- and leptin-induced caspase 1 and JNK inhibition prevented this up-regulation. Therefore, JNK inhibition may protect β-cells from the deleterious effects of high glucose and leptin in diabetes.—Maedler, K., Schulthess, F. T., Bielman, C., Berney, T., Bonny, C., Prentki, M., Donath, M. Y., Roduit, R. Glucose and leptin induce apoptosis in human β-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases.

Key Words: diabetes • islets • capase 1