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This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: 295/1/E92    most recent 90235.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pascal, S. M. A. Articles by Jonas, J.-C. Search for Related Content PubMed PubMed Citation Articles by Pascal, S. M. A. Articles by Jonas, J.-C.

Effects of c-MYC activation on glucose stimulus-secretion coupling events in mouse pancreatic islets

¹Unit of Endocrinology and Metabolism and ²Service of Pathology, Faculty of Medicine, Université catholique de Louvain, Brussels, Belgium; and ³Cancer Biology Group, Biomedical Research Institute, Warwick Medical School, and ⁴Department of Biological Sciences, University of Warwick, Coventry, United Kingdom

Submitted 14 February 2008 ; accepted in final form 14 April 2008

Alteration of pancreatic β-cell survival and Preproinsulin gene expression by prolonged hyperglycemia may result from increased c-MYC expression. However, it is unclear whether c-MYC effects on β-cell function are compatible with its proposed role in glucotoxicity. We therefore tested the effects of short-term c-MYC activation on key β-cell stimulus-secretion coupling events in islets isolated from mice expressing a tamoxifen-switchable form of c-MYC in β-cells (MycER) and their wild-type littermates. Tamoxifen treatment of wild-type islets did not affect their cell survival, Preproinsulin gene expression, and glucose stimulus-secretion coupling. In contrast, tamoxifen-mediated c-MYC activation for 2–3 days triggered cell apoptosis and decreased Preproinsulin gene expression in MycER islets. These effects were accompanied by mitochondrial membrane hyperpolarization at all glucose concentrations, a higher resting intracellular calcium concentration ([Ca²⁺]_i), and lower glucose-induced [Ca²⁺]_i rise and islet insulin content, leading to a strong reduction of glucose-induced insulin secretion. Compared with these effects, 1-wk culture in 30 mmol/l glucose increased the islet sensitivity to glucose stimulation without reducing the maximal glucose effectiveness or the insulin content. In contrast, overnight exposure to a low H₂O₂ concentration increased the islet resting [Ca²⁺]_i and reduced the amplitude of the maximal glucose response as in tamoxifen-treated MycER islets. In conclusion, c-MYC activation rapidly stimulates apoptosis, reduces Preproinsulin gene expression and insulin content, and triggers functional alterations of β-cells that are better mimicked by overnight exposure to a low H₂O₂ concentration than by prolonged culture in high glucose.

β-cell mass; apoptosis; cytosolic calcium concentration; insulin secretion; mitochondrial membrane potential