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Effects of c-MYC activation on glucose stimulus-secretion coupling events in mouse pancreatic islets.
- Source :
- American Journal of Physiology: Endocrinology & Metabolism; Jul2008, Vol. 295, pE92-E102, 11p, 2 Diagrams, 4 Charts, 5 Graphs
- Publication Year :
- 2008
-
Abstract
- 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 ([Ca<superscript>2+</superscript>]<subscript>i</subscript>), and lower glucose-induced [Ca<superscript>2+</superscript>]<subscript>i</subscript> 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 H<subscript>2</subscript>O<subscript>2</subscript> concentration increased the islet resting [Ca<superscript>2+</superscript>]<subscript>i</subscript> 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 H<subscript>2</subscript>O<subscript>2</subscript> concentration than by prolonged culture in high glucose. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01931849
- Volume :
- 295
- Database :
- Complementary Index
- Journal :
- American Journal of Physiology: Endocrinology & Metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 34067625
- Full Text :
- https://doi.org/10.1152/ajpendo.90235.2008