Effects of c-MYC activation on glucose stimulus-secretion coupling events in mouse pancreatic islets.
Alteration of pancreatic beta-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 beta-cell function are compatible with its proposed role in glucotoxicity. We therefore tested the effects of short-term c-MYC activation on key beta-cell stimulus-secretion coupling events in islets isolated from mice expressing a tamoxifen-switchable form of c-MYC in beta-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(2+)](i)), and lower glucose-induced [Ca(2+)](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 H(2)O(2) concentration increased the islet resting [Ca(2+)](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 beta-cells that are better mimicked by overnight exposure to a low H(2)O(2) concentration than by prolonged culture in high glucose.
Pascal
Séverine M A
SM
Unit of Endocrinology and Metabolism, Faculty of Medicine, Université catholique de Louvain, Brussels, Belgium.
Guiot
Yves
Y
Pelengaris
Stella
S
Khan
Michael
M
Jonas
Jean-Christophe
JC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003433:Crosses, Genetic; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; C489428:Myc protein, mouse; D011498:Protein Precursors; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D013629:Tamoxifen; C013737:preproinsulin; D006861:Hydrogen Peroxide; D005947:Glucose; D002118:Calcium