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

Abstract
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.
AuthorsSéverine M A Pascal, Yves Guiot, Stella Pelengaris, Michael Khan, Jean-Christophe Jonas
JournalAmerican journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 295 Issue 1 Pg. E92-102 (Jul 2008) ISSN: 0193-1849 [Print] United States
PMID18413670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Blood Glucose
  • Insulin
  • Myc protein, mouse
  • Protein Precursors
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Tamoxifen
  • preproinsulin
  • Hydrogen Peroxide
  • Glucose
  • Calcium
Topics
  • Animals
  • Apoptosis (drug effects, genetics)
  • Blood Glucose (metabolism)
  • Calcium (metabolism)
  • Crosses, Genetic
  • Female
  • Gene Expression Regulation
  • Glucose (administration & dosage, metabolism)
  • Hydrogen Peroxide (pharmacology)
  • Insulin (biosynthesis, genetics, metabolism)
  • Insulin-Secreting Cells (drug effects, metabolism, physiology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Mitochondrial Membranes (drug effects, physiology)
  • Protein Precursors (biosynthesis, genetics)
  • Proto-Oncogene Proteins c-myc (biosynthesis, genetics)
  • RNA, Messenger (biosynthesis, genetics)
  • Tamoxifen (pharmacology)

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