Pascal, Severine M. A., Guiot, Yves, Pelengaris, Stella, Khan, Michael and Jonas, Jean-Christophe. (2008) Effects of c-MYC activation on glucose stimulus-secretion coupling events in mouse pancreatic islets. American Journal of Physiology: Endocrinology and Metabolism, Vol.295 (No.1). E92-E102. ISSN 0193-1849

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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 ([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 beta-cells that are better mimicked by overnight exposure to a low H2O2 concentration than by prolonged culture in high glucose.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QP Physiology R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Insulin -- Research, Apoptosis, Mitochondrial membranes, Islands of Langerhans, Mice -- Endocrinology, Mice -- Physiology
Journal or Publication Title:	American Journal of Physiology: Endocrinology and Metabolism
Publisher:	American Physiological Society
ISSN:	0193-1849
Official Date:	July 2008
Dates:	Date Event July 2008 Published
Volume:	Vol.295
Number:	No.1
Number of Pages:	11
Page Range:	E92-E102
Identification Number:	10.1152/ajpendo.90235.2008
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Fonds national de la recherche scientifique (Belgium) (FNRS), Interuniversity Poles of Attraction Program (P6/42) - Belgian Science Policy, Communauté française de Belgique
Grant number:	3.4616.05 (FNRS), 3.4506.05 (FNRS), ARC 05/10-328 (CFB)
URI:	http://wrap.warwick.ac.uk/id/eprint/29661

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