Effects of c-MYC activation on glucose stimulus-secretion coupling events in mouse pancreatic islets.
(2008) American journal of physiology. Endocrinology and metabolism — Vol. 295, n° 1, p. E92-102 (2008)
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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 ([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 week culture in 30 mmol.l(-1) glucose increased the islet sensitivity to glucose stimulation without reducing the maximal glucose effectiveness nor the insulin content. In contrast, overnight exposure to a low H2O2 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 H2O2 concentration than by prolonged culture in high glucose. Key words: beta-cell mass, insulin secretion, mitochondrial membrane potential, cytosolic calcium concentration.
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Pascal, S., Guiot, Y., Pelengaris, S., Khan, M., & Jonas, J.-C. (2008). Effects of c-MYC activation on glucose stimulus-secretion coupling events in mouse pancreatic islets. American journal of physiology. Endocrinology and metabolism, 295(1), E92-102. https://doi.org/10.1152/ajpendo.90235.2008 (Original work published 2008)