Pascal Séverine M A, Guiot Yves, Pelengaris Stella, Khan Michael, Jonas Jean-Christophe
Unit of Endocrinology and Metabolism, Faculty of Medicine, Université catholique de Louvain, Brussels, Belgium.
Am J Physiol Endocrinol Metab. 2008 Jul;295(1):E92-102. doi: 10.1152/ajpendo.90235.2008. Epub 2008 Apr 15.
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+)), and lower glucose-induced Ca(2+) 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+) 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.
长期高血糖导致的胰腺β细胞存活改变和前胰岛素原基因表达变化可能是由于c-MYC表达增加所致。然而，尚不清楚c-MYC对β细胞功能的影响是否与其在糖毒性中所起的作用相符。因此，我们测试了短期激活c-MYC对从在β细胞中表达他莫昔芬可转换形式的c-MYC（MycER）的小鼠及其野生型同窝小鼠分离的胰岛中关键的β细胞刺激-分泌偶联事件的影响。用他莫昔芬处理野生型胰岛不影响其细胞存活、前胰岛素原基因表达和葡萄糖刺激-分泌偶联。相反，他莫昔芬介导的c-MYC激活2-3天会引发MycER胰岛中的细胞凋亡并降低前胰岛素原基因表达。这些效应伴随着在所有葡萄糖浓度下线粒体膜超极化、较高的静息细胞内钙浓度（Ca(2+)）以及较低的葡萄糖诱导的Ca(2+)升高和胰岛胰岛素含量，导致葡萄糖诱导的胰岛素分泌大幅减少。与这些效应相比，在30 mmol/l葡萄糖中培养1周可增加胰岛对葡萄糖刺激的敏感性，而不会降低最大葡萄糖效能或胰岛素含量。相反，过夜暴露于低浓度H(2)O(2)会增加胰岛静息Ca(2+)，并降低最大葡萄糖反应的幅度，这与用他莫昔芬处理的MycER胰岛中的情况相同。总之，c-MYC激活会迅速刺激细胞凋亡，降低前胰岛素原基因表达和胰岛素含量，并引发β细胞的功能改变，与过夜暴露于低浓度H(2)O(2)相比，高糖长期培养对这些改变的模拟效果更好。
