Disruption of Tsc2 in pancreatic β cells induces β cell mass expansion and improved glucose tolerance in a TORC1-dependent manner

被引:161
作者
Rachdi, Latif [1 ]
Balcazar, Norman [1 ]
Osorio-Duque, Fernando [1 ]
Elghazi, Lynda [1 ]
Weiss, Aaron [1 ]
Gould, Aaron [1 ]
Chang-Chen, Karen J. [1 ]
Gambello, Michael J. [2 ]
Bernal-Mizrachi, Ernesto [1 ]
机构
[1] Washington Univ, Sch Med, Div Endocrinol Metab & Lipid Res, St Louis, MO 63110 USA
[2] Univ Texas Houston, Hlth Sci Ctr, Dept Pediat, Div Med Genet, Houston, TX 77030 USA
关键词
mTOR; pancreas; islets;
D O I
10.1073/pnas.0803047105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Regulation of pancreatic beta cell mass and function is a major determinant for the development of diabetes. Growth factors and nutrients are important regulators of beta cell mass and function. The signaling pathways by which these growth signals modulate these processes have not been completely elucidated. Tsc2 is an attractive candidate to modulate these processes, because it is a converging point for growth factor and nutrient signals. In these experiments, we generated mice with conditional deletion of Tsc2 in beta cells (beta Tsc2(-/-)). These mice exhibited decreased glucose levels and hyperinsulinemia in the fasting and fed state. Improved glucose tolerance in these mice was observed as early is 4 weeks of age and was still present in 52-week-old mice. Deletion of Tsc2 in beta cells induced expansion of beta cell mass by increased proliferation and cell size. Rapamycin treatment reversed the metabolic changes in beta Tsc2(-/-) mice by induction of insulin resistance and reduction of beta cell mass. The reduction of beta cell mass in beta Tsc2(-/-) mice by inhibition of the mTOR/Raptor (TORC1) complex with rapamycin treatment suggests that TORC1 mediates proliferative and growth signals induced by deletion of Tsc2 in beta cells. These studies uncover a critical role for the Tsc2/mTOR pathway in regulation of beta cell mass and carbohydrate metabolism in vivo.
引用
收藏
页码:9250 / 9255
页数:6
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