Open AccessDisruption of Tsc2 in pancreatic β cells induces β cell mass expansion and improved glucose tolerance in a TORC1-dependent manner
Author(s) -
Latif Rachdi,
Norman Balcázar,
Fernando Osorio-Duque,
Lynda Elghazi,
Aaron Weiss,
Aaron P. Gould,
Karen J. Chang-Chen,
Michael J. Gambello,
Ernesto Bernal-Mizrachi
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0803047105
Subject(s) - beta cell , endocrinology , hyperinsulinemia , cell growth , medicine , pi3k/akt/mtor pathway , biology , microbiology and biotechnology , beta (programming language) , mechanistic target of rapamycin , tsc2 , carbohydrate metabolism , insulin , cell , insulin resistance , chemistry , signal transduction , biochemistry , islet , computer science , programming language
Regulation of pancreatic β cell mass and function is a major determinant for the development of diabetes. Growth factors and nutrients are important regulators of β 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 ofTsc2 in β cells (βTsc2 −/− ). These mice exhibited decreased glucose levels and hyperinsulinemia in the fasting and fed state. Improved glucose tolerance in these mice was observed as early as 4 weeks of age and was still present in 52-week-old mice. Deletion ofTsc2 in β cells induced expansion of β cell mass by increased proliferation and cell size. Rapamycin treatment reversed the metabolic changes in βTsc2 −/− mice by induction of insulin resistance and reduction of β cell mass. The reduction of β cell mass in βTsc2 −/− mice by inhibition of the mTOR/Raptor (TORC1) complex with rapamycin treatment suggests that TORC1 mediates proliferative and growth signals induced by deletion ofTsc2 in β cells. These studies uncover a critical role for the Tsc2/mTOR pathway in regulation of β cell mass and carbohydrate metabolismin vivo .