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

Latif Rachdi, Norman Balcazar, Fernando Osorio-Duque, Lynda Elghazi, Aaron Weiss, Aaron Gould, Karen J. Chang-Chen, Michael J. Gambello, Ernesto Bernal-Mizrachi

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

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 of Tsc2 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 of Tsc2 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 of Tsc2 in β cells. These studies uncover a critical role for the Tsc2/mTOR pathway in regulation of β cell mass and carbohydrate metabolism in vivo.

Original languageEnglish (US)
Pages (from-to)9250-9255
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number27
DOIs
StatePublished - Jul 8 2008

Keywords

  • Islets
  • Pancreas
  • mTOR

ASJC Scopus subject areas

  • General

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