Disruption of Tsc2 in pancreatic beta cells induces beta cell mass expansion and improved glucose tolerance in a TORC1-dependent manner.
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 (betaTsc2(-/-)). 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 beta cells induced expansion of beta cell mass by increased proliferation and cell size. Rapamycin treatment reversed the metabolic changes in betaTsc2(-/-) mice by induction of insulin resistance and reduction of beta cell mass. The reduction of beta cell mass in betaTsc2(-/-) 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.
Rachdi
Latif
L
Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8127, St. Louis, MO 63110, USA.
Balcazar
Norman
N
Osorio-Duque
Fernando
F
Elghazi
Lynda
L
Weiss
Aaron
A
Gould
Aaron
A
Chang-Chen
Karen J
KJ
Gambello
Michael J
MJ
Bernal-Mizrachi
Ernesto
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D050260:Carbohydrate Metabolism / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
C519509:Crtc1 protein, mouse; D007328:Insulin; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus