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

Abstract

Regulation of pancreatic ␤ cell mass and function is a major determinant for the development of diabetes. Growth factors and nutrients are important regulators of ␤ 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 ␤ cells (␤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 as 4 weeks of age and was still present in 52-week-old mice. Deletion of Tsc2 in ␤ cells induced expansion of ␤ cell mass by increased proliferation and cell size. Rapamycin treatment reversed the metabolic changes in ␤Tsc2 ؊/؊ mice by induction of insulin resistance and reduction of ␤ cell mass. The reduction of ␤ cell mass in ␤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 ␤ cells. These studies uncover a critical role for the Tsc2/mTOR pathway in regulation of ␤ cell mass and carbohydrate metabolism in vivo.mTOR ͉ pancreas ͉ islets

mTORC1 signaling and regulation of pancreatic β-cell mass

“…These changes are explained by increases in β-cell mass, proliferation and cell size. 7 A separate study demonstrated that conditional Tsc2 deletion in β cells exhibited a similar phenotype, but these mice developed diabetes and β-cell failure after 40 weeks. 8 The differences in the phenotype between these reports are most likely explained by different genetic backgrounds and the RIP-Cre line (hypothalamic expression) used.…”

“…mTORC1 controls growth (cell size), proliferation (cell number) and metabolism directly, by modulating eukaryotic initiation factor 4E-binding proteins (4E-BP 1, 2 and 3) and ribosomal protein S6 kinases (S6K 1 and 2), and indirectly, by attenuating AKT signaling via an mTORC1/ S6K-mediated negative feedback loop. [1][2][3][4][5][6][7][8][9][10] How TSC/mTOR signaling regulates β-cell mass expansion is not completely understood. A better understanding of how mTORC1 regulates β-cell mass and the role of interactions between mTORC1 and other signaling pathways in this process are critical to discovering how β-cell mass adapts to insulin resistance and autoimmune injury and, ultimately, how it impacts diabetes management.…”

mTORC1 signaling in energy balance and metabolic disease

“…110 Hence, mTORC1 signaling is actually a critical mediator of cellular adaptation to nutrient overload and increased insulin demand during diet-induced obesity, which is a conclusion further confirmed by genetically inducing mTORC1 overactivity within b-cells. 98,99,111 Nevertheless, these recent published data also highlight how much remains to be done to better understand the role of the mTORC1 pathway in the physiopathology of obesity and other metabolic diseases. The evidence reported so far clearly suggests that it might be counterproductive to broadly target the mTORC1 pathway for the treatment of obesity and obesity-related metabolic alterations, such as hyperlipidemia, glucose intolerance and insulin resistance.…”

“…Indeed, in vivo overactivity of mTORC1 signaling, due to deletion of either TSC2 (a negative regulator of mTORC1) or loss of LKB1 (a positive regulator of AMPK) in b-cells, increases b-cell mass and improves glucose tolerance. 98,99 Conversely, rapamycin treatment leads to inhibition of b-cell proliferation and apoptosis, 100,101 and worsens hyperglycemia in obese animals by inhibiting glucose-stimulated insulin secretion. 102,103 mTORC1 in the liver As expected, once activated, mTORC1 signaling has a positive effect on hepatocyte growth, protein synthesis and cell cycle, and hence contributes to liver regeneration.…”

“…81 Conversely, S6K1 À/À mice show enhanced insulin sensitivity under HFD, which is accompanied by reduced IRS1 phosphorylation in the skeletal muscle. 82 Regulation of b-cell mass; regulation of glucose-stimulated insulin secretion [95][96][97][98][99][100][101][102][103] Regulation of hepatocytes growth and lipid metabolism [104][105][106][107][108][109] Abbreviation: mTORC1, mammalian target of rapamycin complex 1.…”