Biphasic Response of Pancreatic β-Cell Mass to Ablation of Tuberous Sclerosis Complex 2 in Mice

Abstract

Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic ␤-cell mass. Given the role of tuberous sclerosis complex 2 (TSC2) as an upstream molecule of mTOR (mammalian target of rapamycin), we examined the effect of TSC2 deficiency on ␤-cell function. Here, we show that mice deficient in TSC2, specifically in pancreatic ␤ cells (␤TSC2 ؊/؊ mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual ␤ cells. These mice also exhibit hypoglycemia and hyperinsulinemia at young ages (4 to 28 weeks). After 40 weeks of age, however, the ␤TSC2 ؊/؊ mice develop progressive hyperglycemia and hypoinsulinemia accompanied by a reduction in islet mass due predominantly to a decrease in the number of ␤ cells. These results thus indicate that TSC2 regulates pancreatic ␤-cell mass in a biphasic manner.

mTORC1 signaling and regulation of pancreatic β-cell mass

“…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. Further confirmation of the effect of mTORC1 activation in increased β-cell mass impaired insulin secretion.…”

“…Interestingly, this biphasic phenotype observed is similar to that observed in mice with conditional deletion of Tsc2 in β cells using the same RIP2-Cre line. 8 Therefore, it remains unclear if the disparate β-cell phenotypes observed following conditional deletion of Tsc1 vs. to Tsc2 are consequences of β-cell specific functions of these proteins or alterations resulting from the Cre line used.…”

“…1,4,5 Additionally, chronic mTORC1 activation plays an important role in the pathogenesis of insulin resistance in states of nutrient excess. 1,4,8 This effect is mediated by an S6K1-dependent negative feedback loop resulting in phosphorylation and degradation of IRS1. [1][2][3][4] Until recently, most of the evidence supporting the role of mTORC1 in insulin-sensitive tissues was derived from the use of rapamycin and alterations in insulin sensitivity in global S6K and 4E-bp-deficient mice.…”

“…63,64 In addition, it is now accepted that a major limitation of rapamycin for in vivo and in vitro studies is the inhibition of mTORC1 activity toward only a subset of mTORC1 substrates. 8,9,[65][66][67] Therefore, inhibiting mTORC1 signaling in vivo by genetic deletion of Raptor in β cells will provide new insights into the role of this pathway in nutrient-and growth factor-dependent regulation of β-cell proliferation.…”

“…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.…”