mTORC1 signaling and regulation of pancreatic β-cell mass

The capacity of beta cells to expand in response to insulin resistance is a critical factor in the development of type 2 diabetes. Proliferation of beta cells is a major component for these adaptive responses in animal models. The extracellular signals responsible for beta-cell expansion include growth factors, such as insulin, and nutrients, such as glucose and amino acids. AKT activation is one of the important components linking growth signals to the regulation of beta-cell expansion. Downstream of AKT, tuberous sclerosis complex 1 and 2 (TSC1/2) and mechanistic target of rapamycin complex 1 (mTORC1) signaling have emerged as prime candidates in this process, because they integrate signals from growth factors and nutrients. Recent studies demonstrate the importance of mTORC1 signaling in beta cells. This review will discuss recent advances in the understanding of how this pathway regulates beta-cell mass and present data on the role of TSC1 in modulation of beta-cell mass. Herein, we also demonstrate that deletion of Tsc1 in pancreatic beta cells results in improved glucose tolerance, hyperinsulinemia and expansion of beta-cell mass that persists with aging.