The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of metabolic and nutrient cues that integrates environmental inputs into downstream signaling pathways to control cellular metabolism, growth, and survival. While numerous in vitro and in vivo studies reported the positive functions of mTORC1 in the regulation of β cell survival and proliferation under physiological conditions, more recent work demonstrates the opposite in the long term; this is exemplified by the constitutive inappropriate hyper-activation of mTORC1 in diabetic islets or β cells under conditions of increased β cell stress and metabolic demands. These recent findings uncover mTORC1‘s importance as an emerging significant player in the development and progression of β cell failure in type 2 diabetes and suggest that mTORC1 may act as a “double edge sword” in the regulation of β cell mass and function in response to metabolic stress such as nutrient overload and insulin resistance. In this review, Ardestani et al. present the positive and negative effects of mTORC1 signaling in the β cell and discuss the implications for metabolic disease therapies. While essential for β cell development, function, and survival, mTORC1’s hyperactivation under constant metabolic stress contributes to β cell failure.
Bibliographical noteFunding Information:
Work conducted in the authors’ laboratory is supported by the German Research Foundation (DFG), the European Research Council (ERC), the JDRF , and the EFSD/Lilly Fellowship Programme . We thank Erol Cerasi for excellent proofreading and support and David Sabatini and Claes Wollheim for supporting the concept of this review. We apologize that we were unable to cite many primary references due to space limitations.
© 2017 Elsevier Inc.