mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress

Abstract

Through in vivo analyses of mTOR deficiency and in vitro studies of human and mouse pancreatic islets, Chau et al. show that mTOR plays a critical role in β cell survival in diabetes. mTOR associates with and inhibits the transcriptional ChREBP–Mlx complex, suppressing TXNIP expression and β cell death.

mTORC in β cells: more Than Only Recognizing Comestibles

“…These data suggest that β cell-specific ablation of mTOR exacerbated progressive hyperglycemia and further potentiated glucose intolerance and impaired insulin secretion in the STZ mouse model of β cell destruction and diabetes. These defects are β cell specific; Chau et al (2017) reproduced earlier findings from pharmacologic mTOR inhibition by rapamycin (Barlow et al, 2013) Correspondence to Kathrin Maedler: kmaedler@uni-bremen.de; Amin Ardestani: ardestani.amin@gmail.com smaller and exhibit reduced β cell mass together with defective glucose-stimulated insulin secretion. This is in line with the loss of important factors for β cell proliferation, i.e., cyclin D2 and D3 and Cdk4 upon mTOR inhibition (Balcazar et al, 2009).…”

“…mTORC1 inhibition in β cells prevents β cell death and enhances insulin secretion (Bachar et al, 2009;Yuan et al, 2017). High glucose-induced mTORC1 activation (as demonstrated by phosphorylation of its downstream proteins including S6K1 and S6) is also confirmed by the study from Chau et al (2017). Consistently, although constitutive activation of mTORC1 by β cell-specific deletion of TSC2, a negative regulator of mTORC1, shows increased β cell mass in the early phase of their life, mice become hyperglycemic and severely hypo-insulinemic as a result of a dramatic loss of β cells at an older age because of chronic mTORC1 activation (Shigeyama et al, 2008).…”

“…In this issue a well-designed study by Chau et al provides the underlying mechanisms for the connection of mTOR deficiency to β cell death and the progression of diabetes. Chau et al (2017) initially show that genetic disruption of mTOR selectively in pancreatic β cells leads to defective glucose-induced insulin secretion and glucose intolerance as a result of impaired β cell survival and reduced β cell mass. Further analysis of islets isolated from β cell-specific mTOR knockout (β-mTOR KO) mice as well as an mTOR-deficient β cell line revealed that mitochondrial membrane potential and respiration is compromised, which leads to impaired ATP production, lower intracellular Ca 2+ , and elevated ROS production.…”

“…Interestingly, Chau et al (2017) identified that mTOR functions as an apoptosis-protecting signal in β cells by interfering with the activation of Thioredoxin-interacting protein (TXN IP), a key regulator of the intracellular redox state. Loss of mTOR induces TXN IP at both the mRNA and protein level and amplifies TXN IP up-regulation in stressed β cells challenged with STZ or increased glucose concentrations.…”

mTORC1-to-AMPK switching underlies β cell metabolic plasticity during maturation and diabetes

“…Furthermore, β cell-specific ablation of TSC1 or TSC2 (the upstream inhibitors of mTOR) results in increased postnatal β cell mass (10,14,15). On the other hand, β cell-specific deletion of mTORC1 in mice results in severe glucose intolerance due to underdeveloped β cell mass (16)(17)(18). Collectively, these data indicate that mTORC1 expression is required for the development and growth of β cells during embryonic and early postnatal life.…”