Pancreatic β-Cell Failure Mediated by mTORC1 Hyperactivity and Autophagic Impairment

Abstract

Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) in b-cells is usually found as a consequence of increased metabolic load. Although it plays an essential role in b-cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using a mouse model with b-cell-specific deletion of Tsc2 (bTsc2 2/2 ) and, consequently, mTORC1 hyperactivation, we focused on the role that chronic mTORC1 hyperactivation might have on b-cell failure. mTORC1 hyperactivation drove an early increase in b-cell mass that later declined, triggering hyperglycemia. Apoptosis and endoplasmic reticulum stress markers were found in islets of older bTsc2 2/2 mice as well as accumulation of p62/SQSTM1 and an impaired autophagic response. Mitochondrial mass was increased in b-cells of bTsc2 2/2 mice, but mitophagy was also impaired under these circumstances. We provide evidence of b-cell autophagy impairment as a link between mTORC1 hyperactivation and mitochondrial dysfunction that probably contributes to b-cell failure.Nutrient overload is one of the main causes of insulin resistance. This triggers the compensatory mechanisms leading to b-cell mass increase and hyperinsulinemia. Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) is elicited under nutrient overload conditions (1-3). mTORC1 plays a positive role in b-cell mass expansion (3-6), and rapamycin treatment impairs b-cell mass adaptation (7,8). On the other hand, mTORC1 hyperactivation is also a cause of insulin resistance (1) and endoplasmic reticulum (ER) stress (9), conditions linked with b-cell dysfunction and diabetes progression (10,11). We previously described how Tsc2 deletion in b-cells (bTsc2 2/2 ) results in chronic mTORC1 hyperactivation leading to a biphasic phenotype with early b-cell mass increase, hyperinsulinemia, and hypoglycemia. This was followed by b-cell failure and hyperglycemia in older mice (3). We also found how the first phase in bTsc2 2/2 mice is characterized by both an increase of mitochondrial mass and enhanced glucose-stimulated insulin secretion (12). Autophagy is a cytoprotective mechanism also found essential for b-cell homeostasis (13,14). Autophagy plays a protective role under stress conditions, such as ER stress (15), and we and others have described its positive role in b-cells under these conditions (16,17). Autophagy is also responsible for the turnover of mitochondria by the specific elimination of defective or damaged organelles. mTORC1 is a critical negative regulator of autophagy (18), and studies have shown how TSC deficiency leads to impaired autophagy in human tumors and cell lines (19,20). In this study, we explored the intriguing possibility that mTORC1 hyperactivity in b-cells, apart from being essential for b-cell compensatory mechanisms, might

Inhibition of Autophagic Turnover in β-Cells by Fatty Acids and Glucose Leads to Apoptotic Cell Death

“…We speculate that activated mTORC1 in ␤-cells treated with PA and glucose inhibits autophagy leading to accumulation of SQSTM1/p62 and ubiquitinated proteins. This is consistent with recent observations (14), where hyperactivation of mTORC1 in Ulk Ϫ/Ϫ islets and Tsc2…”

“…Inhibition of autophagy in ␤-cell lines by down-regulating Bif-1 expression or treatment with bafilomycin A1 increased FFA-induced apoptotic cell death, suggesting a protective role for autophagy in ␤-cells. mTORC1, which inhibits autophagy, is activated by nutrient overload (14). We speculate that activated mTORC1 in ␤-cells treated with PA and glucose inhibits autophagy leading to accumulation of SQSTM1/p62 and ubiquitinated proteins.…”

“…mTORC1 is also activated by nutrient overload (14). Because treatment of ␤-cells with PA and glucose increases p62 levels, we asked whether PA and glucose exposure induce the activation of mTORC1 in ␤-cells.…”

“…7D). Recent studies have shown that hyperactivation of mTORC1 in TSC1 or TSC2 (tuberous sclerosis 1 and 2)-deficient fibroblasts leads to an increase in the unfolded protein response caused by ER stress (14). Because accumulation of polyubiquitinated proteins in ␤-cells leads to increased ER stress (38), we next asked whether activation of mTORC1 in ␤-cell lines and human islets induces ER stress.…”

System-L amino acid transporters play a key role in pancreatic β-cell signalling and function

“…However, the chronic hyperactivation of mTORC1 inhibits insulin/ growth factor signalling mediated by ribosomal protein S6 kinase (S6K) inhibitory phosphorylation of insulin receptor substrate (Um et al 2004(Um et al , 2006. Indeed, although β-cell-specific mTORC1 gain-of-function mutant adult mice have initially increased β-cell function and mass (Shigeyama et al 2008, Hamada et al 2009) with age, there is a decline in β-cell function and mass mediated by feedback inhibition of mTORC1 and the induction of autophagy (Shigeyama et al 2008, Bartolomé et al 2014. Interestingly, obese diabetic humans have increased circulating levels of BCAA, which is predictive of T2DM progression (Newgard et al 2009, Fiehn et al 2010, Wang et al 2011b.…”