Auto Vo Lam Bi Su 16 15 ##VERIFIED##
Auto Vo Lam Bi Su 16 15 ##VERIFIED##
Auto Vo Lam Bi Su 16 15
This study examined the role of genetic and environmental factors in determining age-at-onset of type 1 diabetes. A cohort of 60 UK sib-pair families with 14 probands born since 1985 with type 1 diabetes was assembled. All family members were interviewed and their records scrutinised. Pedigree and proband assessments were completed including age at onset of diabetes and type 1 diabetes-related autoantibodies.
Materials and methods: We showed that TSC2 has low acetylation status and its acetylation level increased with an elevation of glucose concentration. Acetylation status was correlated positively with glucose concentration and glucose concentration was related with mTORC1 and p70S6K activation, indicating that TSC2 acetylation alters mTORC1 activity as well as glucose concentration. In addition, we observed by Western Blot that TSC2 acetylation decreased in the presence of a low glucose concentration. Cell viability and proliferation decreased in the presence of high glucose concentration and increased in the presence of low glucose concentration.P= 0.0001. This suggests that TSC2 acetylation stimulates autophagy and mitophagy processes in pancreatic cells under normal conditions and impair the ability of pancreatic cells to maintain homeostasis in the presence of high glucose concentration.
Conclusions: Altogether, these findings identify a novel regulatory mechanism controlling survival of pancreatic islets: hypoxia promotes a dysregulation of Tfeb transcriptional activity by promoting its acetylation that results in lysosomal dysfunction. TOR inhibition not only restores autophagy flux but also improves ER stress-induced apoptosis, suggesting that combined pharmacological targeting of both processes is necessary for functional recovery of islets after transplantation.
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