The activity and levels of SIRT1, which promotes cell survival in several models, are linked to glucose concentrations and cellular energy metabolism. The present study aimed to determine whether impaired Sirt1 activity is involved in the induction of apoptosis by the nutrientsensing hexosamine biosynthesis pathway (HBP). Pancreatic Nit-1, Rin-m5F, and Min6 b-cells were acutely treated at different doses and times with glucosamine, which enters and stimulates the HBP. Sirt1 levels were genetically modulated by retroviral infection. Expression levels, cellular localization, and activity of apoptosis-related markers were determined by qPCR, immunoblotting, and co-immunoprecipitation. Glucosamine treatment dose-and time dependently induced cell apoptosis in all cell lines studied. HBP stimulation time dependently modified SIRT1 protein levels, notably in the cytoplasm. This was concomitant with increased E2F1 binding to the c-myc promoter. In both NIT-1 and min6 b-cells, genetic knockdown of Sirt1 expression resulted in higher susceptibility to HBPstimulated apoptosis, whereas overexpression of Sirt1 had the opposite impact. These findings indicate that reduction of SIRT1 levels by hexosamines contributes to b-cell apoptosis. Methods to increase SIRT1 levels or activity could thus prevent the decrease in b-cell mass, notably that observed in type 2 diabetes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.