SIRT6 Is a Key Regulator of Pancreatic β-cell Survival and Function During Aging

Abstract

Pancreatic β cells undergo senescence and death during aging; however, the underlying mechanisms remain incompletely understood. The aims of this study were to investigate the role of sirtuin 6 (SIRT6) in the regulation of β-cell survival and function during aging. Pancreatic β-cell-specific SIRT6 transgenic mice (TgSIRT6) were generated for the study. DNA damage, cell death, and cell proliferation were analyzed by immunofluorescence microscopy. Gene expression was analyzed by RNA-seq. Candidate genes and pathways were validated in the INS-1 cell line. SIRT6 protein levels were decreased in pancreatic β cells during aging. TgSIRT6 mice exhibited less DNA damage and cell death including apoptosis, necroptosis, and pyroptosis in β cells than that in wildtype mice. TgSIRT6 mice had increased number of large islets and an increase in total islet area in pancreas compared to wildtype mice. As a result, TgSIRT6 mice showed better glucose tolerance and glucose-stimulated insulin secretion than wildtype mice. RRAD and GEM like GTPase 2 (REM2), an endogenous inhibitor of high-voltage-activated calcium channels, was negatively regulated by SIRT6. Knockdown of Rem2 in INS-1 cells partially rescued the SIRT6 deficiency- and palmitic acids-induced DNA damage, lipid peroxidation, and cell death. Rem2 β-cell-specific knockout mice had less DNA damage and cell death in β cells than that in wildtype mice. Our data suggest that SIRT6 is a critical anti-aging factor in pancreatic β cells. SIRT6 overexpression significantly reduces DNA damage and cell death. Thus, SIRT6 can be a therapeutic target for reversing β-cell aging.