Progressive beta cell apoptosis is a major cause leading to a decline in beta cell mass in type 2 diabetes.While it has been discovered that mitochondrial protein Sirtuin 5 (SIRT5) functions as the primary site of oxidative metabolism and plays crucial roles in apoptosis and intracellular signaling, the contribution of SIRT5 in beta cell remains to be fully defined.Given the potential benefit of SIRT5 activation in cell metabolism, this study aimed to examine whether overexpression of SIRT5 in beta cells is sufiicient to prevent saturated fatty acid induced impairment in insulin secretion and apoptosis, thus elucidating the role of SIRT5 in beta cell protection.In line with our previous study, two kinds of pancreatic beta cell lines were selected for the detection.Mousederived NIT1 cells as well as humanderived PANC1 cells were transfected with GFPSIRT5Ad plasmid and cell apoptosis was induced by palmitic acid (0.5 mM), validated with TUNELDAPI double staining and RTCA iCelligence cell growth monitor system.Compared with control group, it was shown that SIRT5 overexpression could significantly reduce the quantity of apoptotic beta cells under chronic exposure to palmitic acid, accompanied with decreased Caspase 3 and Caspase 9 activities.Accordingly, cytochrome C oxidase activity in cells was also suppressed.Meanwhile, palmitic acid suppressed glucosestimulated insulin secretion, but SIRT5 overexpression could recover the beta cell insulin secretion capacity against glucose fluctuation.Moreover, it is discovered that novel binding relationship exists between SIRT5 and BclXL, providing a reliable explanation for the antiapoptosis role of SIRT5.Together, these resuits reveal a potential role of SIRT5 in improvement of saturated fatty acidinduced beta cell dysfunction and apoptosis.Considering the role of beta cell apoptosis in T2DM, overexpression or activation of SIRT5 may provide an erumpent approach as a potential target for beta cell protection.This approach might actually reverse the disease to a degree rather than just palliate glycemia.