WldS Enhances Insulin Transcription and Secretion via a SIRT1-Dependent Pathway and Improves Glucose Homeostasis

Abstract

OBJECTIVE: WldS (Wallerian degeneration slow), a fusion protein from a spontaneous mutation containing full-length nicotinamide mononucleotide adenylyltransferase 1, has NAD biosynthesis activity and protects axon from degeneration robustly. NAD biosynthesis is also implicated in insulin secretion in β-cells. The aim of this study was to investigate the effect of WldS on β-cells and glucose homeostasis. RESEARCH DESIGN AND METHODS: Using the WldS mice, we measured the expression of WldS in pancreas and analyzed the effect of WldS on glucose homeostasis. The direct effect of WldS on insulin transcription and secretion and the related mechanisms was measured in isolated islets or β-cell lines. Silent information regulator 1 (SIRT1), an NAD-dependent protein deacetylase, is involved in insulin secretion. Thus, WldS mice with SIRT1 deficiency were generated to study whether the SIRT1-dependent pathway is involved. RESULTS: WldS is highly expressed in the pancreas and improves glucose homeostasis. WldS mice are resistant to high-fat diet–induced glucose intolerance and streptozotocin (STZ)-induced hyperglycemia. WldS increases insulin transcription dependent on its NAD biosynthesis activity and enhances insulin secretion. SIRT1 is required for the improved insulin transcription, secretion, and resistance to STZ-induced hyperglycemia caused by WldS. Moreover, WldS associates with SIRT1 and increases NAD levels in the pancreas, causing the enhanced SIRT1 activity to downregulate uncoupling protein 2 (UCP2) expression and upregulate ATP levels. CONCLUSIONS: Our results demonstrate that WldS combines an insulinotropic effect with protection against β-cell failure and suggest that enhancing NAD biosynthesis in β-cells to increase SIRT1 activity could be a potential therapeutic approach for diabetes.