title: WldS enhances insulin transcription and secretion via a SIRT1-dependent pathway and improves glucose homeostasis.
abstract: OBJECTIVE Wld(S) (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 Wld(S) on β-cells and glucose homeostasis.
  
  
  METHODS
  Using the Wld(S) mice, we measured the expression of Wld(S) in pancreas and analyzed the effect of Wld(S) on glucose homeostasis. The direct effect of Wld(S) 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, Wld(S) mice with SIRT1 deficiency were generated to study whether the SIRT1-dependent pathway is involved.
  
  
  RESULTS
  Wld(S) is highly expressed in the pancreas and improves glucose homeostasis. Wld(S) mice are resistant to high-fat diet-induced glucose intolerance and streptozotocin (STZ)-induced hyperglycemia. Wld(S) 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 Wld(S). Moreover, Wld(S) 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 Wld(S) 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.
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors: Jingxia
authors: J
authors: Wu
authors: Fang
authors: F
authors: Zhang
authors: Menghong
authors: M
authors: Yan
authors: Dongmei
authors: D
authors: Wu
authors: Qiujing
authors: Q
authors: Yu
authors: Yi
authors: Y
authors: Zhang
authors: Ben
authors: B
authors: Zhou
authors: Michael W
authors: MW
authors: McBurney
authors: Qiwei
authors: Q
authors: Zhai
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002096:C-Peptide / Q000378:metabolism; D045744:Cell Line, Tumor; D059305:Diet, High-Fat / Q000009:adverse effects; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009525:Niacin; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002096:C-Peptide; D007328:Insulin; D009419:Nerve Tissue Proteins; C442580:Wld protein, mouse; D009243:NAD; D009525:Niacin; D009249:NADP; D000255:Adenosine Triphosphate; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose