WldS enhances insulin transcription and secretion via a SIRT1-dependent pathway and improves glucose homeostasis.
WldS enhances insulin transcription and secretion via a SIRT1-dependent pathway and improves glucose homeostasis.
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作者：
Wu J;Zhang F;Yan M;Wu D;Yu Q;Zhang Y;Zhou B;McBurney MW;Zhai Q
WldS是一种来自自发突变的融合蛋白，含有全长烟酰胺单核苷酸腺基转移酶1，具有NAD生物合成活性，并能有效地保护轴突免于变性。NAD的生物合成也与β细胞的胰岛素分泌有关。本研究的目的是探讨WldS对β-细胞和血糖稳态的影响。利用WldS小鼠，检测WldS在胰腺中的表达，分析WldS对血糖稳态的影响。在分离的胰岛或β细胞系中检测WldS对胰岛素转录和分泌的直接影响及其相关机制。沉默信息调节因子1(SIRT1)是一种依赖NAD的蛋白质去乙酰基酶，参与胰岛素的分泌。因此，我们建立了SIRT1缺乏的WldS小鼠，以研究SIRT1依赖的途径是否参与其中。WldS在胰腺中高度表达，并改善血糖稳态。WldS小鼠对高脂饮食诱导的糖耐量异常和链脲佐菌素(STZ)诱导的高血糖具有抵抗力。WldS依赖其NAD生物合成活性增加胰岛素转录，促进胰岛素分泌。SIRT1是改善胰岛素转录、分泌和抵抗由WldS引起的STZ引起的高血糖所必需的。此外，WldS与SIRT1结合，增加胰腺中NAD水平，导致SIRT1活性增强，下调解偶联蛋白2(UCP2)的表达，上调ATP水平。我们的结果表明，WldS结合了胰岛素调节作用和对β细胞衰竭的保护作用，并提示增强β细胞中NAD的生物合成以提高SIRT1活性可能是一种潜在的糖尿病治疗方法。
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. 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. 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. 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.