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WldS 通过 SIRT1 依赖性途径增强胰岛素转录和分泌，改善葡萄糖内稳态。

WldS enhances insulin transcription and secretion via a SIRT1-dependent pathway and improves glucose homeostasis.

机构信息

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.

出版信息

Diabetes. 2011 Dec;60(12):3197-207. doi: 10.2337/db11-0232. Epub 2011 Oct 13.

DOI:10.2337/db11-0232
PMID:21998399
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3219932/
Abstract

UNLABELLED

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.

RESEARCH DESIGN AND 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.

摘要

未加标签

目的 Wld(S)（Wallerian 变性慢），一种来自自发突变的融合蛋白，包含全长烟酰胺单核苷酸腺嘌呤二核苷酸转移酶 1，具有 NAD 生物合成活性，可显著保护轴突免受变性。NAD 生物合成也与β细胞中的胰岛素分泌有关。本研究旨在研究 Wld(S)对β细胞和葡萄糖稳态的影响。

研究设计和方法

使用 Wld(S) 小鼠，我们测量了胰腺中 Wld(S) 的表达，并分析了 Wld(S) 对葡萄糖稳态的影响。在分离的胰岛或β细胞系中测量了 Wld(S) 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)，一种 NAD 依赖性蛋白去乙酰化酶，参与胰岛素分泌。因此，生成了 SIRT1 缺陷型 Wld(S) 小鼠以研究 SIRT1 依赖性途径是否参与其中。

结果

Wld(S) 在胰腺中高度表达并改善葡萄糖稳态。Wld(S) 小鼠对高脂肪饮食诱导的葡萄糖不耐受和链脲佐菌素 (STZ) 诱导的高血糖有抵抗力。Wld(S) 增加胰岛素转录，依赖于其 NAD 生物合成活性，并增强胰岛素分泌。SIRT1 是 Wld(S) 引起的胰岛素转录、分泌增强和对 STZ 诱导的高血糖的抵抗力所必需的。此外，Wld(S) 与 SIRT1 结合并增加胰腺中的 NAD 水平，导致增强的 SIRT1 活性下调解偶联蛋白 2(UCP2)表达并上调 ATP 水平。

结论

我们的结果表明，Wld(S) 将胰岛素刺激作用与对β细胞衰竭的保护作用结合在一起，并表明增强β细胞中的 NAD 生物合成以增加 SIRT1 活性可能是治疗糖尿病的一种潜在治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/6c91be039cda/3197fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/00524eeb9ac4/3197fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/9f17dc0f3d62/3197fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/e9148c80b522/3197fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/1e055298661b/3197fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/84e482f6768d/3197fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/cb2dfac9b8c9/3197fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/6c91be039cda/3197fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/00524eeb9ac4/3197fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/9f17dc0f3d62/3197fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/e9148c80b522/3197fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/1e055298661b/3197fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/84e482f6768d/3197fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/cb2dfac9b8c9/3197fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/733d/3219932/6c91be039cda/3197fig7.jpg

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