Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine, Shinagawa, Tokyo 142-0064, Japan.
Int J Mol Sci. 2021 Dec 8;22(24):13224. doi: 10.3390/ijms222413224.
The NAD-dependent deacetylase SIRT1 improves β cell function. Accordingly, nicotinamide mononucleotide (NMN), the product of the rate-limiting step in NAD synthesis, prevents β cell dysfunction and glucose intolerance in mice fed a high-fat diet. The current study was performed to assess the effects of NMN on β cell dysfunction and glucose intolerance that are caused specifically by increased circulating free fatty acids (FFAs). NMN was intravenously infused, with or without oleate, in C57BL/6J mice over a 48-h-period to elevate intracellular NAD levels and consequently increase SIRT1 activity. Administration of NMN in the context of elevated plasma FFA levels considerably improved glucose tolerance. This was due not only to partial protection from FFA-induced β cell dysfunction but also, unexpectedly, to a significant decrease in insulin clearance. However, in conditions of normal FFA levels, NMN impaired glucose tolerance due to decreased β cell function. The presence of this dual action of NMN suggests caution in its proposed therapeutic use in humans.
NAD 依赖性去乙酰化酶 SIRT1 可改善β细胞功能。因此，烟酰胺单核苷酸（NMN），即 NAD 合成限速步骤的产物，可预防高脂肪饮食喂养的小鼠的β细胞功能障碍和葡萄糖耐量受损。本研究旨在评估 NMN 对由循环游离脂肪酸（FFA）增加引起的β细胞功能障碍和葡萄糖耐量受损的影响。在 C57BL/6J 小鼠中，静脉输注 NMN（或不输注）和油酸，以在 48 小时内升高细胞内 NAD 水平，从而增加 SIRT1 活性。在升高的血浆 FFA 水平下给予 NMN 可显著改善葡萄糖耐量。这不仅归因于对 FFA 诱导的β细胞功能障碍的部分保护，而且出乎意料的是，还归因于胰岛素清除率的显著降低。然而，在正常 FFA 水平的情况下，NMN 会因β细胞功能下降而损害葡萄糖耐量。NMN 的这种双重作用表明，在人类中对其进行治疗性应用时需要谨慎。
