Xiangya School of Public Health, Central South University, Changsha 410078, China.
Int J Mol Sci. 2024 Sep 30;25(19):10534. doi: 10.3390/ijms251910534.
As the sole producers of insulin under physiological conditions, the normal functioning of pancreatic β cells is crucial for maintaining glucose homeostasis in the body. Due to the high oxygen and energy demands required for insulin secretion, hypoxia has been shown to play a critical role in pancreatic β-cell dysfunction. Lipid metabolism abnormalities, a common metabolic feature in type 2 diabetic patients, are often accompanied by tissue hypoxia caused by metabolic overload and lead to increased free fatty acid (FFA) levels. However, the specific mechanisms underlying FFA-induced β-cell dysfunction remain unclear. Nicotinamide mononucleotide (NMN), a naturally occurring bioactive nucleotide, has garnered significant attention in recent years for its effectiveness in replenishing NAD and alleviating various diseases. Nevertheless, studies exploring the mechanisms through which NMN influences β-cell dysfunction remain scarce. In this study, we established an in vitro β-cell dysfunction model by treating INS-1 cells with palmitate (PA), including control, PA-treated, and PA combined with NMN or activator/inhibitor groups. Compared to the control group, cells treated with PA alone showed significantly reduced insulin secretion capacity and decreased expression of proteins related to the NAD/AMPK/SIRT1/HIF-1α pathway. In contrast, NMN supplementation significantly restored the expression of pathway-related proteins by activating NAD and effectively improved insulin secretion. Results obtained using HIF-1α and AMPK inhibitors/activators further supported these findings. In conclusion, our study demonstrates that NMN reversed the PA-induced downregulation of the NAD/AMPK/SIRT1/HIF-1α pathway, thereby alleviating β-cell dysfunction. Our study investigated the mechanisms underlying PA-induced β-cell dysfunction, examined how NMN mitigates this dysfunction and offered new insights into the therapeutic potential of NMN for treating β-cell dysfunction and T2DM.
在生理条件下，胰岛β细胞是胰岛素的唯一产生细胞，其正常功能对于维持体内葡萄糖稳态至关重要。由于胰岛素分泌需要高氧和高能量，缺氧被证明在胰岛β细胞功能障碍中起着关键作用。脂代谢异常是 2 型糖尿病患者的常见代谢特征，通常伴随着代谢超负荷引起的组织缺氧，导致游离脂肪酸（FFA）水平升高。然而，FFA 诱导的β细胞功能障碍的具体机制尚不清楚。烟酰胺单核苷酸（NMN）作为一种天然存在的生物活性核苷酸，近年来因其有效补充 NAD 和缓解各种疾病而受到广泛关注。然而，研究 NMN 影响β细胞功能障碍的机制的研究仍然很少。在这项研究中，我们通过用棕榈酸（PA）处理 INS-1 细胞建立了体外β细胞功能障碍模型，包括对照组、PA 处理组以及与 NMN 或激活剂/抑制剂联合处理的组。与对照组相比，单独用 PA 处理的细胞胰岛素分泌能力显著降低，与 NAD/AMPK/SIRT1/HIF-1α通路相关的蛋白表达减少。相比之下，NMN 补充通过激活 NAD 显著恢复了通路相关蛋白的表达，并有效改善了胰岛素分泌。使用 HIF-1α 和 AMPK 抑制剂/激活剂得到的结果进一步支持了这些发现。总之，我们的研究表明，NMN 逆转了 PA 诱导的 NAD/AMPK/SIRT1/HIF-1α 通路下调，从而缓解了β细胞功能障碍。我们的研究探讨了 PA 诱导的β细胞功能障碍的机制，研究了 NMN 如何减轻这种功能障碍，并为 NMN 治疗β细胞功能障碍和 T2DM 的治疗潜力提供了新的见解。
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