Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
Mol Med Rep. 2021 Apr;23(4). doi: 10.3892/mmr.2021.11909. Epub 2021 Feb 12.
Insulin resistance is one of important factors causing type 2 diabetes; therefore, regulating insulin sensitivity is considered a beneficial therapeutic approach against type 2 diabetes. The present study aimed to determine the effects of N1‑methylnicotinamide (MNAM) on insulin resistance (IR) in skeletal muscle from a mouse model of type 2 diabetes mellitus (T2DM), and to investigate the regulatory mechanisms of the sirtuin 1 (SIRT1)/peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α) signaling pathway. C57BL/6 mice were fed a normal diet with or without 1% MNAM and ob/ob mice were also fed a normal diet with or without 0.3 or 1% MNAM. Blood glucose, insulin levels, insulin resistance (IR), sensitivity indices and triglyceride (TG) content were detected using ELISAs. The expression of gluconeogenesis‑related, insulin signaling‑related and SIRT1/PGC‑1α pathway‑related proteins was analyzed using reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. , C2C12 cells were used to establish an IR muscle cell model by 0.75 mM palmitic acid (PA) treatment (PA group). The IR cell model was subsequently supplemented with 1 mM MNAM (PM group) or 1 mM MNAM + 30 M SIRT1 inhibitor, EX527 (PME group). After treatment the glucose levels and insulin signaling‑related proteins were detected by ELISAs and western blotting, respectively. Furthermore, the expression levels of SIRT1/PGC‑1α signaling pathway‑related mRNA and proteins under MNAM treatment were detected by RT‑qPCR and western blotting. MNAM reduced body weight gain in T2DM mice, decreased fasting blood glucose and fasting insulin levels, and inhibited IR. MNAM also regulated insulin signal transduction and promoted glucose utilization in skeletal muscle, and reduced lipid deposition. Thus, MNAM improved IR in the skeletal muscle of T2DM mice. Following application of a SIRT1 inhibitor, the effects of MNAM on the increased glucose utilization in insulin‑resistant myocytes and the insulin signaling pathway were suppressed. The mechanism of action was associated with activation of the SIRT1/PGC‑1α signaling pathway, which promoted the activation of the insulin receptor substrate IRS1/PI3K/AKT pathway.
胰岛素抵抗是导致 2 型糖尿病的重要因素之一；因此，调节胰岛素敏感性被认为是一种针对 2 型糖尿病的有益治疗方法。本研究旨在确定 N1-甲基烟酰胺（MNAM）对 2 型糖尿病（T2DM）小鼠模型骨骼肌胰岛素抵抗（IR）的影响，并探讨沉默信息调节因子 1（SIRT1）/过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC-1α）信号通路的调节机制。C57BL/6 小鼠给予正常饮食，或给予正常饮食并添加 1%MNAM；ob/ob 小鼠给予正常饮食，或给予正常饮食并添加 0.3%或 1%MNAM。采用 ELISA 法检测血糖、胰岛素水平、胰岛素抵抗（IR）、敏感性指数和甘油三酯（TG）含量。采用逆转录定量 PCR（RT-qPCR）和 Western blot 法分析糖异生相关、胰岛素信号相关和 SIRT1/PGC-1α 通路相关蛋白的表达。利用 0.75 mM 棕榈酸（PA）处理 C2C12 细胞建立 IR 肌细胞模型（PA 组）。随后，IR 细胞模型中添加 1 mM MNAM（PM 组）或 1 mM MNAM+30 μM SIRT1 抑制剂 EX527（PME 组）。处理后，采用 ELISA 和 Western blot 法分别检测葡萄糖水平和胰岛素信号相关蛋白。此外，采用 RT-qPCR 和 Western blot 法检测 MNAM 处理后 SIRT1/PGC-1α 信号通路相关 mRNA 和蛋白的表达水平。MNAM 降低 T2DM 小鼠体重增加，降低空腹血糖和空腹胰岛素水平，抑制 IR。MNAM 还调节胰岛素信号转导，促进骨骼肌葡萄糖利用，减少脂质沉积。因此，MNAM 改善了 T2DM 小鼠骨骼肌的 IR。应用 SIRT1 抑制剂后，MNAM 对胰岛素抵抗肌细胞葡萄糖利用增加和胰岛素信号通路的作用被抑制。其作用机制与激活 SIRT1/PGC-1α 信号通路有关，该通路促进胰岛素受体底物 IRS1/PI3K/AKT 通路的激活。
