N1‑methylnicotinamide ameliorates insulin resistance in skeletal muscle of type 2 diabetic mice by activating the SIRT1/PGC‑1α signaling pathway

Chen,Yu; Zhang,Jingfan; Li,Ping; Liu,Cong; Li,Ling

doi:10.3892/mmr.2021.11909

N1‑methylnicotinamide ameliorates insulin resistance in skeletal muscle of type 2 diabetic mice by activating the SIRT1/PGC‑1α signaling pathway

Authors:
- Yu Chen
- Jingfan Zhang
- Ping Li
- Cong Liu
- Ling Li
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Affiliations: Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
Published online on: February 9, 2021 https://doi.org/10.3892/mmr.2021.11909
Article Number: 270

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Abstract

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. In vitro, 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 µM 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.

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