Insulin resistance is defined as a failure to trigger the activation of the PI3K-AKT pathway by normal levels of insulin; therefore, it is well linked to metabolic disorders. Although multiple mechanisms contribute to insulin resistance, one major cause is elevated concentrations of plasma free fatty acids, which are known to suppress insulin signaling. However, the underlying mechanism is still elusive. Here, we found that palmitic acid increased the expression of two miRNAs, miR-3180-3p and miR-4632-5p, in HepG2 cells. Transfection of HepG2 cells with miR-3180-3p or miR-4632-5p reduced insulin-induced activation of the PI3K-AKT pathway. Moreover, palmitic acid or two miRNAs inhibited insulin-induced phosphorylation of Tyr612 on IRS-1 without affecting insulin receptor activation. Therefore, two miRNAs are suggested to be involved in palmitic acid-induced insulin resistance through suppression of insulin-induced IRS-1 phosphorylation. Identification of miR-3180-3p and miR-4632-5p targets could provide valuable information for the development of therapeutic drugs for type 2 diabetes.

胰岛素抵抗被定义为无法通过正常水平的胰岛素触发 PI3K-AKT 通路的激活；因此，它与代谢紊乱密切相关。尽管多种机制导致胰岛素抵抗，但一个主要原因是血浆游离脂肪酸浓度升高，已知其会抑制胰岛素信号传导。然而，潜在的机制仍然难以捉摸。在这里，我们发现棕榈酸增加了 HepG2 细胞中两种 miRNA，miR-3180-3p 和 miR-4632-5p 的表达。用 miR-3180-3p 或 miR-4632-5p 转染 HepG2 细胞可减少胰岛素诱导的 PI3K-AKT 通路激活。此外，棕榈酸或两种 miRNA 抑制胰岛素诱导的 IRS-1 上 Tyr612 的磷酸化，而不影响胰岛素受体的激活。所以，两种 miRNA 被认为通过抑制胰岛素诱导的 IRS-1 磷酸化参与棕榈酸诱导的胰岛素抵抗。鉴定 miR-3180-3p 和 miR-4632-5p 靶标可为 2 型糖尿病治疗药物的开发提供有价值的信息。