The incidence of diabetes, obesity, and metabolic diseases has reached an epidemic status worldwide. Insulin resistance is a common link in the development of these conditions, and hyperinsulinemia is a central hallmark of peripheral insulin resistance. However, how hyperinsulinemia leads to systemic insulin resistance is less clear. We now provide evidence that hyperinsulinemia promotes the release of soluble pro-inflammatory mediators from macrophages that lead to systemic insulin resistance. Our observations suggest that hyperinsulinemia induces sirtuin1 (SIRT1) repression and stimulates NF-κB p65 nuclear translocation and transactivation of NF-κB to promote the extracellular release of pro-inflammatory mediators. We further showed that low-dose naltrexone (LDN) abrogates hyperinsulinemia-mediated SIRT1 repression and prevents NF-κB p65 nuclear translocation. This, in turn, attenuates the hyperinsulinemia-induced release of pro-inflammatory cytokines and reinstates insulin sensitivity both in in vitro and in vivo diet-induced hyperinsulinemic mouse model. Notably, our data indicate that Sirt1 knockdown or inhibition blunts the anti-inflammatory properties of LDN in vitro. Using numerous complementary in silico and in vitro experimental approaches, we demonstrated that LDN can bind to SIRT1 and increase its deacetylase activity. Together, these data support a critical role of SIRT1 in inflammation and insulin resistance in hyperinsulinemia. LDN improves hyperinsulinemia-induced insulin resistance by reorienting macrophages toward anti-inflammation. Thus, LDN treatment may provide a novel therapeutic approach against hyperinsulinemia-associated insulin resistance.

中文翻译：

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低剂量纳曲酮可挽救与高胰岛素血症相关的炎症和胰岛素抵抗。

糖尿病、肥胖症和代谢性疾病的发病率已达到全球流行状态。胰岛素抵抗是这些疾病发展的常见环节，而高胰岛素血症是外周胰岛素抵抗的核心标志。然而，高胰岛素血症如何导致全身胰岛素抵抗尚不清楚。我们现在提供的证据表明，高胰岛素血症会促进巨噬细胞释放可溶性促炎介质，从而导致全身胰岛素抵抗。我们的观察结果表明，高胰岛素血症诱导 ​​Sirtuin1 (SIRT1) 抑制并刺激 NF-κB p65 核易位和 NF-κB 的反式激活，以促进促炎介质的细胞外释放。我们进一步表明，低剂量纳曲酮 (LDN) 可消除高胰岛素血症介导的 SIRT1 抑制并防止 NF-κB p65 核易位。这反过来又减弱了高胰岛素血症诱导的促炎细胞因子的释放，并在体外和体内饮食诱导的高胰岛素血症小鼠模型中恢复了胰岛素敏感性。值得注意的是，我们的数据表明，Sirt1 敲低或抑制减弱了 LDN 体外的抗炎特性。使用许多互补的计算机和体外实验方法，我们证明了 LDN 可以与 SIRT1 结合并增加其脱乙酰酶活性。总之，这些数据支持 SIRT1 在高胰岛素血症的炎症和胰岛素抵抗中的关键作用。LDN 通过将巨噬细胞重新定向为抗炎作用来改善高胰岛素血症引起的胰岛素抵抗。因此，