The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance.
The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance.
复制标题
胰岛素受体的动态聚类是其信号传导的基础，并在胰岛素抵抗中被破坏。
DOI：
10.1038/s41467-022-35176-7
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发表时间：
2022-12-06
影响因子：
16.6
通讯作者：
Young, Richard A.
中科院分区：
文献类型：
--
作者：
Dall'Agnese, Alessandra;Platt, Jesse M.;Zheng, Ming M.;Friesen, Max;Dall'Agnese, Giuseppe;Blaise, Alyssa M.;Spinelli, Jessica B.;Henninger, Jonathan E.;Tevonian, Erin N.;Hannett, Nancy M.;Lazaris, Charalampos;Drescher, Hannah K.;Bartsch, Lea M.;Kilgore, Henry R.;Jaenisch, Rudolf;Griffith, Linda G.;Cisse, Ibrahim I.;Jeppesen, Jacob F.;Lee, Tong I.;Young, Richard A.
胰岛素受体（IR）信号传导是正常代谢控制的核心，并且在代谢疾病如2型糖尿病中失调。我们在这里报告，IR被纳入动态集群在质膜，在细胞质和细胞核中的人肝细胞和脂肪细胞。胰岛素刺激促进IR进一步并入胰岛素敏感细胞中的这些动态簇中，但在胰岛素抵抗细胞中不促进IR进一步并入这些动态簇中，在胰岛素抵抗细胞中IR积累和动态行为都减少。用二甲双胍（用于治疗2型糖尿病的一线药物）治疗胰岛素抵抗细胞，可以挽救IR积聚和这些簇的动态行为。这种补救与二甲双胍在减少干扰正常动力学的活性氧方面的作用有关。这些结果表明，IR簇的物理机械特征的变化有助于胰岛素抵抗，并对改善治疗方法有影响。作者发现，胰岛素受体在胰岛素信号传导过程中形成动态簇，这些簇在胰岛素抵抗中变得功能失调。二甲双胍是一种用于治疗2型糖尿病的药物，可部分挽救这种功能障碍。
Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches. The authors find that the insulin receptor forms dynamic clusters during insulin signaling and that these clusters become dysfunctional in insulin resistance. This dysfunction is partially rescued by metformin, a drug used to treat type 2 diabetes.
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影响因子：
8.2
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