The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance

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.

胰岛素受体（Insulin Receptor, IR）信号转导是正常代谢调控的核心机制，在2型糖尿病等代谢疾病中会发生失调。本研究证实，在人类肝细胞与脂肪细胞内，胰岛素受体可于细胞膜、细胞质及细胞核中形成动态簇结构。胰岛素敏感细胞经胰岛素刺激后，胰岛素受体会进一步向此类动态簇中募集；而在胰岛素抵抗细胞中，这一募集过程无法发生，且该类细胞内胰岛素受体的聚集水平与簇结构的动态行为均出现显著降低。使用临床治疗2型糖尿病的一线药物二甲双胍处理胰岛素抵抗细胞，可恢复胰岛素受体的聚集水平与这些簇结构的动态行为。该恢复效应与二甲双胍能够清除干扰正常动态过程的活性氧（Reactive Oxygen Species, ROS）密切相关。上述研究结果表明，胰岛素受体簇的物理力学特性改变是胰岛素抵抗的重要致病因素之一，同时也为优化代谢疾病的治疗策略提供了潜在方向。