Burchfield James G, Diaz-Vegas Alexis, James David E
School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia.
Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia.
Nat Metab. 2025 Aug 11. doi: 10.1038/s42255-025-01349-z.
Insulin signalling is a central regulator of metabolism, orchestrating nutrient homeostasis and coordinating carbohydrate, protein and lipid metabolism. This network operates through dynamic, tightly regulated protein phosphorylation events involving key kinases such as AKT, shaping cellular responses with remarkable precision. Advances in phosphoproteomics have expanded our understanding of insulin signalling, revealing its intricate regulation and links to disease, particularly cardiometabolic disease. Major insights, such as the mechanisms of AKT activation and the influence of genetic and environmental factors, have emerged from studying this network. In this Review, we examine the architecture of insulin signalling, focusing on its precise temporal regulation. We highlight AKT's central role in insulin action and its vast substrate repertoire, which governs diverse cellular functions. Additionally, we explore feedback and crosstalk mechanisms, such as insulin receptor substrate protein signalling, which integrates inputs through phosphorylation at hundreds of distinct sites. Crucially, phosphoproteomics has uncovered complexities in insulin-resistant states, where network rewiring is characterized by disrupted phosphorylation and the emergence of novel sites that are absent in healthy cells. These insights redefine insulin signalling and its dysfunction, highlighting new therapeutic opportunities.
胰岛素信号传导是新陈代谢的核心调节因子，协调营养物质的稳态，并协调碳水化合物、蛋白质和脂质代谢。该网络通过涉及关键激酶（如AKT）的动态、严格调控的蛋白质磷酸化事件发挥作用，以极高的精度塑造细胞反应。磷酸化蛋白质组学的进展扩展了我们对胰岛素信号传导的理解，揭示了其复杂的调控机制以及与疾病（特别是心脏代谢疾病）的关联。通过研究这个网络，已经获得了一些重要的见解，如AKT激活机制以及遗传和环境因素的影响。在本综述中，我们研究胰岛素信号传导的架构，重点关注其精确的时间调控。我们强调AKT在胰岛素作用中的核心作用及其庞大的底物库，这些底物库控制着多种细胞功能。此外，我们探讨反馈和串扰机制，如胰岛素受体底物蛋白信号传导，它通过数百个不同位点的磷酸化整合输入信号。至关重要的是，磷酸化蛋白质组学揭示了胰岛素抵抗状态下的复杂性，在这种状态下，网络重新布线的特征是磷酸化破坏以及健康细胞中不存在的新位点的出现。这些见解重新定义了胰岛素信号传导及其功能障碍，突出了新的治疗机会。
