丹麦哥本哈根大学Jørgen F.P. Wojtaszewski等研究人员合作发现，骨骼肌胰岛素抵抗和运动的个性化磷酸蛋白质组学，研究将MINDY1与胰岛素作用联系起来。2024年11月21日，《细胞—代谢》杂志在线发表了这一最新研究成果。

研究人员探讨了胰岛素抵抗如何改变骨骼肌信号传导，以及运动如何部分抵消这一影响。研究人员对胰岛素抵抗（IR）和胰岛素敏感（IS）男性，在运动和胰岛素作用下的反应进行了研究（n=19，共114次活检），在每次活检中量化了超过12000种磷酸肽。胰岛素抵抗涉及选择性和时间依赖性的信号变化，包括胰岛素刺激的mTORC1和非经典信号反应的减少。

先前的运动通过在胰岛素注入前“预激”部分胰岛素信号，即使在IR个体中也能促进胰岛素敏感性。其中包括MINDY1 S441位点，研究人员证明这是AKT的一个底物。研究人员发现，敲低MINDY1可增强大鼠肌管中胰岛素刺激的葡萄糖摄取。该研究揭示了IR骨骼肌中的信号变化，并确定了MINDY1作为胰岛素作用的一个调节因子。

据悉，2型糖尿病的发生之前存在胰岛素反应缺陷，但其具体机制尚未完全了解。

附：英文原文

Title: Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action

Author: Elise J. Needham, Janne R. Hingst, Johan D. Onslev, Alexis Diaz-Vegas, Magnus R. Leandersson, Hannah Huckstep, Jonas M. Kristensen, Kohei Kido, Erik A. Richter, Kurt Hjlund, Benjamin L. Parker, Kristen Cooke, Guang Yang, Christian Pehmller, Sean J. Humphrey, David E. James, Jrgen F.P. Wojtaszewski

Issue&Volume: 2024-11-21

Abstract: Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters skeletal muscle signaling and how exercise partially counteracts this effect. We measured parallel phenotypes and phosphoproteomes of insulin-resistant (IR) and insulin-sensitive (IS) men as they responded to exercise and insulin (n = 19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy. Insulin resistance involves selective and time-dependent alterations to signaling, including reduced insulin-stimulated mTORC1 and non-canonical signaling responses. Prior exercise promotes insulin sensitivity even in IR individuals by “priming” a portion of insulin signaling prior to insulin infusion. This includes MINDY1 S441, which we show is an AKT substrate. We found that MINDY1 knockdown enhances insulin-stimulated glucose uptake in rat myotubes. This work delineates the signaling alterations in IR skeletal muscle and identifies MINDY1 as a regulator of insulin action.

DOI: 10.1016/j.cmet.2024.10.020

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00416-9