Kjærgaard Jeppe, Stocks Ben, Henderson John, Freemantle Jordana B, Rizo-Roca David, Puglia Michele, Madrazo Montoya Maria, Andersson Daniel, Bäckdahl Jesper, Eriksson-Hogling Daniel, Stidsen Jacob V, Wierer Michael, Rasmussen Simon, Sakamoto Kei, Højlund Kurt, Rydén Mikael, Zierath Juleen R, Krook Anna, Deshmukh Atul S
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
Cell. 2025 Jul 24;188(15):4106-4122.e16. doi: 10.1016/j.cell.2025.05.005. Epub 2025 May 27.
Insulin resistance is a hallmark of type 2 diabetes, which is a highly heterogeneous disease with diverse pathology. Understanding the molecular signatures of insulin resistance and its association with individual phenotypic traits is crucial for advancing precision medicine in type 2 diabetes. Utilizing cutting-edge proteomics technology, we mapped the proteome and phosphoproteome of skeletal muscle from >120 men and women with normal glucose tolerance or type 2 diabetes, with varying degrees of insulin sensitivity. Leveraging deep in vivo phenotyping, we reveal that fasting proteome and phosphoproteome signatures strongly predict insulin sensitivity. Furthermore, the insulin-stimulated phosphoproteome revealed both dysregulated and preserved signaling nodes-even in individuals with severe insulin resistance. While substantial sex-specific differences in the proteome and phosphoproteome were identified, molecular signatures of insulin resistance remained largely similar between men and women. These findings emphasize the necessity of incorporating disease heterogeneity into type 2 diabetes care strategies.
胰岛素抵抗是2型糖尿病的一个标志，2型糖尿病是一种具有高度异质性且病理多样的疾病。了解胰岛素抵抗的分子特征及其与个体表型特征的关联对于推进2型糖尿病的精准医疗至关重要。利用前沿的蛋白质组学技术，我们绘制了120多名糖耐量正常或患有2型糖尿病、胰岛素敏感性程度各异的男性和女性骨骼肌的蛋白质组和磷酸化蛋白质组图谱。借助深入的体内表型分析，我们发现空腹蛋白质组和磷酸化蛋白质组特征能够强有力地预测胰岛素敏感性。此外，胰岛素刺激后的磷酸化蛋白质组揭示出信号节点既有失调的，也有保持完整的——即使在严重胰岛素抵抗的个体中也是如此。虽然在蛋白质组和磷酸化蛋白质组中发现了显著的性别差异，但胰岛素抵抗的分子特征在男性和女性之间仍大体相似。这些发现强调了将疾病异质性纳入2型糖尿病护理策略的必要性。
