Personalized molecular signatures of insulin resistance and type 2 diabetes

Affiliations

• 1. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
• 2. 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.
• 3. Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
• 4. Proteomics Research Infrastructure, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
• 5. Department of Medicine Huddinge (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, 141 83 Huddinge, Sweden.
• 6. Steno Diabetes Center Odense, Odense University Hospital, Odense C, Denmark.
• 7. Steno Diabetes Center Odense, Odense University Hospital, Odense C, Denmark; Department of Clinical Research, University of Southern Denmark, Odense C, Denmark.
• 8. Department of Medicine Huddinge (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, 141 83 Huddinge, Sweden; Steno Diabetes Center Copenhagen, Herlev, Denmark.
• 9. 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; Department of Molecular Medicine and Surgery, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
• 10. Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
• 11. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

PMID: 40436015 DOI: 10.1016/j.cell.2025.05.005

Abstract

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.

摘要

胰岛素抵抗是2型糖尿病的特征之一，而2型糖尿病是一种病理变化高度异质性的疾病。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。利用尖端的蛋白质组学技术，我们绘制了120多名糖耐量正常或2型糖尿病患者的骨骼肌蛋白质组和磷酸蛋白组图谱，这些患者具有不同程度的胰岛素敏感性。通过深入的体内表型分析，我们发现空腹蛋白质组和磷酸蛋白质组特征可强烈预测胰岛素敏感性。此外，胰岛素刺激的磷酸化蛋白质组显示出信号节点失调和信号节点保留两种情况--即使在胰岛素抵抗严重的个体中也是如此。虽然蛋白质组和磷酸蛋白组存在很大的性别差异，但胰岛素抵抗的分子特征在男性和女性之间基本相似。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

Keywords: disease heterogeneity; glucose metabolism; phosphoproteomics; sex differences; signaling; skeletal muscle.

关键词：疾病异质性、糖代谢、磷蛋白组学、性别差异、信号传导、骨骼肌、兔单抗、、标签抗体、二抗、佰乐博、佰乐博生物