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Abstract <p>Decreased insulin-mediated glucose uptake by skeletal muscle, which accounts for one-third of total body mass, plays a crucial role in the development of type&#xa0;2 diabetes (T2D). However, the molecular mechanisms underlying this disorder remain poorly understood. In contrast to previous studies examining changes in phosphorylation of individual sites or global phosphoproteome profile of human skeletal muscle in response to insulin (euglycemic-hyperinsulinemic clamp test), the present study is the first to investigate changes in skeletal muscle signaling in response to a mixed meal normalized to body mass (a model of physiological postprandial response). Using mass spectrometry-based phosphoproteomics, postprandial changes across 4205 phosphorylation sites in 1208 proteins/protein groups were analyzed in healthy individuals (<i>n</i>&#xa0;=&#xa0;8) and patients with obesity and T2D (<i>n</i>&#xa0;=&#xa0;8) and key kinases associated with these changes were identified. Food intake altered phosphorylation levels of 70 sites in healthy individuals and 36 sites in patients. However, postprandial phosphorylation of canonical insulin cascade proteins was comparable between the groups, which might be attributed to significantly elevated postprandial blood insulin levels in the patients caused by a reduced insulin-dependent glucose uptake by tissues and a greater food intake compared to healthy individuals. Only healthy individuals exhibited changes in postprandial phosphorylation levels of several proteins regulating the translocation and/or exposure of GLUT4-containing vesicles (SRBS1, CIP4/2, ABI1, SVIL, CPZIP, PLEC, and COBL), suggesting that impaired insulin-dependent glucose uptake in skeletal muscle in patients with obesity and T2D is primarily due to impaired regulation of GLUT4-containing vesicles trafficking.</p>

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Early Postprandial Response of Skeletal Muscle Phosphoproteome in Type 2 Diabetes Is Comparable to That in Healthy Individuals

  • 期刊论文

  • 发表日期：

    2026年2月1日

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  • Elmira I. Yakupova,
  • Nikita V. Podkuychenko,
  • Igor P. Smirnov,
  • Viktor G. Zgoda,
  • Nikita E. Vavilov,
  • Egor M. Lednev,
  • Tatiana F. Vepkhvadze,
  • Alina O. Tomilova,
  • Marina V. Shestakova,
  • Alexander V. Vorotnikov,
  • Daniil V. Popov

摘要

Abstract

Decreased insulin-mediated glucose uptake by skeletal muscle, which accounts for one-third of total body mass, plays a crucial role in the development of type 2 diabetes (T2D). However, the molecular mechanisms underlying this disorder remain poorly understood. In contrast to previous studies examining changes in phosphorylation of individual sites or global phosphoproteome profile of human skeletal muscle in response to insulin (euglycemic-hyperinsulinemic clamp test), the present study is the first to investigate changes in skeletal muscle signaling in response to a mixed meal normalized to body mass (a model of physiological postprandial response). Using mass spectrometry-based phosphoproteomics, postprandial changes across 4205 phosphorylation sites in 1208 proteins/protein groups were analyzed in healthy individuals (n = 8) and patients with obesity and T2D (n = 8) and key kinases associated with these changes were identified. Food intake altered phosphorylation levels of 70 sites in healthy individuals and 36 sites in patients. However, postprandial phosphorylation of canonical insulin cascade proteins was comparable between the groups, which might be attributed to significantly elevated postprandial blood insulin levels in the patients caused by a reduced insulin-dependent glucose uptake by tissues and a greater food intake compared to healthy individuals. Only healthy individuals exhibited changes in postprandial phosphorylation levels of several proteins regulating the translocation and/or exposure of GLUT4-containing vesicles (SRBS1, CIP4/2, ABI1, SVIL, CPZIP, PLEC, and COBL), suggesting that impaired insulin-dependent glucose uptake in skeletal muscle in patients with obesity and T2D is primarily due to impaired regulation of GLUT4-containing vesicles trafficking.