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

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Elmira I. Yakupova¹, Nikita V. Podkuychenko^1,2, Igor P. Smirnov³, Viktor G. Zgoda⁴, Nikita E. Vavilov⁴, Egor M. Lednev¹, Tatiana F. Vepkhvadze¹, Alina O. Tomilova⁵, Marina V. Shestakova⁵, Alexander V. Vorotnikov², and Daniil V. Popov^1,a*

¹Institute of Biomedical Problems of the Russian Academy of Sciences, 123007 Moscow, Russia

²National Medical Research Center of Cardiology, Ministry of Healthcare of the Russian Federation, 121552 Moscow, Russia

³Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, 143007 Moscow, Russia

⁴Orekhovich Research Institute of Biomedical Chemistry, 119121 Moscow, Russia

⁵Diabetes Institute, National Medical Research Centre for Endocrinology, 117292 Moscow, Russia

^* To whom correspondence should be addressed.

Received: October 29, 2025; Revised: December 22, 2025; Accepted: January 22, 2026

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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.

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KEY WORDS: type 2 diabetes mellitus, phosphoprotein, phosphorylation site, insulin, skeletal muscle

DOI: 10.1134/S0006297925603855

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