Glucose‐Responsive PAGR1‐Regulated Skeletal Muscle Gene Program Controls Systemic Glucose Homeostasis and Hepatic Metabolism

Chronic hyperglycemia, a defining feature of type 2 diabetes (T2D) and related metabolic disorders, exacerbates insulin resistance and impairs muscle glucose utilization, contributing to systemic metabolic dysfunction. While skeletal muscle is the primary site for postprandial glucose uptake and plays a pivotal role in maintaining whole-body glucose homeostasis, the molecular mechanisms by which hyperglycemia induces maladaptive responses in muscle remain poorly understood. Here, PAXIP1-associated glutamate-rich protein 1 (PAGR1) is identified as a glucose-responsive regulator in skeletal muscle, whose expression is induced by high glucose levels and modulates systemic glucose homeostasis and hepatic metabolism. Using muscle-specific PAGR1-knockout mice, it is demonstrated that PAGR1 deficiency enhances insulin signaling, promotes glucose transporter 4 (GLUT4) translocation, and increases muscle glucose uptake and utilization. Mechanistically, PAGR1 directly activates the expression of TBC1 Domain Family Member 4 (TBC1D4), a RAB GTPase Activating Protein (RabGAP) known to negatively regulate GLUT4 translocation. Importantly, muscle-specific deletion of PAGR1 protects against high-fat-diet-induced insulin resistance and hepatic steatosis. These findings establish PAGR1 as a critical mediator of muscle glucose sensing and utilization, positioning it as a potential target for therapeutic strategies aimed at mitigating glucotoxicity and preventing metabolic diseases such as T2D.

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Journal
Advanced Science
Published
2025-07-24
DOI
https://doi.org/10.1002/advs.202502763
Citations
1
Primary Topic
Metabolism, Diabetes, and Cancer
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article
Field-Weighted Citation Impact
0.81

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article

Glucose‐Responsive PAGR1‐Regulated Skeletal Muscle Gene Program Controls Systemic Glucose Homeostasis and Hepatic Metabolism

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1 citations
Advanced Science
Metabolism, Diabetes, and Cancer
0.81
article

Glucose‐Responsive PAGR1‐Regulated Skeletal Muscle Gene Program Controls Systemic Glucose Homeostasis and Hepatic Metabolism

Likun Yang, Qiqi Guo, Zhen‐Yu Du, Zheng Zhou, Zongchao Sun, Kai Ge, Hai‐long Piao, Danxia Zhou, Zhenji Gan, Liwei Xiao, Wen Wang, Tingting Fu, Yuhuan Jia, Xinyi Chen, Yujing Yin, Chenyun Ding, Yan Mao, Di Chen, Lin Liu, Caizhi Liu
article en
1 citations

Abstract

Chronic hyperglycemia, a defining feature of type 2 diabetes (T2D) and related metabolic disorders, exacerbates insulin resistance and impairs muscle glucose utilization, contributing to systemic metabolic dysfunction. While skeletal muscle is the primary site for postprandial glucose uptake and plays a pivotal role in maintaining whole-body glucose homeostasis, the molecular mechanisms by which hyperglycemia induces maladaptive responses in muscle remain poorly understood. Here, PAXIP1-associated glutamate-rich protein 1 (PAGR1) is identified as a glucose-responsive regulator in skeletal muscle, whose expression is induced by high glucose levels and modulates systemic glucose homeostasis and hepatic metabolism. Using muscle-specific PAGR1-knockout mice, it is demonstrated that PAGR1 deficiency enhances insulin signaling, promotes glucose transporter 4 (GLUT4) translocation, and increases muscle glucose uptake and utilization. Mechanistically, PAGR1 directly activates the expression of TBC1 Domain Family Member 4 (TBC1D4), a RAB GTPase Activating Protein (RabGAP) known to negatively regulate GLUT4 translocation. Importantly, muscle-specific deletion of PAGR1 protects against high-fat-diet-induced insulin resistance and hepatic steatosis. These findings establish PAGR1 as a critical mediator of muscle glucose sensing and utilization, positioning it as a potential target for therapeutic strategies aimed at mitigating glucotoxicity and preventing metabolic diseases such as T2D.

Advanced ScienceVol. 12(39)
Dalian Institute of Chemical Physics (CN), Chinese Academy of Sciences (CN), National Institute of Diabetes and Digestive and Kidney Diseases (US), Model Animal Research Center (CN), Shanghai Sixth People's Hospital (CN), East China Normal University (CN), China Medical University (CN)
National Natural Science Foundation of China, Ministry of Science and Technology of the People's Republic of China, China Postdoctoral Science Foundation, Natural Science Foundation of Jiangsu Province, Fundamental Research Funds for the Central Universities
Good health and well-being
Openalex Percentile: Top 25%
Metabolism, Diabetes, and Cancer
0.81
DOIOpen Access PDFOpenAlex
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