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journal article·2025-10Open access

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

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

Advanced Science· Volume 12· Issue 39
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Source abstract

Abstract

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.
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Research context

OpenAlex topics: Metabolism, Diabetes, and Cancer · Hyperglycemia and glycemic control in critically ill and hospitalized patients · Pancreatic function and diabetes

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study Division of Spine Surgery Department of Orthopedic Surgery Nanjing Drum Tower Hospital Affiliated Hospital of Nanjing University Medical School Chemistry and Biomedicine Innovation Center (ChemBIC) Model Animal Research Center Medical School of Nanjing University Nanjing University Nanjing 210061 China

State Key Laboratory of Phytochemistry and Natural Medicines Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian 116023 China

Department of Endocrinology and Metabolism Shanghai Diabetes Institute Shanghai Clinical Center for Diabetes Shanghai Key Laboratory of Diabetes Mellitus Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai 200233 China

LANEH School of Life Sciences East China Normal University Shanghai 200241 China

Adipocyte Biology and Gene Regulation Section National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda MD 20892 USA

Department of Biochemistry & Molecular Biology School of Life Sciences China Medical University Shenyang 110122 China

Funding

Ministry of Science and Technology of the People's Republic of China · National Natural Science Foundation of China · Natural Science Foundation of Jiangsu Province · Fundamental Research Funds for the Central Universities · China Postdoctoral Science Foundation

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