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

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.