Core Viewpoint - The research indicates that targeting GPR81 represents a potential new strategy for treating hyperglycemia independent of insulin [5] Group 1: Research Findings - The study identifies L-lactate as an insulin-independent glucose uptake regulator that can alleviate hyperglycemia [4] - The absence of LDHA in muscle reduces lactate production, impairing glucose homeostasis in mice, while administering lactate or genetically enhancing lactate production improves glucose control [4] - Knockout of the lactate receptor GPR81 in skeletal muscle worsens glucose tolerance, whereas its ectopic expression or pharmacological activation enhances carbohydrate metabolism [4] Group 2: Mechanism of Action - Mechanistically, GPR81 recruits FARP1 to activate RAC1, promoting GLUT4 translocation independent of insulin signaling [4] - Notably, the expression of LDHA, GPR81, and FARP1 is upregulated after exercise, and the GPR81 variant is highly correlated with human fasting insulin levels, emphasizing the synergistic role of the GPR81-FARP1-GLUT4 signaling axis in glucose regulation alongside insulin [4]