Lactate-activated GPR81/FARP1 signaling drives insulin-independent glucose uptake and metabolic control.

Insulin-stimulated glucose uptake is central to global carbohydrate metabolism, yet metabolites that enhance glucose uptake independently of insulin remain undefined. Here, we identify L-lactate as an insulin-independent regulator of glucose uptake that mitigates hyperglycemia. Loss of LDHA in muscle reduces lactate production, impairing glucose homeostasis in mice. By contrast, lactate administration or genetic upregulation of lactate production improves glucose control. Knockout of the lactate receptor GPR81 in skeletal muscle worsens glucose tolerance, whereas its ectopic expression or pharmacological activation enhances carbohydrate metabolism. Mechanistically, GPR81 recruits FARP1 to activate RAC1, promoting GLUT4 translocation independently of insulin signaling. Notably, the expression of LDHA, GPR81, and FARP1 is upregulated after exercise, and GPR81 variants are highly correlated with fasting insulin levels in humans, underscoring the synergy of the GPR81-FARP1-GLUT4 axis with insulin in glucose regulation. Our findings suggest that targeting GPR81 represents a potential insulin-independent strategy for the treatment of hyperglycemia.