The study investigates the mechanism by which the adipose-derived protein Acrp30 (adiponectin) inhibits endogenous glucose production in mice. Intraperitoneal injection of purified recombinant Acrp30 lowers glucose levels in mice. In a pancreatic euglycemic clamp study, Acrp30 infusion increased circulating Acrp30 levels by about twofold and stimulated glucose metabolism. The hypoglycemic effect was attributed to a 65% reduction in glucose production, without affecting glucose uptake, glycolysis, or glycogen synthesis. Acrp30 decreased glucose flux through glucose-6-phosphatase (G6Pase) and increased the activity of the direct pathway of glucose-6-phosphate biosynthesis, indicating enhanced hepatic glucose phosphorylation. Acrp30 also reduced the expression of gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and G6Pase mRNA by more than 50%. These findings suggest that Acrp30 inhibits endogenous glucose production by modulating hepatic glucose metabolism, without affecting peripheral glucose uptake.The study investigates the mechanism by which the adipose-derived protein Acrp30 (adiponectin) inhibits endogenous glucose production in mice. Intraperitoneal injection of purified recombinant Acrp30 lowers glucose levels in mice. In a pancreatic euglycemic clamp study, Acrp30 infusion increased circulating Acrp30 levels by about twofold and stimulated glucose metabolism. The hypoglycemic effect was attributed to a 65% reduction in glucose production, without affecting glucose uptake, glycolysis, or glycogen synthesis. Acrp30 decreased glucose flux through glucose-6-phosphatase (G6Pase) and increased the activity of the direct pathway of glucose-6-phosphate biosynthesis, indicating enhanced hepatic glucose phosphorylation. Acrp30 also reduced the expression of gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and G6Pase mRNA by more than 50%. These findings suggest that Acrp30 inhibits endogenous glucose production by modulating hepatic glucose metabolism, without affecting peripheral glucose uptake.