Glucagon stimulates gluconeogenesis by InsP(3)R-I mediated hepatic lipolysis

While it is well-established that alterations in the portal vein insulin/glucagon ratio play a major role in causing dysregulated hepatic glucose metabolism in type 2 diabetes (T2D)(1–3), the mechanisms by which glucagon alters hepatic glucose production and mitochondrial oxidation remain poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing hepatic adipose triglyceride lipase activity, intrahepatic lipolysis, hepatic acetyl-CoA content, and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation, mediated by stimulation of the inositol triphosphate receptor-1 (InsP(3)R-I). Chronic physiological increases in plasma glucagon concentrations increased mitochondrial hepatic fat oxidation and reversed diet-induced hepatic steatosis and insulin resistance in rats and mice; however, the effect of chronic glucagon treatment to reverse hepatic steatosis and glucose intolerance was abrogated in InsP(3)R-I knockout mice. These results provide new insights into glucagon biology and suggest that InsP(3)R-I may be a novel therapeutic target to reverse nonalcoholic fatty liver disease and T2D.