Peripheral glucose homeostasis: does brain insulin matter?

Much controversy surrounds the relative role of insulin signaling in the brain in the control of hepatic glucose metabolism. In this issue of the JCI, Ramnanan and colleagues demonstrate that arterial infusion of insulin into the brains of dogs reduces net hepatic glucose output without altering endogenous glucose production. However, this effect was modest and required both prolonged fasting and prolonged exposure of the brain to insulin, raising doubts about the overall physiological relevance of insulin action in the brain on hepatic glucose metabolism. Given the dominant direct role that insulin plays in inhibiting glucose production in the liver, we suggest that the main effect of central insulin on hepatic glucose metabolism may be more chronic and assume greater significance either when portal insulin is deficient, as occurs during exogenous insulin treatment of type 1 diabetes, or when chronic hyperinsulinemia and central insulin resistance develops, as occurs in type 2 diabetes.