Abstract
Dysregulation of hepatic glucose uptake (HGU) and inability of insulin to suppress hepatic glucose production (HGP) contribute to hyperglycaemia in patients with type 2 diabetes (T2D). Growing evidence suggests that insulin can inhibit HGP not only through a direct effect on the liver but also through a mechanism involving the brain. Yet, the notion that insulin action in the brain plays a physiological role in the control of HGP continues to be controversial. Although studies in dogs suggest that the direct hepatic effect of insulin is sufficient to explain day-to-day control of HGP, a surprising outcome has been revealed by recent studies in mice, investigating whether the direct hepatic action of insulin is necessary for normal HGP: when the hepatic insulin signalling pathway was genetically disrupted, HGP was maintained normally even in the absence of direct input from insulin. Here, we present evidence that points to a potentially important role of the brain in the physiological control of both HGU and HGP in response to input from insulin as well as other hormones and nutrients.