Unraveling the Regulation of Hepatic Metabolism by Insulin

TrendsInsulin action in liver coordinately regulates lipid synthesis and glucose production by cell-autonomous and non-autonomous mechanisms.Liver insulin action is required for lipid synthesis and the development of fatty liver.The ability of insulin to suppress hepatic glucose production is determined by both direct and indirect mechanisms, including the contribution of adipose tissue lipolysis and gluconeogenic regulation by glucagon.Defining the molecular mechanisms responsible for selective insulin control of lipid synthesis and glucose production may allow the development of therapeutic agents that reduce hyperglycemia without inducing hypertriglyceridemia.AbstractDuring insulin-resistant states such as type 2 diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production but promotes lipid synthesis leading to hyperglycemia and hypertriglyceridemia. Defining the downstream signaling pathways underlying the control of hepatic metabolism by insulin is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We summarize recent literature highlighting the importance of both hepatic and extrahepatic mechanisms in insulin regulation of liver glucose and lipid metabolism. We posit that a failure of insulin to inappropriately regulate liver metabolism during T2DM is not exclusively from an inherent defect in canonical liver insulin signaling but is instead due to a combination of hyperinsulinemia, altered substrate supply, and the input of several extrahepatic signals.