The Inhibitory Effects of Insulin on Hepatic Glucose Production Are Both Direct and Indirect

Previous studies suggest that insulin can inhibit hepatic glucose production by both direct and indirect actions. The indirect effects include inhibition of glucagon secretion, reduction in plasma nonesterified fatty acid levels, reduction of the amount of gluconeogenic precursor supplied to the liver, and change in neural input to the liver. There is a controversy concerning the fact that the dominant action of insulin on hepatic glucose production is direct, as suggested by studies in fed dogs, or indirect, via the hypothalamus, as suggested by studies in rodents. A possible explanation for this discrepancy will be proposed involving the relative importance of glycogenolysis and gluconeogenesis in hepatic glucose production in dogs and rodents. Finally, the relative importance of direct and/or indirect effects of insulin on hepatic glucose production for the treatment of diabetes will be discussed.