Direct and indirect control of hepatic glucose production by insulin

• Published in: Cell metabolism Vol. 33; no. 4; pp. 709 - 720
• Main Authors: Lewis, Gary F., Carpentier, Andre C., Pereira, Sandra, Hahn, Margaret, Giacca, Adria
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.04.2021
• Subjects: Adipose Tissue - metabolism; Animals; central nervous system; Central Nervous System - drug effects; Central Nervous System - metabolism; Fatty Acids, Nonesterified - metabolism; free fatty acids; glucagon; Gluconeogenesis; glucose; Glucose - metabolism; hepatic; Humans; insulin; Insulin - metabolism; Insulin - pharmacology; Liver - drug effects; Liver - metabolism; portal vein; Signal Transduction; portal vein; glucose; insulin; hepatic; glucagon; free fatty acids; central nervous system
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2021.03.007

There is general agreement that the acute suppression of hepatic glucose production by insulin is mediated by both a direct and an indirect effect on the liver. There is, however, no consensus regarding the relative magnitude of these effects under physiological conditions. Extensive research over the past three decades in humans and animal models has provided discordant results between these two modes of insulin action. Here, we review the field to make the case that physiologically direct hepatic insulin action dominates acute suppression of glucose production, but that there is also a delayed, second order regulation of this process via extrahepatic effects. We further provide our views regarding the timing, dominance, and physiological relevance of these effects and discuss novel concepts regarding insulin regulation of adipose tissue fatty acid metabolism and central nervous system (CNS) signaling to the liver, as regulators of insulin’s extrahepatic effects on glucose production. In this review, the acute suppression of glucose production by insulin is highlighted. This insulin action can be mediated partly by a direct hepatic effect but also partly by extrahepatic effects via suppression of fatty acids, glucagon, and CNS signaling.