• Gary F Lewis, Andre C Carpentier, Sandra Pereira, Margaret Hahn, and Adria Giacca.
• Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada; Banting & Best Diabetes Centre, University of Toronto, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. Electronic address: gary.lewis@uhn.ca.
• Cell Metab. 2021 Apr 6; 33 (4): 709-720.

AbstractThere 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.Copyright © 2021 Elsevier Inc. All rights reserved.

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