Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis.

Nature
Rachel J PerryGerald I Shulman

Abstract

Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes1-3, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation-all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment-reversing hepatic steatosis and glucose intolerance-were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes.

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Citations

Apr 16, 2020·Journal of Clinical Medicine·Jessica GambardellaGaetano Santulli
Aug 17, 2020·The Journal of Biological Chemistry·Rachel J Perry, Gerald I Shulman
Sep 29, 2020·American Journal of Physiology. Endocrinology and Metabolism·Logan K TownsendMarcelo A Mori
Mar 9, 2021·Trends in Cell Biology·Jens LonckeGeert Bultynck
Oct 27, 2020·Medicine and Science in Sports and Exercise·Timothy D AllertonJacqueline M Stephens
Dec 19, 2020·Journal of Clinical Medicine·Katrine D Galsgaard
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kai YangPeilong Sun
Apr 20, 2021·Cellular Signalling·Siddharth SunilkumarMichael D Dennis
Apr 13, 2021·American Journal of Physiology. Endocrinology and Metabolism·Kitt Falk PetersenGerald I Shulman
Jul 25, 2021·Molecular Metabolism·Wen DaiLale Ozcan
Aug 6, 2021·Expert Opinion on Pharmacotherapy·Marc S Rendell
Sep 18, 2021·Journal of Cell Science·Vikas ArigeDavid I Yule

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Methods Mentioned

BETA
nuclear magnetic resonance
NMR
enzyme-linked immunosorbent assay
ELISA
protein assay

Software Mentioned

PINTA

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