Mechanisms by Which Glucagon Acutely Stimulates Hepatic Mitochondrial Oxidation and Gluconeogenesis

Glucagon has been suggested to be both pathogenic and protective against type 2 diabetes (T2D) reflecting our poor understanding of the molecular mechanisms by which glucagon alters hepatic metabolism. Using Positional Isotopomer NMR Tracer Analysis (PINTA) we found that acute glucagon infusion stimulates rates of hepatic gluconeogenesisin glycogen-depleted mice by promoting increases in intrahepatic lipolysis and hepatic acetyl-CoA content (75±6 vs. 101±6 nmol/g, p=0.01), pyruvate carboxylase flux (VPC, 70.9±3.9 vs. 99.9±7.1 µmol/[kg-min], p=0.008) and mitochondrial oxidation (90.0±12.9 vs. 452.1±78.3 µmol/[kg-min], p=0.001) in vivo. Each of these effects was abrogated in liver-specific Inositol Trisphosphate Receptor-I (InsP3R-I) knockout mice demonstrating that intracellular calcium signaling is necessary for these processes. Liver specific knockdown of adipocyte triglyceride lipase abolished acute glucagon stimulation of gluconeogenesis (control 70.5±2.9 vs. 103.3±3.3 µmol/[kg-min], p Disclosure R.J. Perry: None. Y. Wang: None. A.L. Brill: None. L. Peng: None. D. Zhang: None. S. Dufour: None. Y. Zhang: None. X. Zhang: None. Y. Nozaki: None. G. Cline: None. B.E. Ehrlich: None. K. Petersen: Research Support; Spouse/Partner; Gilead Sciences, Inc.. Advisory Panel; Spouse/Partner; AstraZeneca, Merck & Co., Inc., Novo Nordisk A/S. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..