Abstract
It is well established that glucagon can stimulate adipose lipolysis, myocardial contractility, and hepatic glucose output by activating a GPCR and adenylate cyclase (AC) and increasing cAMP production. It is also widely reported that activation of AC in all three tissues requires pharmacological levels of the hormone, exceeding 0.1 nM. Extensive evidence is presented here supporting the view that cAMP does not mediate metabolic actions of glucagon on adipose, heart, or liver in vivo. Only pharmacological levels stimulate AC, adipose lipolysis, or cardiac contractility. Physiological concentrations of glucagon (below 0.1 nM) duplicate metabolic effects of insulin on the heart by activating a PI3K-dependent signal without stimulating AC. In the liver, glucagon can enhance gluconeogenesis and glucose output - by increasing the expression of PEPCK or inhibiting the activity of PK - at pharmacological concentrations by activating AC coupled to a low-affinity GPCR, but also at physiological concentrations by activating a high affinity receptor without generating cAMP. Plausible AC/cAMP-independent signals mediating the increase in gluconeogenesis include p38 MAPK (PEPCK expression) and IP3/DAG/Ca(2+) (PK activity). None of glucagon'...Continue Reading
Citations
Apr 9, 2013·European Journal of Pharmacology·Nigel IrwinFinbarr P M O'Harte
Apr 7, 2016·Surgery for Obesity and Related Diseases : Official Journal of the American Society for Bariatric Surgery·Harold BaysCraig Primack
Nov 19, 2013·The American Journal of Emergency Medicine·Violetta RaffayTheodoros Xanthos
Apr 5, 2016·Chemical Reviews·Denise WoottenPatrick M Sexton
Nov 6, 2013·Journal of Signal Transduction·Alexander O Shpakov, Kira V Derkach
Jul 31, 2013·Molecular and Cellular Endocrinology·F P M O'HarteN Irwin
Jan 9, 2015·The Journal of Endocrinology·Maureen J Charron, Patricia M Vuguin
Jul 30, 2015·PloS One·Beatriz MerinoJesús Hernández-Cascales
Sep 7, 2016·Gene·Xianguang YangCunshuan Xu
Jan 18, 2017·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Makoto ShigetoKohei Kaku
Mar 17, 2018·The Journal of Clinical Endocrinology and Metabolism·Kasper Meidahl PetersenMikkel Bring Christensen
May 16, 2018·Journal of Cellular Biochemistry·Giuliana R BiaziHelenir M de Souza
Aug 18, 2018·Endocrine·Bingjie ZhangMingming Zhang
May 17, 2017·Journal of Biomolecular NMR·Yaguang HouKurt Wüthrich
Oct 3, 2020·Scientific Reports·Sang R LeeEui-Ju Hong
Sep 26, 2019·Frontiers in Endocrinology·Jin BaiAnderson O L Wong
Dec 29, 2020·The FEBS Journal·Huixia WangKurt Wüthrich
May 8, 2019·JACC. Basic to Translational Science·Chen GaoYibin Wang
Jun 20, 2021·Life Science Alliance·Angel Loza-ValdesGrzegorz Sumara
Jun 25, 2021·Reviews in Endocrine & Metabolic Disorders·Olakunle Sanni, G Terre'Blanche
Jul 29, 2021·Science Signaling·Ivan K ChinnKirk M Druey
Jul 20, 2021·American Journal of Physiology. Endocrinology and Metabolism·Robert L Rodgers
Aug 10, 2021·American Journal of Physiology. Endocrinology and Metabolism·Nicolai J Wewer Albrechtsen