Abstract
Glucagon receptor (GCGR) agonists cause hyperglycemia but also weight loss. However, GCG-like peptide 1 receptor (GLP1R)/GCGR mixed agonists do not exhibit the diabetogenic effects often attributed to GCGR activity. Thus, we sought to investigate the effect of glucagon agonism on insulin action and glucose homeostasis. Acute GCGR agonism induced immediate hyperglycemia, followed by improved glucose tolerance and enhanced glucose-stimulated insulin secretion. Moreover, acute GCGR agonism improved insulin tolerance in a dose-dependent manner in both lean and obese mice. Improved insulin tolerance was independent of GLP1R, FGF21, and hepatic glycogenolysis. Moreover, we observed increased glucose infusion rate, disposal, uptake, and suppressed endogenous glucose production during euglycemic clamps. Mice treated with insulin and GCGR agonist had enhanced phosphorylation of hepatic AKT at Ser473; this effect was reproduced in isolated mouse primary hepatocytes and resulted in increased AKT kinase activity. These data reveal that GCGR agonism enhances glucose tolerance, in part, by augmenting insulin action, with implications for the use of GCGR agonism in therapeutic strategies for diabetes.
References
Jan 1, 1977·Psychological Review·T L Powley
Jan 1, 1990·Neuroscience and Biobehavioral Reviews·N Geary
Jan 1, 1995·Peptides·L H HansenE Nishimura
Nov 1, 1996·Nature Medicine·L A ScrocchiD J Drucker
Aug 19, 2000·American Journal of Physiology. Endocrinology and Metabolism·M G KrishnaD H Wasserman
Sep 16, 2000·Diabetologia·P HuypensF Schuit
Aug 9, 2002·Molecular and Cellular Biology·Michael P ScheidJames R Woodgett
Mar 30, 2004·Diabetes·Hyo-Jeong KimJason K Kim
Jul 23, 2004·Current Biology : CB·D D SarbassovDavid M Sabatini
Feb 19, 2005·Science·D D SarbassovDavid M Sabatini
Apr 6, 2005·Molecular Cell·Tianyan GaoAlexandra C Newton
Jul 11, 2009·Endocrinology·Yuhei HottaNobuyuki Itoh
Jul 15, 2009·Nature Chemical Biology·Jonathan W DayMatthias H Tschöp
Mar 6, 2010·Methods in Molecular Biology·Wan-Chun LiDavid Tosh
Oct 20, 2010·Nature Reviews. Endocrinology·Kirk M HabeggerMatthias H Tschöp
Apr 17, 2012·Cell·Mathieu Laplante, David M Sabatini
Aug 28, 2012·Diabetes·Jason J WinnickAlan D Cherrington
Aug 31, 2012·Diabetes·Sarah H LockieDiego Perez-Tilve
Nov 20, 2012·Diabetes·Christine LonguetDaniel J Drucker
Dec 19, 2012·Diabetes·Tricia M TanStephen R Bloom
Jan 12, 2013·Diabetes·Kirk M HabeggerMatthias H Tschöp
Aug 14, 2013·Nature Communications·Yoshihiko IzumidaHitoshi Shimano
Sep 26, 2013·Diabetes·Bilal A OmarBo Ahrén
Nov 5, 2013·Diabetes·Kirk M HabeggerMatthias H Tschöp
Nov 12, 2013·Surgery for Obesity and Related Diseases : Official Journal of the American Society for Bariatric Surgery·Guilherme M CamposKathleen Mulligan
Jan 1, 2014·Diabetes·Christoffer ClemmensenTimo D Müller
Apr 10, 2014·British Journal of Pharmacology·C WestonG Ladds
Jun 17, 2014·The New England Journal of Medicine·Steven J RussellEdward R Damiano
Dec 9, 2014·Nature Medicine·Brian FinanMatthias H Tschöp
Jan 13, 2015·Journal of Diabetes & Metabolism·Teayoun KimQinglin Yang
May 13, 2015·Nature Communications·Paul M TitchenellMorris J Birnbaum
Oct 22, 2016·Cell·Brian FinanTimo D Müller
Feb 12, 2017·The Journal of Biological Chemistry·Kimberly M AlongeF Bradley Hillgartner
Mar 10, 2017·Physiological Reviews·T D MüllerM H Tschöp
Jun 22, 2018·Diabetes·Teayoun KimKirk M Habegger
Citations
Feb 6, 2019·JCI Insight·Megan E CapozziJonathan E Campbell
Aug 28, 2019·Applied Physiology, Nutrition, and Metabolism = Physiologie Appliquée, Nutrition Et Métabolisme·Scott A WillisJames A King
Nov 30, 2019·Endocrinology·Jacqueline L Beaudry, Daniel J Drucker
Nov 2, 2019·Endocrinology·Shelly R NasonKirk M Habegger
Jun 11, 2019·Diabetes·Brian FinanJonathan E Campbell
Jul 9, 2020·Aging·Fang ZhangLiou Y Sun
Jul 25, 2019·JCI Insight·Megan E CapozziJonathan E Campbell
Oct 21, 2020·Biomolecules·Takefumi KimuraNaoki Tanaka
Nov 27, 2020·Diabetes·Nadejda Bozadjieva KramerErnesto Bernal-Mizrachi
Nov 28, 2019·Journal of Medicinal Chemistry·Joseph ChabenneRichard D DiMarchi
Sep 24, 2020·Endocrinology·Kimberley ElJonathan E Campbell
Mar 10, 2020·Peptides·Mohan PatilGanesh V Sangle
Mar 9, 2021·The FEBS Journal·Luiz F BarellaSai P Pydi
Sep 29, 2020·Molecular Metabolism·Laurie L Baggio, Daniel J Drucker
Apr 20, 2021·Cellular Signalling·Siddharth SunilkumarMichael D Dennis
May 3, 2021·Molecular Metabolism·Phil PickfordStephen R Bloom
Jun 9, 2021·Nature Communications·Aijun QiaoGangjian Qin
Jun 3, 2021·Nutrients·Mona Farhadipour, Inge Depoortere
Jul 2, 2021·Molecular Metabolism·Jessica D KeppleChad S Hunter
Jul 30, 2020·Cell Metabolism·Lance A ThielenAnath Shalev