Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice
Authors: Yiyi Zhang
Zheqing Cai
Hai Yan
Mackenzie J Pearson
Young Lee
Joshua A Johnson
John Lu
Sarah A Martin
Andie C Dorn
Ankit X Sharma
Zhao V Wang
Shiuhwei Chen
Dung Thai
Xinxin Yu
May-Yun Wang
Ezekiel B Quittner-Strom
Jianping Li
Ruth Gordillo
Roger H Unger
William L Holland
Jeffrey G McDonald
Journal: Cell Reports (2018)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: adiponectin; ceramide; lipotoxicity; sphingolipid.
Affiliations: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA., Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Medical Service, Veteran's Administration North Texas Health Care System, Dallas, TX 75216, USA., Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA., Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA., REMD Biotherapeutics Inc., Camarillo, CA 93012, USA., Cardio-lab, Baltimore, MD 21205, USA., Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA., Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA. Electronic address: .

Abstract:  The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Leprdb/db and Lepob/ob mice with REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor. As expected, REMD 2.59 suppresses hepatic glucose production and improves glycemia. Surprisingly, it also enhances insulin action in both liver and skeletal muscle, coinciding with an increase in AMP-activated protein kinase (AMPK)-mediated lipid oxidation. Furthermore, weekly REMD 2.59 treatment over a period of months protects against diabetic cardiomyopathy. These functional improvements are not derived simply from correcting the systemic milieu; nondiabetic mice with cardiac-specific overexpression of lipoprotein lipase also show improvements in contractile function after REMD 2.59 treatment. These observations suggest that hyperglucagonemia enables lipotoxic conditions, allowing the development of insulin resistance and cardiac dysfunction during disease progression. 

Retracted: No

PubPeer comments:
 There seems to be an image duplication in Figure 2. Both images are of the control group, but they are supposed to be different IHC stainings, which is clearly not the case. ![file] Moreover, there is something wrong with the flow cytometry plots. Even though the images are crips and high resolution, the individual data points are indiscernible. What has happened here? ![file] Of particular note is the plot where the authors have been coloring outside the lines. ![file] , 
 Can the authors confirm if theyu2019ve been in touch with the journal? ,