Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice
Ankit X. Sharma,
Ezekiel B. Quittner-Strom,
Young Lee,
Joshua A. Johnson,
Sarah A. Martin,
Xinxin Yu,
Jianping Li,
John Lu,
Zheqing Cai,
Shiuhwei Chen,
May-yun Wang,
Yiyi Zhang,
Mackenzie J. Pearson,
Andie C. Dorn,
Jeffrey G. McDonald,
Ruth Gordillo,
Hai Yan,
Dung Thai,
Zhao V. Wang,
Roger H. Unger,
William L. Holland
Affiliations
Ankit X. Sharma
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
Ezekiel B. Quittner-Strom
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
Young Lee
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
Joshua A. Johnson
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
Sarah A. Martin
Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
Xinxin Yu
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
Jianping Li
Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
John Lu
REMD Biotherapeutics Inc., Camarillo, CA 93012, USA
Zheqing Cai
Cardio-lab, Baltimore, MD 21205, USA
Shiuhwei Chen
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
May-yun Wang
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
Yiyi Zhang
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
Mackenzie J. Pearson
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
Andie C. Dorn
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
Jeffrey G. McDonald
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
Ruth Gordillo
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
Hai Yan
REMD Biotherapeutics Inc., Camarillo, CA 93012, USA
Dung Thai
REMD Biotherapeutics Inc., Camarillo, CA 93012, USA
Zhao V. Wang
Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA
Roger H. Unger
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
William L. Holland
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Corresponding author
Summary: 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.
