Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice

• DOI: 10.1016/j.celrep.2018.01.065
• Publication Date: 2018-02-13T17:13:48Z
• Authors: Ankit X. Sharma; Ezekiel B. Quittn...; 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
• Keywords: Diabetic Cardiomyopathy; Glucagon receptor; AMP-Activated Protein Kinase

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