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

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. [Display omitted] •REMD 2.59 restores euglycemia, glucose tolerance, and insulin action•REMD 2.59 suppresses hepatic gluconeogenesis by improving insulin signaling to Akt•REMD 2.59 enhances AMPK-induced lipid oxidation in liver, muscle, and heart•REMD 2.59 improves cardiac function in mouse models of heart injury Sharma et al. highlight the regulatory roles for glucagon in managing type 2 diabetes and diabetic cardiomyopathy. REMD 2.59 is a fully humanized antibody that competitively inhibits glucagon receptor signaling, increasing lipid oxidation in liver, skeletal muscle, and heart and improving whole-body insulin sensitivity and cardiac function.