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 H 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 Wang, Roger H UngerWilliam L Holland

Research output: Contribution to journalArticle

13 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)1760-1773
Number of pages14
JournalCell Reports
Volume22
Issue number7
DOIs
StatePublished - Feb 13 2018

Keywords

  • adiponectin
  • ceramide
  • lipotoxicity
  • sphingolipid

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Sharma, A. X., Quittner-Strom, E. B., Lee, Y. H., Johnson, J. A., Martin, S. A., Yu, X., Li, J., Lu, J., Cai, Z., Chen, S., Wang, M-Y., Zhang, Y., Pearson, M. J., Dorn, A. C., McDonald, J. G., Gordillo, R., Yan, H., Thai, D., Wang, Z., ... Holland, W. L. (2018). Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice. Cell Reports, 22(7), 1760-1773. https://doi.org/10.1016/j.celrep.2018.01.065