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

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Feb 15

PMID 29444429

Citations 37

Authors

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

Soon will be listed here.

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 Lepr and Lep 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.

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