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Glucagon Switches between GLP-1 and Glucagon Receptors in Normal and Hyperglycemic Mice

27 Pages Posted: 22 Feb 2019 Sneak Peek Status: Review Complete

See all articles by Chengsheng Han

Chengsheng Han

Peking University - State Key Laboratory of Membrane Biology

Yulin Zhang

Peking University - State Key Laboratory of Membrane Biology

Wenzhen Zhu

Peking University - State Key Laboratory of Membrane Biology

Guoyi Yang

Peking University - State Key Laboratory of Membrane Biology

Xiaohong Peng

Peking University - State Key Laboratory of Membrane Biology

Sohum Mehta

University of California, San Diego (UCSD) - Department of Pharmacology

Jin Zhang

University of California, San Diego (UCSD) - Department of Pharmacology

Yanmei Liu

Peking University - State Key Laboratory of Membrane Biology

Liangyi Chen

Peking University - State Key Laboratory of Membrane Biology

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Abstract

Despite the well-known role of the GLP-1 receptor (GLP-1R) in potentiating glucose-stimulated insulin secretion (GSIS) and as a therapeutic drug target in diabetes treatment, how GLP-1R is activated under physiological and pathological conditions remains elusive. Against preconceptions in the field, we prove that glucagon released from pancreatic α-cells serves as the principal ligand for GLP-1R on β-cells and is essential for GSIS in normal mice. Activation of the cognate glucagon receptor (GCGR) by glucagon amplifies GSIS evoked by intermediate concentrations of glucose only, as high glucose bypasses GCGR in increasing cytosolic cAMP from the same downstream pool. As the endogenous dual-receptor agonist, glucagon switches from GLP-1R to GCGR in β-cells of mice fed a high-fat diet, which significantly enhances GSIS and reduces body weight. Therefore, developing dual-receptor agonists that target balanced activation of GCGR and GLP-1R in vivo may better preserve glycemic control than the activation of GLP-1R alone.

Keywords: Glucagon, GLP-1, GCGR, GLP-1R, α-cells, β-cells, glucose-stimulated insulin 43 secretion, cAMP, dual-receptor agonist

Suggested Citation

Han, Chengsheng and Zhang, Yulin and Zhu, Wenzhen and Yang, Guoyi and Peng, Xiaohong and Mehta, Sohum and Zhang, Jin and Liu, Yanmei and Chen, Liangyi, Glucagon Switches between GLP-1 and Glucagon Receptors in Normal and Hyperglycemic Mice (October 26, 2018). Available at SSRN: https://ssrn.com/abstract=3273389 or http://dx.doi.org/10.2139/ssrn.3273389
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Chengsheng Han

Peking University - State Key Laboratory of Membrane Biology

Beijing, 100871
China

Yulin Zhang

Peking University - State Key Laboratory of Membrane Biology

Beijing, 100871
China

Wenzhen Zhu

Peking University - State Key Laboratory of Membrane Biology

Beijing, 100871
China

Guoyi Yang

Peking University - State Key Laboratory of Membrane Biology

Beijing, 100871
China

Xiaohong Peng

Peking University - State Key Laboratory of Membrane Biology

Beijing, 100871
China

Sohum Mehta

University of California, San Diego (UCSD) - Department of Pharmacology

9500 Gilman Drive, Dept. 0636
La Jolla, CA 92093-0636
United States

Jin Zhang

University of California, San Diego (UCSD) - Department of Pharmacology

9500 Gilman Drive, Dept. 0636
La Jolla, CA 92093-0636
United States

Yanmei Liu

Peking University - State Key Laboratory of Membrane Biology ( email )

Beijing, 100871
China

Liangyi Chen (Contact Author)

Peking University - State Key Laboratory of Membrane Biology ( email )

Beijing, 100871
China

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