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This article is part of the Research Topic

Gastrointestinal Hormones

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Front. Endocrinol. | doi: 10.3389/fendo.2018.00672

Pleiotropic Effects of GLP-1 and analogs on cell signaling, metabolism and function

Jordan Rowlands1,  Rodrigo Carlessi1*, Philip Newsholme1* and  Julian Heng1
  • 1School of Pharmacy and Biomedical Sciences, Curtin University, Australia

The incretin hormone Glucagon-Like Peptide-1 (GLP-1) is best known for its ‘incretin effect’ in restoring glucose homeostasis in diabetics, however, it is now apparent that it has a broader range of physiological effects in the body. Both in vitro and in vivo studies have demonstrated that GLP-1 mimetics alleviate endoplasmic reticulum stress, regulate autophagy, promote metabolic reprogramming, stimulate anti-inflammatory signaling, alter gene expression and influence neuroprotective pathways. A substantial body of evidence has accumulated with respect to how GLP-1 and its analogues act to restore and maintain normal cellular functions. These findings have prompted several clinical trials which have reported GLP-1 analogues improve cardiac function, restore lung function and reduce mortality in patients with obstructive lung disease, influence blood pressure and lipid storage, and even prevent synaptic loss and neurodegeneration. Mechanistically, GLP-1 elicits its effects via acute elevation in cAMP levels, and subsequent protein kinase(s) activation, pathways well defined in pancreatic β-cells which stimulate insulin secretion in conjunction with elevated Ca2+ and ATP. More recently, new studies have shed light on additional downstream pathways stimulated by chronic GLP-1 exposure, findings which have direct relevance to our understanding of the potential therapeutic effects of longer lasting analogues recently developed for clinical use. In this review, we provide a comprehensive description of the diverse roles for GLP-1 across multiple tissues, describe downstream pathways stimulated by acute and chronic exposure, and discuss novel pleiotropic applications of GLP-1 mimetics in the treatment of human disease.

Keywords: GLP-1, signaling, diabetes, Metabolism, Cell function, Cell integrity

Received: 22 Aug 2018; Accepted: 29 Oct 2018.

Edited by:

Damien Keating, Flinders University, Australia

Reviewed by:

Rudy M. Ortiz, University of California, Merced, United States
Carol Huang, University of Calgary, Canada  

Copyright: © 2018 Rowlands, Carlessi, Newsholme and Heng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Rodrigo Carlessi, School of Pharmacy and Biomedical Sciences, Curtin University, Perth, 6102, Australia, rodrigo.carlessi@curtin.edu.au
Prof. Philip Newsholme, School of Pharmacy and Biomedical Sciences, Curtin University, Perth, 6102, Australia, philip.newsholme@curtin.edu.au