Abstract
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 analogs act to restore and maintain normal cellular functions. These findings have prompted several clinical trials which have reported GLP-1 analogs 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 analogs 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.
Highlights
While its gene was first cloned in 1983, and protein product approved as a therapeutic agent for Type 2 diabetes mellitus (T2D) in 2005, the mammalian glucagon-like peptide-1 (GLP-1), its modes of action, and various analogs, have been and are still widely studied
Glucagon-like peptide (GLP)-1 acts through binding to its receptor (GLP-1R), triggering a downstream signaling cascade able to induce a potent stimulation of glucose stimulated insulin secretion (GSIS) in β-cells, as well as inhibition of α-cell glucagon release
Most recent studies unveiled that GLP-1 analogs act in the CNS and various peripheral tissues to restore and maintain normal cellular functions
Summary
While its gene was first cloned in 1983, and protein product approved as a therapeutic agent for Type 2 diabetes mellitus (T2D) in 2005, the mammalian glucagon-like peptide-1 (GLP-1), its modes of action, and various analogs, have been and are still widely studied. Van de Velde et al reported that chronic GLP-1R activation led to metabolic reprogramming marked by increased ATP production and upregulation of glycolytic enzymes, occurring as a result of late activation of subunit alpha of HIF-1 (HIF-1α) downstream of mTOR This finding is consistent with a recent study demonstrating that depletion of HIF-1α or inhibition of mTOR impaired the effects of GLP-1R signaling on glycolysis [18]. Primarily studied in the pancreatic β-cell, the beneficial effects of GLP-1 and its analogs have recently been shown to be advantageous to a variety of tissues in several disease pathologies, such as the heart, liver, lung, muscle, and brain, as detailed below It remains to be clarified, as to whether the metabolic and pro-survival responses arising from chronic GLP-1R mediated signaling cascades are relevant to extra-pancreatic tissues as well
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