Metabolic responses and benefits of glucagon-like peptide-1 (GLP-1) receptor ligands.

Neil Tanday,Peter R Flatt,Nigel Irwin

doi:10.1111/bph.15485

Neil Tanday, Peter R Flatt + Show 1 more

Open Access

https://doi.org/10.1111/bph.15485

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Abstract

Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone that has undergone a revolutionary turnaround from discovery to clinically approved therapeutic. Rapid progress in drug design and formulation has led from initial development of short‐ and long‐acting drugs suitable for daily or weekly parenteral administration, respectively, through to the most recent approval of an orally active GLP‐1 agent. The current review outlines the biological action profile of GLP‐1 including the various beneficial metabolic responses in pancreatic and extra‐pancreatic tissues, including the gastrointestinal tract, liver, bone and kidney as well as the reproductive cardiovascular and CNS. We then briefly consider clinically approved GLP‐1 receptor ligands and recent advances in this field. Given the sustained evolution in the area of GLP‐1 drug development and excellent safety profile, as well as the plethora of metabolic benefits, clinical approval for use in diseases beyond diabetes and obesity is very much conceivable.LINKED ARTICLESThis article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc

Highlights

The physiological role of the gastrointestinal tract (GIT) was traditionally thought to involve nutrient digestion and absorption, but it is known to be the source of a plethora of peptide hormones involved in the regulation of metabolism and other body functions [Baggio and Drucker, 2007]
Two major GIT-derived hormones involved in regulation of postprandial glucose have been identified, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), secreted from L-cells and K-cells of the GIT, respectively
The amino acid peptide sequence of GLP-1 was first discovered by Habener and colleagues in the early 1980s through decoding of recombinant cDNA clones in anglerfish [Lund et al, 1982], and subsequently found to enhance insulin secretion in the perfused rat pancreas [Mojsov et al, 1987], with clinical approval of GLP-1 mimetic for the treatment of type 2 diabetes mellitus (T2DM) following in 2005 [Kolterman et al, 2005]

Summary

Introduction

The physiological role of the gastrointestinal tract (GIT) was traditionally thought to involve nutrient digestion and absorption, but it is known to be the source of a plethora of peptide hormones involved in the regulation of metabolism and other body functions [Baggio and Drucker, 2007]. The amino acid peptide sequence of GLP-1 was first discovered by Habener and colleagues in the early 1980s through decoding of recombinant cDNA clones in anglerfish [Lund et al, 1982], and subsequently found to enhance insulin secretion in the perfused rat pancreas [Mojsov et al, 1987], with clinical approval of GLP-1 mimetic for the treatment of type 2 diabetes mellitus (T2DM) following in 2005 [Kolterman et al, 2005] This original approval was largely based on the potent glucose-dependent insulinotropic properties of GLP-1 receptor (GLP-1R) activation on pancreatic beta-cells, it is clear that the GLP-1R is expressed on various other metabolically active tissues eliciting a range of biological effects across diverse organ systems [Figure 1]

GLP-1 secretion

Findings

Clinically approved GLP-1R ligands