Abstract
Glucagon-like peptide-1 (GLP-1) released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R). GLP-1 7–36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9–36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently ‘compound 2’ has been described as both an agonist and positive allosteric modulator of GLP-1 7–36 amide affinity, but not potency, at the GLP-1R. Importantly, we demonstrated previously that exendin 9–39, generally considered a GLP-1R antagonist, enhances compound 2 efficacy (or vice versa) at the GLP-1R. Given that GLP-1 9–36 amide is the major circulating form of GLP-1 post-prandially and is a low affinity weak partial agonist or antagonist at the GLP-1R, we investigated interaction between this metabolite and compound 2 in a cell line with recombinant expression of the human GLP-1R and the rat insulinoma cell line, INS-1E, with native expression of the GLP-1R. We show compound 2 markedly enhances efficacy and potency of GLP-1 9–36 amide for key cellular responses including AMP generation, Ca2+ signaling and extracellular signal-regulated kinase. Thus, metabolites of peptide hormones including GLP-1 that are often considered inactive may provide a means of manipulating key aspects of receptor function and a novel therapeutic strategy.
Highlights
Glucagon-like peptide-1 (GLP-1) is released from intestinal Lcells in response to nutrient ingestion and is a key incretin hormone, potentiating glucose-dependent insulin release but contributing to glucose homeostasis by enhancing insulin biosynthesis, suppressing glucagon secretion, stimulating b-cell mass and suppressing appetite [1,2,3]
The GLP-1/GLP-1 receptor (GLP-1R) system is a validated target for treatment of type 2 diabetes and both DPP-IV inhibitors and GLP-1 peptide mimetics have emerged as alternative therapies
A number of potential problems associated with inhibition of DPP-IV, along with the inferior clinical efficacy of DPP-IV inhibitors compared to GLP-1R agonists as second line treatments to reduce HbA1c and body weight [2,27,28], the relative metabolic instability of peptide ligands and the requirement for injection of peptides and associated issues with patient compliance have driven the search for small molecule, orally active GLP-1R agonists
Summary
Glucagon-like peptide-1 (GLP-1) is released from intestinal Lcells in response to nutrient ingestion and is a key incretin hormone, potentiating glucose-dependent insulin release but contributing to glucose homeostasis by enhancing insulin biosynthesis, suppressing glucagon secretion, stimulating b-cell mass and suppressing appetite [1,2,3]. These effects are mediated by the GLP-1 receptor (GLP-1R), a Family B G-protein-coupled receptor that is coupled preferentially to Gas but which may couple to other G-proteins [4,5,6,7]. Strategies focusing on GLP-1 and its receptor have become targets for the treatment of this condition
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
