Journal
DIABETES OBESITY & METABOLISM
Volume 24, Issue 11, Pages 2090-2101Publisher
WILEY
DOI: 10.1111/dom.14794
Keywords
antidiabetic drug; antiobesity drug; beta-cell function; drug development; GLP-1 analogue; incretin therapy
Categories
Funding
- Sun Pharmaceuticals Inc.
- Wellcome Trust Investigator Award [WT212625/Z/18/Z]
- MRC Program [MR/R022259/1]
- John R. Evans Leaders Award from Innovation Canada
- MRC Project [MR/R010676/1]
- European Union [115881RHAPSODY]
- Diabetes UK
- European Federation for the Study of Diabetes
- Commonwealth
- Integrated Biological Imaging Network
- Lilly Research Award Program
- Imperial Post-doctoral PostCCT Research Fellowship scheme
- Academy of Medical Sciences
- Society for Endocrinology
- British Society for Neuroendocrinology
- Engineering and Physical Sciences Research Council
- JDRF award [31-2008-416]
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This study describes the in vitro characteristics and antidiabetic efficacy of GL0034, a novel GLP-1RA. GL0034 showed increased binding affinity and bias towards cAMP signaling compared to semaglutide. In vivo studies in mice demonstrated that GL0034 had powerful antidiabetic effects, including weight loss and improved glycemic control.
Aims To describe the in vitro characteristics and antidiabetic in vivo efficacy of the novel glucagon-like peptide-1 receptor agonist (GLP-1RA) GL0034. Materials and Methods Glucagon-like peptide-1 receptor (GLP-1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis and recycling were measured using HEK293 and INS-1832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1832/3 cells, mouse islets and human islets. Chronic administration studies to evaluate weight loss and glycaemic effects were performed in db/db and diet-induced obese mice. Results Compared to the leading GLP-1RA semaglutide, GL0034 showed increased binding affinity and potency-driven bias in favour of cAMP over GLP-1R endocytosis and beta-arrestin-2 recruitment. Insulin secretory responses were similar for both ligands. GL0034 (6 nmol/kg) led to at least as much weight loss and lowering of blood glucose as did semaglutide at a higher dose (14 nmol/kg). Conclusions GL0034 is a G protein-biased agonist that shows powerful antidiabetic effects in mice, and may serve as a promising new GLP-1RA for obese patients with type 2 diabetes.
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