Back to Search
Start Over
Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects
- Source :
- Nature Communications
- Publication Year :
- 2015
-
Abstract
- Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have emerged as treatment options for type 2 diabetes mellitus (T2DM). GLP-1R signals through G-protein-dependent, and G-protein-independent pathways by engaging the scaffold protein β-arrestin; preferential signalling of ligands through one or the other of these branches is known as ‘ligand bias'. Here we report the discovery of the potent and selective GLP-1R G-protein-biased agonist, P5. We identified P5 in a high-throughput autocrine-based screening of large combinatorial peptide libraries, and show that P5 promotes G-protein signalling comparable to GLP-1 and Exendin-4, but exhibited a significantly reduced β-arrestin response. Preclinical studies using different mouse models of T2DM demonstrate that P5 is a weak insulin secretagogue. Nevertheless, chronic treatment of diabetic mice with P5 increased adipogenesis, reduced adipose tissue inflammation as well as hepatic steatosis and was more effective at correcting hyperglycaemia and lowering haemoglobin A1c levels than Exendin-4, suggesting that GLP-1R G-protein-biased agonists may provide a novel therapeutic approach to T2DM.<br />GLP-1 is a gut hormone with glucose-lowering activity. Here the authors report the peptide, P5, a variant of the GLP-1 receptor agonist exendin-4, with 'biased' signalling activity, and show that P5 improves glucose homeostasis in diabetic mice by increasing adipose tissue hyperplasia.
- Subjects :
- Agonist
Male
medicine.medical_specialty
endocrine system
medicine.drug_class
G protein
medicine.medical_treatment
Drug Evaluation, Preclinical
General Physics and Astronomy
Adipose tissue
Biology
General Biochemistry, Genetics and Molecular Biology
Glucagon-Like Peptide-1 Receptor
Article
Mice
Internal medicine
medicine
Animals
Humans
Hypoglycemic Agents
Insulin
Receptor
Autocrine signalling
Multidisciplinary
Adipogenesis
digestive, oral, and skin physiology
General Chemistry
Mice, Inbred C57BL
Endocrinology
Adipose Tissue
Diabetes Mellitus, Type 2
Secretagogue
Peptides
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Nature communications
- Accession number :
- edsair.doi.dedup.....f555a13dcf174de4e58e5e85bf5f3069