title: Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects.
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.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Hongkai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sturchler
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Nieto
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cistrone
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: LinLing
authors.initials: L
authors.lastname: He
authors.affiliation: Shanghai Institute for Advance Immunological Studies, Shanghai Tech University, Shanghai 200031, China.
authors.forename: Kyungmoo
authors.initials: K
authors.lastname: Yea
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Jones
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Turn
authors.affiliation: Zebra Biologics Inc., Concord, Massachusetts 01742, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Di Stefano
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Dawson
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Patricia H
authors.initials: PH
authors.lastname: McDonald
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lerner
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004353:Drug Evaluation, Preclinical; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000008:administration & dosage*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides