Abstract
G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic β cells and enteroendocrine cells. It is involved in glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) release, thereby representing a promising target for the treatment of type 2 diabetes. Although a number of GPR119 agonists were developed, no positive allosteric modulator (PAM) to this receptor has been reported. Here we describe a high-throughput assay for screening GPR119 PAMs and agonists simultaneously. Following screening of a small molecule compound library containing 312,000 synthetic and natural product-derived samples, one potent GPR119 agonist with novel chemical structure, MW1219, was identified. Exposure of MIN6 and GLUTag cells to MW1219 enhanced glucose-stimulated insulin secretion and GLP-1 release; once-daily oral dosing of MW1219 for 6 weeks in diabetic db/db mice reduced hemoglobin A1c (HbA1c) and improved plasma glucose, insulin and GLP-1 levels; it also increased glucose tolerance. The results demonstrate that MW1219 is capable of effectively controlling blood glucose level and may have the potential to be developed as a new class of anti-diabetic agents.
Highlights
Type 2 diabetes mellitus (T2DM), characteristic of defects in both insulin secretion and sensitivity [1,2], is an increasing threat to human health
We studied the allosteric activity between OEA and the first small molecule G protein-coupled receptor 119 (GPR119) agonist, AR-231453 [13]
Cell Culture HEK293 cells stably transfected with a human GPR119 vector and a cAMP response element-driven luciferase reporter plasmid (HEK293-hGPR119 cells) and HEK293 cells transfected only with a cAMP response element-driven luciferase reporter plasmid were cultured in Dulbecco’s modified Eagle medium (DMEM) (Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (FBS), 4.5 g/l glucose, 100 units/ml penicillin and 100 mg/ml streptomycin at 37uC in 5% CO2
Summary
Type 2 diabetes mellitus (T2DM), characteristic of defects in both insulin secretion and sensitivity [1,2], is an increasing threat to human health. Due to the multiplicity of pathologies and the complexity of control mechanism of human body, there exist many therapeutics for T2DM presently [3]. Compounds that enhance incretin activities have been of particular interest to pharmaceutical companies. Incretinbased therapies are becoming popular which use either GLP1 mimetics or DPP-4 inhibitors [4]. The efficacy of DPP-4 inhibitors is modest because their action is dependent upon endogenous GLP-1 while GLP-1 mimetics require frequent injections [5]. The strategy to identify orally active agents capable of stimulating GLP-1 release remains attractive [6]
Sign-in/Register to view highlights & summary 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.
