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. 2013 May 21;8(5):e63861.
doi: 10.1371/journal.pone.0063861. Print 2013.

High-throughput Screening for GPR119 Modulators Identifies a Novel Compound With Anti-Diabetic Efficacy in Db/Db Mice

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Free PMC article

High-throughput Screening for GPR119 Modulators Identifies a Novel Compound With Anti-Diabetic Efficacy in Db/Db Mice

Meng Zhang et al. PLoS One. .
Free PMC article

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.

Conflict of interest statement

Competing Interests: Olivier Nosjean, Jean Boutin and Pierre Renard are research collaborators, and are affiliated to Les Laboratoires Servier, one of the funders of this study. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1
Figure 1. Biological activities of AR-231453 and OEA in vitro and development of a high-throughput screening assay for GPR119 modulators.
Agonist activities of AR-231453 and OEA were measured with a reporter gene assay (A), in which allosteric properties of both were studied in the presence of different concentrations of (B) AR-231453 vs. OEA or (D) OEA vs. AR-231453. The experiments were repeated in a cAMP accumulation assay (C and E). (F) Validation of the high-throughput screening assay. All data points were representatives of three independent experiments, determined in triplicate.
Figure 2
Figure 2. Identification and characterization of a novel GPR119 agonist.
(A) Chemical structure of compound MW1219. Agonist activity of MW1219 was studied in HEK293-hGPR119 cells (B) and control HEK293 cells (C) employed in a reporter gene assay system, respectively. The effect of MW1219 was confirmed in a cAMP accumulation assay using HEK293-hGPR119 cells and control HEK293 cells (D and E). Allosteric activities of MW1219 for OEA were measured in both reporter gene and cAMP assays (F and G). All data points were representatives of three independent experiments, determined in triplicate.
Figure 3
Figure 3. Effects of MW1219 on insulin and GLP-1 secretion in vitro .
The effect of MW1219 to stimulate insulin secretion in MIN6 cells was studied in 2.8 mM and 16.8 mM glucose (A). Influence of GPR119 knockdown on MW1219-induced insulin secretion (C). Effect of MW1219 on GLP-1 release in GLUTag cells (B). After siRNA treatment, the effect of MW1219 on GLP-1 release was determined with GLUTag cells (D). All data points were representatives of three independent experiments, determined in triplicate. *P<0.05 and **P<0.01 denote a statistically significant difference between vehicle vs. compound-treated cells using One-Way ANOVA test.
Figure 4
Figure 4. The effects of chronically administered MW1219 in db/db mice.
(A) Time course of the effect on fasting blood glucose. After 6 weeks of treatment, (B) HbA1c, (C) oral glucose tolerance and (D) area-under-the-curve were quantified. Symbols are means ± SEM in all panels. *P<0.05, **P<0.01 vs. vehicle group, and #P<0.05 vs. 1 mg/kg sitagliptin treatment group as determined with One-Way ANOVA test.
Figure 5
Figure 5. Activities of MW1219 on insulin and GLP-1 secretion in db/db mice.
Following 6 weeks of oral treatment with MW1219, (A) insulin and (B) GLP-1 levels after an oral glucose bonus were determined. *P<0.05, **P<0.01 vs. vehicle group, and #P<0.05 vs. sitagliptin group (1 mg/kg) as determined with One-Way ANOVA test.

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Grant support

This work was supported in part by grants from the Ministry of Health of China (2012ZX09304011 and 2013ZX09507002), Shanghai Science and Technology Development Fund (11DZ2292200) and Les Laboratories Servier (France). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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