Homology modeling of FFA2 identifies novel agonists that potentiate insulin secretion

Stephanie R Villa,Annette Gilchrist,Medha Priyadarshini,Joseph L Zapater,Rama K Mishra,Gary E Schiltz,Helena Mancebo,Brian T Layden

doi:10.1136/jim-2017-000523

Abstract

Critical aspects of maintaining glucose homeostasis in the face of chronic insulin resistance and type 2 diabetes (T2D) are increased insulin secretion and adaptive expansion of beta cell mass. Nutrient...

Highlights

As type 2 diabetes (T2D) continues to grow as a global public health challenge, so too does the urgent need for new therapies
The set of 140 compounds was cross-docked to the FFA3 binding pocket, and compounds that demonstrated binding to FFA3 were eliminated, resulting in the identification of 59 compounds with predicted selectivity and enhanced potency for free fatty acid receptor 2 (FFA2) over FFA3
Increasing evidence suggests that FFA2 may be a viable target to promote glucose stimulated insulin secretion (GSIS)

Summary

Introduction

As type 2 diabetes (T2D) continues to grow as a global public health challenge, so too does the urgent need for new therapies. The long-chain FFA, FFA1 (GPR40), has been shown to regulate glucose stimulated insulin secretion (GSIS), and several FFA1 agonists have shown promise in early stage clinical trials, though concerns over potential toxicity have slowed the progression of some of these agonists through trials.[2]. Another member of the FFA family, FFA2 (GPR43), has recently gained attention as a potential metabolic regulator. These data, along with recent reports from us and others that activation of FFA2 regulates insulin secretion,[11,12,13] suggest that FFA2 may represent a novel T2D target through its involvement in the pancreatic β cell response to insulin resistance

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Results

Conclusion