Selective Small-Molecule Agonists of G protein-coupled Receptor 40 Promote Glucose-Dependent Insulin Secretion and Reduce Blood Glucose in Mice

Abstract

Objectives: Acute activation of G protein-coupled Receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate if activation of GPR40 would be beneficial for the treatment of type 2 diabetes since chronic exposure to FFAs impairs islet function. We sought to evaluate the specific role of GPR40 in islets and its potential as a therapeutic target using compounds that specifically activate GPR40.

Research Design and Methods: We developed a series of GPR40 selective small molecule agonists and studied their acute and chronic effects on glucose-dependent insulin secretion (GDIS) in isolated islets, as well as effects on blood glucose levels during intraperitoneal glucose tolerance tests (IPGTT) in wild-type (WT) and in GPR40 knock-out mice (GPR40-/-).

Results: Small molecule GPR40 agonists significantly enhanced GDIS in isolated islets and improve glucose tolerance in WT mice, but not in GPR40-/- mice. While a 72-hour exposure to FFA in tissue culture significantly impaired GDIS in islets from both WT and GPR40-/- mice, similar exposure to the GPR40 agonist did not impair GDIS in islets from WT mice. Furthermore, the GPR40 agonist enhanced insulin secretion in perfused pancreata from neonatal streptozotocin-induced diabetic rats, and improved glucose levels in high fat diet-induced obese mice acutely and chronically.

Conclusions: GPR40 does not mediate the chronic toxic effects of FFAs on islet function. Pharmacological activation of GPR40 may potentiate GDIS in humans and be beneficial on overall glucose control in patients with type 2 diabetes mellitus.