The Role of GPR40 (FFAR1) in Pharmacological vs Physiological Control of Incretin Secretion

Abstract

G protein‐coupled receptor 40 (GPR40), also known as free fatty acid receptor 1 (FFAR1), is a member of a family of lipid‐activated receptors that is highly expressed in the pancreas and enteroendocrine cells with lower levels expressed in the brain. GPR40 mediates medium and long chain fatty acid stimulated insulin secretion in the presence of elevated glucose levels. This glucose‐dependent insulin secretion property has established GPR40 agonists as attractive therapeutic agents for the treatment of type 2 diabetes.We have shown previously that synthetic, small molecule GPR40 agonists normalize glucose levels during oral glucose tolerance tests performed in mice after acute oral administration. In addition, incretin levels, total and active GLP‐1 and GIP, are significantly elevated immediately following oral administration of the GPR40 agonists. These findings suggest that GPR40 may play an important role in the incretin secretion following a meal. The following studies were performed to address this hypothesis.A synthetic GPR40 agonist, liquid mixed meal, or vehicle alone was administered orally at t = 0 minutes to wild type (WT) or GPR40 knockout (KO) mice and blood was collected for incretin determination at 0.5, 1.5 and 3 hours. Administration of the GPR40 agonist in WT mice led to a robust increase in active GLP‐1 with peak concentrations reaching 12 pg/ml at the 0.5 hour time point followed by levels falling to 5 pg/ml for the remainder of the study (3 hours). The changes in active GIP levels were similar. In contrast, elevations in GLP‐1 and GIP levels were absent in GPR40 KO mice demonstrating that the incretin effect following administration of the GPR40 agonist was GPR40 mediated.The same experimental design was performed in mice orally administrated a liquid mixed meal. Active GLP‐1 levels peaked at the 1 hour time point (5.5 pg/ml) and fell to levels equivalent to those seen with the vehicle control at 6 hours. Changes in active GIP levels were mild demonstrating a peak concentration at 0.5 hour (0.75 pg/ml) and rapidly returning to normal levels. Interestingly, the same changes in active GLP‐1 and GIP were seen in the GPR40 KO mice compared to those in the WT mice. These findings demonstrate that the incretin secretion following a liquid mixed meal does not require GPR40, suggesting that other receptors are responsible for the meal‐stimulated elevation in active GLP‐1 and GIP.