Lipid receptors and islet function: therapeutic implications?

Abstract

G‐protein coupled receptors (GPCRs) are targets of approximately 30% of currently marketed drugs. Over the last few years, a number of GPCRs expressed in pancreatic β‐cells and activated by lipids have been discovered. GPR40 was shown to be activated by medium‐ to long‐chain fatty acids (FAs). It has since been shown that GPR40 contributes to FA amplification of glucose‐induced insulin secretion. Although some controversy still exists as to whether GPR40 agonists or antagonists should be designed as novel type 2 diabetes drugs, data obtained in our laboratory and others strongly suggest that GPR40 agonism might represent a valuable therapeutic approach. GPR119 is expressed in pancreatic β‐cells and enteroendocrine L‐cells, and augments circulating insulin levels both through its direct insulinotropic action on β‐cells and through FA stimulation of glucagon‐like peptide 1 (GLP‐1) secretion. GPR120 is expressed in L‐cells and was also shown to mediate FA‐stimulated GLP‐1 release. Finally, GPR41 and GPR43 are receptors for short‐chain FAs and may indirectly regulate β‐cell function via adipokine secretion. Although the discovery of these various lipid receptors opens new and exciting avenues of research for drug development, a number of questions regarding their mechanisms of action and physiological roles remain to be answered.