Long-chain fatty-acid receptors and pancreatic islet function

抄録

Long-chain fatty acids (LCFA) are important regulators of pancreatic islet function. Acutely, LCFA amplify glucose-induced insulin secretion from pancreatic beta cells. However, when present at excessive levels for prolonged periods of time, LCFAs impair beta-cell function. The discovery of G protein-coupled receptors (GPCRs) that are activated by LCFA in the early 2000s has prompted major drug discovery efforts to target these receptors for the treatment of metabolic diseases. Of these, FFA1 (GPR40) is predominantly expressed in pancreatic beta cells. While some controversy remains as to whether prolonged FFA1 activation would have undesirable side effects, most drug discovery programs have focused on the development of FFA1 agonists to enhance insulin secretion in type 2 diabetes. Studies from our group have provided evidence that FFA1 contributes to the maintenance of glucose homeostasis under normal conditions and in response to insulin resistance in rodents. However, clinical development of an FFA1 agonist was abruptly halted due to liver toxicity. FFA4 (GPR120) is structurally divergent but shares the same endogenous ligands with FFA1. The expression pattern of FFA4 is more ubiquitous, and its activation of this receptor in adipocytes and macrophages has been proposed to mediate the anti-inflammatory and insulin-sensitizing effects of omega-3 fatty acids, although this remains controversial. In islets, FFA4 is preferentially expressed in somatostatin-secreting delta cells and its activation inhibits somatostatin secretion, which indirectly stimulates insulin secretion. Therefore, FFA1 and FFA4 appear to play complementary roles in pancreatic islet function. However, many aspects of the biology and pharmacology of these receptors remain to be clarified.