GPR40 Is Necessary but Not Sufficient for Fatty Acid Stimulation of Insulin Secretion In Vivo

Abstract

Long-chain fatty acids amplify insulin secretion from the pancreatic beta cell. The G protein-coupled receptor GPR40 is specifically expressed in beta cells and is activated by fatty acids. Loss of function of GPR40 was shown to markedly inhibit fatty-acid stimulation of insulin secretion in vitro. However, the role of GPR40 in acute regulation of insulin secretion in vivo remains unclear. To this aim, we generated GPR40 knock-out (KO) mice and examined glucose homeostasis, insulin secretion in response to glucose and Intralipid in vivo, and insulin secretion in vitro after short-and long-term exposure to fatty acids. Our results show that GPR40 KO mice have essentially normal glucose tolerance and insulin secretion in response to glucose. Insulin secretion in response to Intralipid was reduced by approximately 50%. In isolated islets, insulin secretion in response to glucose and other secretagogues was unaltered, but fatty-acid potentiation of insulin release was markedly reduced. Islets from GPR40 KO mice were as sensitive to fatty-acid inhibition of insulin secretion upon prolonged exposure as islets from wild-type animals. We conclude that GPR40 contributes approximately half of the full insulin secretory response to fatty acids in mice, but does not play a role in the mechanisms of lipotoxicity.Long-chain fatty acids are essential regulators of normal pancreatic beta-cell function, and are likely to play a role in the pathogenesis of beta-cell dysfunction in type 2 diabetes (reviewed in (1)). Under normal circumstances, fatty acids do not initiate insulin release, but amplify glucose-stimulated insulin secretion (GSIS) (2-5). Fatty-acid potentiation of insulin secretion has physiological implications, particularly after a period of fasting (6). Until recently, the prevailing model postulated that the effects of fatty acids on the beta cell were mediated by their intracellular metabolism and the generation of lipid derived signals which, in turn, potentiate GSIS (2;7). According to this hypothesis, fatty acids are transported across the plasma membrane and activated into their long-chain coenzyme A esters, which in turn modulate a number of intracellular targets that influence insulin secretion. Moreover, evidence suggests that intracellular fatty-acid metabolism is a key component of both nutrient-and nonnutrient-induced insulin secretion (7). In contrast to their acute, stimulatory effect on GSIS, prolonged exposure to elevated levels of fatty acids impairs beta-cell function, a phenomenon referred to as lipotoxicity (reviewed in (1)). The mechanisms of lipotoxicity remain poorly understood but have been proposed to also involve intracellular metabolism of fatty acids and the generation of lipid-derived metabolites (8).The models described above have been challenged by the observation that fatty acids activate the G-protein coupled receptor (GPCR) GPR40 (9-11), also referred to as the free fatty-acid 1 receptor (FFA 1 R) (12;13). GPR40 belongs to a class of GPCR with high structural conservation, o...

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

“…Increased insulin-releasing capacity of pancreatic islets from CLA-fed mice has been disclosed (34 -36); however, a molecular explanation for the acute insulinotropic action of CLAs is still lacking. In this study, we present several lines of evidence that acute insulinotropic effects of CLAs are mediated via activation of the ␤-cell-specific G proteincoupled receptor FFA1, an emerging therapeutic target to treat type 2 diabetes (15,16,21,27,37,38). First, increase of [Ca 2ϩ ] i and inositol phosphate production in response to CLAs was consistently observed in FFA1-expressing cells regardless of the cellular background, whereas it was not observed in cells lacking FFA1.…”

“…This in turn raises the possibility that FFA1 is responsible for both acute insulinotropic effects but also development of diabetes after long term ingestion of CLAs, two observations that have been made in various clinical studies with oral CLA supplementation (8, 13). So far, FFA1 has been consistently involved in mediating the acute stimulatory effects of various long chain fatty acids on insulin secretion (15,16,21,32,44,45), but it has also been implicated in potential deleterious effects of fatty acids on ␤-cell function (27,38,44), albeit the latter aspect is considered as rather controversial (27,38). Nevertheless, these aspects are of prime importance to antidiabetic drug discovery because a potential contribution of FFA1 to ␤-cell dysfunction would disqualify FFA1 agonists as novel type 2 diabetes drugs.…”

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

“…This is because deletion of GPR40 leads to loss of the acute insulin secretory response to fatty acids in mouse islets [128] and siRNAmediated knockdown of GPR40 in MIN6 cells also results in loss of this response [129].…”

The Free Fatty Acid Receptor G Protein-coupled Receptor 40 (GPR40) Protects from Bone Loss through Inhibition of Osteoclast Differentiation*

“…Ϫ/Ϫ Mice-GPR40 Ϫ/Ϫ mice were obtained from AMGEN Inc. As described by Latour et al (19), GPR40 Ϫ/Ϫ mice on a mixed C57BL/6/129 background were generated by homologous recombination in embryonic stem cells at Lexicon Genetics (The Woodlands, TX). Exon 2 of the GPR40 gene was replaced with a LacZ gene.…”

“…Subsequently, the role of GPR40 (also known as free fatty acid receptor-1/FFAR-1) was mainly examined in beta cells for its involvement in insulin secretion (18). Using GPR40-deficient mice, we showed that GPR40 contributes to fatty acid potentiation of glucose-induced insulin secretion (19). Indeed, the ability of GPR40 to enhance insulin release only when glucose levels are elevated made it an appealing drug target for the treatment of type 2 diabetes, and agonists of GPR40 have shown very encouraging results in recent phase 2 clinical trials (20,21).…”