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 via its direct insulinotropic action on β cells and via 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. While 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.

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.…”

“…5). Both CLA isomers were inactive on the two other fatty acid-binding G protein-coupled receptors, FFA2 and FFA3, respectively, which are also expressed in pancreatic ␤-cells (27) and which are closely related to FFA1 but specifically activated by short chain fatty acids (Fig. 2, E and F) (28 -31).…”

The Therapeutic Potential of Allosteric Ligands for Free Fatty Acid Sensitive GPCRs

“…Early studies in FFA1 -/-mice suggested that both effects were mediated by FFA1 [77], while conflicting subsequent work indicates that only the positive effects on GSIS are FFA1-mediated [78,79]. These conflicting results led to significant controversy and confusion over whether agonists or antagonists of FFA1 would actually be most beneficial for long-term treatment.…”

Les récepteurs membranaires des acides gras de la cellule β

“…Ces observations chez la souris sont corroborées par la découverte récente d'une mutation du gène GPR120 associée à une augmentation de 60 % du risque d'obésité chez l'homme [30]. L'expression de GPR120 dans les cellules β a été détectée par RT-PCR (reverse transcriptase-polymerase chain reaction) [31], mais son rôle physiologique dans ce type cellulaire est mal connu. Son activation par l'EPA semble avoir un effet anti-apoptotique dans les îlots pancréatiques humains [32].…”