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

Abstract

It is increasingly clear that some of the effects of both free and derivatised long chain fatty acids in pancreatic beta-cells are mediated by a group of G-protein coupled receptors. Some of these display close structural homology while others are more divergent. This Commentary reviews the expression and functional roles of three such molecules, GPR40, GPR119 and GPR120. GPR40 is the best characterised of this group and appears to mediate the acute stimulatory effects of long chain fatty acids on insulin secretion. GPR40 has also been proposed as a potential mediator of fatty acid toxicity but this is more controversial. GPR119 is also involved in stimulation of insulin secretion and responds primarily to ethanolamine derivatives of long chain fatty acids and also to some lysophospholipids rather than to free fatty acids. It may represent a useful target for the development of new insulin secretagogues aimed to enhance insulin release in patients with type 2 diabetes. GPR120 is the most enigmatic of the lipid responsive cell-surface receptors and its function remains to be established. It has been proposed to play a cytoprotective role in certain other cell types but it is unclear whether it fulfils a similar function in beta-cells.

Discovery and characterization of novel smallmolecule agonists of G protein-coupled receptor 119

“…Modulating GSIS in the pancreatic β-cells either directly by targeting specific GPCRs on β-cells or indirectly by increasing incretin levels through GLP-1 analogs and DPP4 inhibitors has become the focus of therapeutic strategies for T2D in recent years [21][22][23][24] . Although the latter approach has been quite successful in treating T2D, GLP-1 analogs such as exendin-4 are not orally administrable, while DDP4 inhibitors are limited by the endogenous level of GLP-1.…”

Alteration of the Glucagon Axis in GPR120 (FFAR4) Knockout Mice

“…Although several groups have demonstrated that GPR120 is expressed in islets (1,4,8), the acute role of GPR120 in islets has yet to be examined. LCFAs, which are thought to be endogenous ligands for GPR120, have well-characterized acute effects on hormone secretion from islet ␣-and ␤-cells.…”

GPR40 protein levels are crucial to the regulation of stimulated hormone secretion in pancreatic islets. Lessons from spontaneous obesity-prone and non-obese type 2 diabetes in rats

“…Previously we (Meidute and others (Nolan et al, 2006,Steneberg et al, 2005 showed that long-term exposure of the -cells to elevated levels of FFA leads to a marked impairment of glucosestimulated insulin release and that this FFA-induced impairment most conceivably was transduced through GPR40-related events. These results also suggested that -cell GPR40, during chronic exposure of pancreatic islets to elevated levels of FFA, might play an important role in the pathogenesis of obesity and type 2 diabetes and should be considered a putative target for therapeutic intervention in these worldwide epidemic diseases ,Morgan et al, 2009,Rayasam et al, 2007,Salehi et al, 2005. In previous experiments we found that the thiazolidinedione derivative rosiglitazone strongly counteracted both short-and long-term -cell dysfunction induced by palmitate in normal mouse islets at the GPR40 level .…”

“…Thus, not only long-chain FFA but in particular glucose seems to have a profound regulatory influence on GPR40 protein expression in the -cells and hence on islet hormone secretion. This is most conceivable since both FFA and glucose are known to influence signalling pathways operating through IP 3 -Ca 2+ and DAG ,Briaud et al, 2002,Morgan and Dhayal, 2009). …”