The central event eliciting insulin secretion is the

The central event eliciting insulin secretion is the production of ATP which leads to the inhibition of ATP-sensitive inwardly-rectifying K+ATP channels, a consecutive depolarization of the plasma membrane with opening of voltage-dependent Ca2+ channels and Ca2+ influx into the beta-cell. However, in addition to glucose itself, insulin secretion is highly regulated by metabolites. While amino acids can also activate insulin secretion, incretins and fatty acids enhance GSIS. The potentiatory effects on insulin secretion are mediated through G-protein coupled receptors. Incretins stimulate GLP-1R and GIPR and act through cAMP-dependent signaling pathways involving the stimulation of PKA and EPAC2. This amplifying pathway strongly depends on glucose-induced increase of cytosolic Ca2+. The mechanism by which fatty acids potentiate insulin secretion probably involves both metabolites and receptor activation [5]. The complex interplay of fuel metabolites and coupling factors of 3 intracellular metabolic networks, the (i) tricarboxylic-acid (Krebs/Szent-Györgyi) cycle, (ii) pyruvate cycle and (iii) glycerolipid/FFA cycle has been sophisticatedly modeled by Nolan and Prentki in 2008 [6]. In 2003, when the role of a cell-membrane receptor, the orphan G-protein coupled receptor 40 (GPR40) was established [7], it was renamed free fatty Caspase Inhibitor Set I receptor 1 (FFAR1) and is now considered as an important mediator of FFA-induced insulin secretion [3]. This receptor, in contrast to incretin receptors which couple to adenylyl cyclase through Gs-proteins, is linked to Gq-protein-dependent stimulation of Phospholipase C and activates protein kinase D1 [8].
Pathomechanisms of decreased insulin secretion in type 2 diabetes
Genetic and metabolic interactions on insulin secretion
Conclusion Using two examples, namely genetic variation in TCF7L2 and FFAR1, we have shown that interaction of genetic and metabolic parameters has an impact on beta-cell function. In both examples, this may influence the success of a pharmacotherapy: existing ones like DPP-4 inhibitors and GLP-1 agonists in the case of TCF7L2 and upcoming ones like FFAR1-agonist in the case of FFAR1. There are several other interactive factors which influence the efficacy of pharmacotherapy in the two examples of this review which are shown in Figure. 2a and b. We propose a hypothetical example of a new therapeutic strategy which incorporates these data on TCF7L2 in Figure. 3. Of course, future clinical studies should support these concepts.
Conflict of interest
Introduction 2-Lysophosphatidylcholines (1-acyl-glycero-3-phosphocholines, 2-LPCs, LPCs), which maintain the acyl chain in sn-1 position, are the most abundant lysophospholipid in nature (D'Arrigo and Servi, 2010). Lipidomic analysis has revealed a correlation of lower plasma concentrations of LPCs with impaired glucose tolerance and obesity (Zhao et al., 2010, Barber et al., 2012). LPC 16∶0 is the most abundant species in human plasma (146 ± 37 μM) followed by LPC 18∶0 (56.5 ± 14.9 μM) and LPC 18∶1 (28.4 ± 12.5 μM) (Heimerl et al., 2014). Although the presence of LPCs in plasma was observed at the beginning of the twentieth century (Kihara et al., 2015), the original observation from Metz's laboratory on dose-dependent lysophospholipid-induced insulin secretion was shown already in 1986 (Metz, 1986) while the involvement of G protein coupled receptor for the effect of LPC on insulin secretion was identified as GPR119 in 2005 (Soga et al., 2005). GPR119 is preferentially expressed on β-cells of the islets of Langerhans but its expression has also been demonstrated in intestinal L- and K-cells, where its activation was associated with secretion of glucagon-like peptide 1 and glucose-dependent insulinotropic peptide (Overton et al., 2006, Sakamoto et al., 2006, Ahlkvist et al., 2013). GPR119 has been shown to bind a variety of lipid-derived ligands, as well as a range of small synthetic molecules. Recent literature data indicate that lysophospholipids also have the ability to interact with other pancreatic receptors regulating carbohydrate metabolism. GPR55 activated by lysophosphatidylinositols may be another attractive target in type 2 diabetes mellitus (T2DM) (Liu et al., 2016). Treatment of diabetic rats with lysophoshatidylinositol has been found to counteract the symptoms of diabetes such as high blood glucose, lower body weight, increase amplitude of slow wave in stomach smooth muscle, and to improve gastric emptying (Lin et al., 2014). Both GPR119 and GPR55 receptors are stimulated by endocannabinoids such as palmitoylethanolamide (PEA), oleoylethanolamide (OEA), arachidonoylethanolamide (anandamide, AEA), and 2-arachidonoylglycerol (2-AG) (Godlewski et al., 2009). We have recently proved that ligand specificity of GPR55 is much wider and our studies evidence that GPR55 is activated also by LPC (Drzazga et al., 2017). However, GPR40 (also known as the free fatty acid receptor 1 or FFAR1) is the best-studied of the cell-surface receptors on β-cells. GPR40 is the most potently activated by endogenous free fatty acids (FFAs) with medium and long (C12-C22) aliphatic chains, resulting in amplification of insulin secretion only in the presence of elevated glucose levels (Itoh et al., 2003, Itoh and Hinuma, 2005, Briscoe et al., 2003). The glucose dependency of insulin secretion makes this receptor an excellent target for developing efficacious therapies with a desired safety profile for use in the treatment of T2DM.