br Declaration of interest br Acknowledgments br This

Declaration of interest
Acknowledgments
This work was supported by grants from the Polish National Science Centre (PRELUDIUM grant no. 2013/11/N/NZ5/00270) and the European Commission FP7 Project Beta-JUDO (grant number 279 153), European Union EIT Health project DeTecT2D, Swedish Diabetes Association (grant number DIA 2016–146), Family Ernfors Foundation (grant number 170504), EXODIAB, the Swedish Society for Diabetology and the Regional Research Council Uppsala.
Main Text FFAR1 (GPR40) is a long-chain fatty CHAPS sale (LCFA) receptor highly expressed and enriched in enteroendocrine cells, where it senses LCFAs generated from dietary triglycerides, and in pancreatic islet cells, where it acts as a powerful stimulator of insulin secretion. However, the physiological role of FFAR1 in the islets remained unclear until now, as the Offermanns group surprisingly places FFAR1 and the omega-hydroxylated fatty acid 20-hydroxyeicosatetraenoic acid (20-HETE) at center stage in β cell function (Figure 1A) (Tunaru et al., 2018). FFAR1-selective agonists and β cell-specific overexpression of FFAR1 increase glucose-dependent insulin secretion (GDIS) in rodents. TAK-875 or fasiglifam, a first-generation FFAR1 agonist, showed meaningful efficacy in decreasing basal glucose and improving glucose tolerance in diabetic patients up to phase III clinical trials but was eventually stopped due to non-mechanism-based liver toxicity (Kaku et al., 2016). However, this promising pharmacological development occurred without a clear understanding of the physiology of FFAR1. Most strikingly, it has been unclear what the physiological ligand was for FFAR1 in the β cells, as it was obviously not circulating free fatty acids. The problem is that, as opposed to insulin, circulating LCFAs are low after a meal and high during fasting, as they mainly are derived from adipose tissue lipolysis. Instead, it has been proposed that dietary LCFAs released from postprandial chylomicrons through lipoprotein lipase activity locally in islet capillaries could be a physiological stimulus for FFAR1 on β cells (Husted et al., 2017) (Figure 1A). For almost a decade it has been known, but not really appreciated, that FFAR1 is required not only for LCFA-induced insulin secretion, but also for a major part of glucose- and arginine-induced insulin secretion (Alquier et al., 2009, Kebede et al., 2008). Under hyperglycemic clamp conditions, insulin secretion is reduced to less than 50% in Ffar1-deficient DIO mice as compared to littermate controls (Alquier et al., 2009). Similarly, arginine-induced insulin secretion is reduced to less than one-third in Ffar1-deficient animals—importantly, in both cases, without altered fuel metabolism in the islets but via a mechanism involving classical FFAR1 receptor signaling pathways (Alquier et al., 2009). These puzzling observations can now be explained, as Tunaru and coworkers find 20-HETE to be a more potent, efficacious, and selective agonist for FFAR1 than any previously reported LCFA and show that 20-HETE functions as an autocrine feed-forward stimulator of insulin secretion through FFAR1 (Tunaru et al., 2018). Circulating concentrations of 20-HETE are in the low-nanomolar range, which is too low for it to act as an endocrine ligand for FFAR1. Importantly, Tunaru and coworkers demonstrate that islets generate and release 20-HETE in a glucose-dependent manner and that 20-HETE acting through FFAR1 is responsible for a major part of glucose-induced insulin secretion. Thus, inhibition of CYP4- and CYP2-dependent formation of 20-HETE from arachidonic acid or pharmacological blockade of FFAR1 reduces GDIS in murine and human islets. Interestingly, the 20-HETE-mediated positive autocrine regulatory loop is impaired in islets from diabetic animals and patients. Although basal production of 20-HETE in islets from DIO and ob/ob mice and islets from type 2 diabetic patients was slightly increased, the glucose-induced 20-HETE production was significantly decreased (Tunaru et al., 2018).