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  • As recently reviewed a picture is emerging

    2022-06-22

    As recently reviewed, a picture is emerging where metabolites through GPCR sensors act as important autocrine and paracrine regulators of basic metabolic mechanisms (Husted et al., 2017). The concept of 20-HETE acting through FFAR1 as an autocrine amplifier of GDIS on β levosimendan together with, for example, the function of lactate as a major autocrine amplifier of insulin’s inhibition of lipolysis in adipose tissue (Ahmed et al., 2010) exemplifies how major metabolic dogmas are being changed to include metabolite GPCR components. It is likely that the novel insight into the physiology of FFAR1 function will revitalize the receptor as a drug target. Over the last decade and a half, a number of synthetic FFAR1 agonists were developed with the goal of obtaining simultaneous stimulation of gut hormones and insulin through a single drug. However, the first-generation FFAR1 agonists only signaled through Gq and IP3 just like endogenous LCFAs, including 20-HETE (Hauge et al., 2014, Tunaru et al., 2018), and in clinical trials the first-in-class compound fasiglifam displayed only rather limited effects on glucose tolerance and peripheral insulin levels and no effect on GLP-1 (Kaku et al., 2016). In contrast, second-generation FFAR1 agonists, which we now know bind in a different, extrahelical, ago-allosteric site in FFAR1 (Lu et al., 2017), are able to make FFAR1 signal through cAMP in addition to IP3, which empowers these new ago-allosteric compounds with a much more robust stimulatory effect on hormone secretion, including GLP-1 (Figure 1B) (Hauge et al., 2014). Satapati and coworkers recently reported the development of high-potency, dual-specific agonists, which function both as Gq-only FFAR1 agonists and at the same time as agonists for the other LCFA receptor, FFAR4 (Satapati et al., 2017). Importantly, FFAR4 agonism enhances insulin action in adipose tissue, and consequently, combination treatment in diabetic db/db mice with FFAR1 and FFAR4 agonists provides better glycemic control than either monotherapy, almost corresponding to rosiglitazone (Satapati et al., 2017). Now it remains to be seen how clinically efficacious second-generation FFAR1 agonists and dual FFAR1-FFAR4 agonists, which both appear to be highly promising in preclinical rodent models, will in fact be in patients with diabetes and whether the expanded pharmacological profiles can provide improved efficacy without unwanted side effects.
    Introduction Free fatty acid receptor-1 (FFAR1, formerly GPR40) promotes long chain fatty acid-mediated augmentation of glucose-induced insulin secretion (GIIS) [1], [2], [3]. In humans and rodents, high expression of FFAR1 is restricted to pancreatic and gastric endocrine cells, while expression in other tissues, including brain, is much lower [1], [2], [4], [5]. These features make FFAR1 an attractive drug target for the treatment of insufficient insulin secretion, which is the ultimate cause for the onset of hyperglycemia and type-2 diabetes mellitus [6], [7]. Until today, multiple agonists have been generated and tested for their efficacy to treat hyperglycemia in humans [6]. Although FFAR1 agonists counteract glucose intolerance in mice and humans, the beneficial effect of these new therapeutic drugs is still a matter of debate [8], [9]. Thus, the promising drug TAK875 was discontinued after clinical phase III due to its liver toxicity. Confirming this side effect, FFAR1-deficient mice are protected against diet-induced liver steatosis [10]. This observation prompted the investigation of FFAR1-antagonists as therapeutic tools against fatty liver disease. In addition, different FFAR1 agonists exert their effects through different cellular pathways. Thus, fatty acids stimulate insulin secretion mainly via Gq proteins, while TAK875 stimulation is mediated by β-arrestin-2 [11]. An additional, but indirect, stimulatory effect of FFAR1-agonists on insulin secretion is caused by the activation of FFAR1 expressed in intestinal endocrine cells which leads to GLP-1 secretion [12].