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  • An increased sympathetic tone and the hormone

    2021-10-13

    An increased sympathetic tone and the hormone glucagon are the main glucose mobilizing factors [28], [29]. Single-cell transcriptome analysis of human islet cells suggests the expression of Ffar1 not only in β-cells but also in α-cells [30]. Moreover, analysis of rat α-cells indicates that FFAR1 expression is under the control of PAX6 [31]. At least in rodents, long chain fatty acids stimulate glucagon secretion at low glucose, i.e. under hypoglycemic condition [32]. However, there was no significant difference in plasma glucagon levels of CD-fed mutant and wild-type mice under fasting conditions. In HFD-fed mice, glucagon levels were much lower than in CD-fed mice and unfortunately under the detection level. In view of stable glucagon levels in humans during FFAR1-agonist administration and the lack of FFAR1-dependent stimulation of glucagon secretion in isolated human and rat islets at high glucose, it seems unlikely that FFAR1-dependent glucagon secretion inducing hepatic glucose mobilization accounts for higher glucose levels during a glucose load [33], [34]. Recently, evidence was presented that FFAR1 deficient mice display higher noradrenaline levels in brain [35]. The effects of changes in sympathetic nervous function during fat-rich feeding on glucose homeostasis in FFAR1-deficient mice require further studies. During ipGTT, plasma insulin concentrations increased to a similar level in wild-type and Ffar1R258W/R258W mice, reflecting a β-cell glucose-responsiveness independent of FFAR1 function. Indeed, during ipGTT, plasma fatty Spiperone hydrochloride concentrations decline and, therefore, it is unlikely that FFAR1 contributes to insulin secretion during ipGTT [36]. Glucose homeostasis is further regulated by incretins, and FFAR1-agonists increase incretin release in rodents [12], [37], [38]. In contrast to the significantly different plasma glucose levels at 30 min after ip glucose administration, 30 min after an oral glucose load, plasma glucose levels were not significantly different between wild-type and Ffar1R258W/R258W mice. GLP-1 secretion is stimulated by FFAR1 from the vascular but not from the luminal site, making it unlikely that FFAR1 is activated and augments incretin secretion during an oral glucose load when plasma fatty acids decline [36], [38]. Plasma glucose homeostasis is maintained via an interaction of many organs, which generate a large variety of metabolic regulators. Only a detailed analysis of the individual players and the reciprocal influences will give an explanation why Ffar1R258W/R258W mice are protected against diet induced glucose intolerance. This study introduces a mouse model carrying the point mutation R258W in Ffar1, which abolishes the stimulation of insulin secretion in response to long chain fatty acids. The minimal genetic alteration mirrors the human situation and has the advantage over conventional knockout/congenic mouse models. It also circumvents side effects generated by viral constructs, the removal of additional non-coding regions within the deleted gene, and changes in protein–protein interactions such as receptor G-protein coupling due to complete abrogation of a receptor protein.
    Disclosure statement This study was supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.).
    Author contributions GKHP, HUH, MHA, and SU designed the study, SS, SM, and GKHP established the mouse models, SS, GK, FG, TS, and SM generated and analyzed the mouse strains and performed and analyzed the in vivo experiments. GK, FG, MH, ELG, MP, and SU performed the in vitro experiments, analyzed data, and wrote the manuscript. All authors approved the final version.
    Acknowledgments
    Introduction G protein-coupled receptors (GPCRs), the largest and most versatile class of membrane receptors in eukaryotes, represent the most common target of modern therapeutic drugs. They broadly participate in physiological processes and pathophysiological conditions through coupling to specific G protein families (Gαs, Gαi/o, Gαq/11 and others), which in turn trigger the production of second messengers such as cAMP, inositol phosphates and Ca2+ to regulate different intracellular signaling pathways [1,2]. G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1 (FFAR1), belongs to rhodopsin-like GPCR family and demonstrated to be highly expressed in pancreatic β-cells and gastrointestinal enteroendocrine cells. Activation of this receptor by either endogenous long-chain free fatty acids or small-molecule agonists can promote glucose-stimulated insulin secretion (GSIS) by not only directly acting on β-cells but also indirectly through regulation of incretin secretion [3]. Considering that GPR40 only stimulate insulin release in the presence of elevated glucose levels, it has drawn considerable attention from both academia and industry as a novel target for the treatment of type 2 diabetes (T2D) with minimal risk of iatrogenic hypoglycemia [4,5]. As shown in Fig. 1, a variety of synthetic small-molecule GPR40 agonists have been reported based on the 3-phenylpropanoic acid scaffold. Among them, the most successful example was TAK-875 (fasiglifam), which exhibited potent agonist activity and high selectivity towards GPR40 and was advanced into clinical studies as an oral active drug candidate. Treatment with TAK-875 led to improved insulin secretion in T2D patients with a sharp reduction in glucose levels, including an average reduction in glycated haemoglobin (HbA1C) of 1.2%. At the 50 mg dose used in phase 3 clinical trials, TAK-875 primarily demonstrated improvement on fasting plasma glucose levels with increased insulin secretion observed [6]. However, by the end of 2013, Takeda voluntarily decided to terminate the development activities for TAK-875 in phase 3 clinical studies as this compound demonstrated clear signs of liver toxicity in patients. Although it was still unclear whether the hepatotoxicity of TAK-875 was a molecule-specific issue or a target-related issue, a recent study indicated that TAK-875 may affect bile acid and bilirubin homeostasis through inhibiting the efflux transporter and uptake transporters, and therefore produced off-target effects in the liver [7]. Given that the failure of TAK-875 was most likely a molecule-specific issue and GPR40 played a vital role in regulating glucose homeostasis, there was every expectation that some other GPR40 agonists might find their way into future clinical trials as anti-diabetic therapeutics (see Table 1).