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  • All of the abovementioned effects of

    2022-01-24

    All of the abovementioned effects of PUFAs signal their involvement in a cellular phenotype switching phenomenon, which is increasingly recognized as a potential target for future pharmacotherapies of atherosclerosis, especially for individuals who do not respond to the classical lipid-lowering strategies [18]. Indeed, if atherosclerosis is considered as a low-grade, unresolved inflammation, the phenotype switching approach, favoring a macrophage M2-like activation state, with increased capability for the safe removal of chronically activated cells, could hold promise as an improved atherosclerosis treatment. Our study strengthens these expectations, providing evidence that stimulation of free fatty acids receptors by the administration of their synthetic agonist GW9508 results in the attenuation of atherosclerosis in an apoE-/- mice model by targeting pro-inflammatory M1-like macrophages and shifting the balance within plaques toward Dp44mT sale of M2-like phenotype. Clearly, our study has a major limitation in that several of the GW9508-treated apoE-/- mice did not reach the end of the experimental protocol. Thus, when taking measurements, we could detect only trends in the changes of several parameters, not reaching statistical significance, thus making our mechanistic conclusions preliminary. This eventuality was somewhat surprising, since the GW9508 compound has been previously used in mice, usually administered intraperitoneally or orally, even at four-fold higher doses than in our setting [19,20]. The major discrepancy, apart from different mouse models investigated, was the duration of the experiments, ranging from seven to 30 days in the abovementioned studies, whereas our study continued for 16 weeks to ensure the development of sufficient atherosclerotic changes on a chow diet. Therefore, further investigation of the anti-atherosclerotic effect of GW9508, as well as exploration of the specific mechanisms elicited by FFAR1/FFAR4 activation in apoE-/- mice, is undoubtedly required. Different formulation of the GW9508 solution and other routes of drug administration should be considered in long-term experiments carried out on the apoE-/- mice model.
    Conclusions
    Author Contributions
    Funding This research was funded by National Science Centre, grant number 2015/17/D/NZ2/01972.
    Conflicts of Interest
    The progressive escalation of hyperglycaemia that typifies advancing type 2 diabetes is due largely to an ongoing deterioration of insulin-secreting pancreatic β cells. Defects occur in the biosynthesis and processing of proinsulin to insulin and C-peptide, together with faults in the formation, turnover, and intracellular organisation of insulin granules. However, the β cells usually still contain large stores of granules, suggesting that there is a failure of stimulus–secretion coupling. The main stimulus for insulin secretion is normally a rise in circulating glucose above about 5·5 mmol/L, which initiates a prompt short burst of insulin secretion (first phase) lasting a few minutes, followed by a protracted second phase lasting until euglycaemia is reinstated. In type 2 diabetes, circulating glucose exceeds 5·5 mmol/L for most of the time and pancreatic β cells seem to become desensitised to the stimulus of raised glucose, initially losing the first phase and eventually most of the second phase of insulin secretion. Although this change might be accompanied by some loss of β-cell mass, a prime therapeutic challenge is to restore the secretion process for existing insulin-laden cells. In , Charles Burant and colleagues report the glucose-lowering efficacy of a potential new type of insulin-releasing agent—an agonist of free fatty acid receptor 1 (FFAR1; also known as G-protein-coupled receptor 40 [GPR40]). In a 12-week phase 2 randomised double-blind controlled study of 426 patients with type 2 diabetes, Burant and co-workers found that the FFAR1 agonist TAK-875 (50–200 mg/day) produced a similar glucose-lowering effect (reduction of haemoglobin A by roughly 1% from a baseline of 8·4%) to that of the sulphonylurea glimepiride (2–4 mg/day).