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    • In summary PPARG and FFAR are connected in several ways

    2022-05-11

    In summary, PPARG and FFAR1 are connected in several ways, and the presented interaction is mechanistically reasonable. Additional investigations are required to elucidate the exact details of the underlying physiology. However, our findings are of immanent importance for the treatment of type 2 diabetes, because the described genotypic interaction between PPARG and FFAR1 could have bearing on the pharmacologic efficacy of FFAR1 agonists. Although a phase 3 clinical trial of the most promising FFAR1-agonist has been recently halted, several of such agents are still under development [8], [25]. We infer that the variants identified in the current study, under the constellation of the minor PPARG Pro12Ala allele, could have relevant impact on the effectiveness of FFAR1 agonists. Identification of variants which are candidates for pharmacogenetic interactions could pave the way for investigating genotype-based therapeutic responses within clinical studies and on the long run in clinical practice. This would eventually lead to an improved selection of individuals who would benefit from specific therapies [26].
    Acknowledgments
    Introduction Long-term exposure of pancreatic β ampar to high levels of free fatty acids (FFAs) can induce lipotoxicity [1], an important factor in the decline of β-cell function. FFAR1, also known as G protein-coupled receptor 40 (GPR40), is a specific receptor for long-chain FFAs that is highly expressed on the pancreatic β-cell membrane in response to FFA-mediated increases in glucose-stimulated insulin secretion [2]. However, there is no unified conclusion as to whether FFAR1 can mediate the damage of long-term lipotoxicity [3], [4], [5]. The main reason may be that FFA affects β-cell function through not only the signal transduction mechanism, but also intracellular metabolic pathways. So, it has been difficult to completely separate the two ways. Hence, the results of research on the relationship between FFAR1 and lipotoxicity have typically been inconsistent. Our previous studies had demonstrated that downregulation of FFAR1 expression did not protect cells from lipotoxicity. Namely, those studies showed that the detrimental effects of lipotoxicity on β-cell insulin secretion and insulin secretion-related genes such as duodenal homeobox gene-1 (PDX-1) and glucose transporter protein-2 (GLUT-2) were not improved after suppressing the expression of endogenous FFAR1 [6]. These studies had suggested that FFAR1 may not mediate the lipotoxicity of FFA. At present, drugs that act as specific agonists of FFAR1 have been investigated and have entered phase III clinical trials [7], [8], [9]. However, current research on FFAR1 agonists is focused on investigating their effects on promoting insulin secretion, but rarely examines their relationship to lipotoxicity. Studies have shown that peroxisome proliferator activated receptor gamma (PPARγ) agonists, which activate FFAR1 expression [10], exhibit resistance to lipotoxicity in β cells. Whether FFAR1 is involved in the anti-lipotoxic effect of the PPARγ agonists is still unknown. Our preliminary results showed that the anti-lipotoxic effect of the PPARγ agonist PIO in β cells was weakened after silencing the expression of FFAR1 [6]. Our studies had suggested that the anti-lipotoxic effect of PIO at least to some extent was associated with the level of FFAR1 gene expression. Therefore, this study was conducted to investigate whether FFAR1 can mediate the effect of PIO in protecting β cells against lipotoxicity, and discuss the potential underlying mechanism to understand the value of FFAR1 in lipotoxicity protection and its potential role in diabetes.
    Materials and Methods
    Results
    Discussion PA, a free fatty acid abundant in the body, is an important saturated fatty acid that leads to β-cell damage. Previous studies had shown that the long-term action of PA is to inhibit insulin secretion by β cells, inhibit insulin gene suppression [6], and induce endoplasmic reticulum stress [11], [12], which subsequently leads to lipoapoptosis [13], while PPARγ agonists can restore the insulin secretion of β cells induced by lipotoxicity [6]. Therefore, this study aimed to further investigate the intervening effect of PIO on β-cell lipoapoptosis and the pathway that may underlie this effect. The results showed that PIO reduced β-cell lipoapoptosis in a dose- and time-dependent manner. New research also confirmed the protective action of PIO on β cells, as Alba M et al. reported that PIO can enhance β-cell function after 12weeks in patients with type 2 diabetes [14], and Yin H et al. found that PIO can enhance pancreatic β-cell regeneration in vivo [15]. Li Y et al. demonstrated that PIO could ameliorate palmitate-induced damage to the mitochondrion ultrastructure and function and restore glucose-stimulated insulin secretion (GSIS) [16].