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  • Next we conducted subgroup analyses with stratification

    2022-07-02

    Next, we conducted subgroup analyses with stratification along interaction variables, namely the PPARG SNP and fasting NEFA. The study population was thus stratified into high and low NEFA (along the median NEFA, 561 μmol/L), and PPARG minor allele (Ala) carriers. This stratification resulted in 4 subgroups (I: low NEFA and PPARG Pro homozygotes, n = 718, II: low NEFA and PPARG Ala carriers, n = 237, III: high NEFA and PPARG Pro homozygotes, n = 744, IV: high NEFA and PPARG Ala carriers, n = 229). An effect of the FFAR1 genotype on insulin secretion was only evident in the subgroup IV comprising participants with at least one PPARG Ala allele and high fasting NEFA (Figure 1A and B bottom right diagrams [diagrams IV]). In this subpopulation, carriers of the minor allele of rs10422744 and rs12462800 in FFAR1 had lower insulin secretion (β = −0.18, p = 0.001 and β = −0.19, p = 0.0006, respectively) than homozygotes of the major allele, after controlling for sex, age and insulin sensitivity.
    Discussion The Pro12Ala variant in PPARG has been one of the first candidate SNPs for type 2 diabetes [16], [17]. The rare allele of this variant is associated with a 25% reduced risk for the disease [18]. Given the role of PPARG as both a receptor for NEFA and itself a regulator of fat metabolism, our group had earlier investigated the hypothesis that PPARG-mediated alterations in fatty MK0752 synthesis signaling could have an impact on insulin secretion. In those hyperglycemic clamp studies, we had compared insulin secretion between Pro/Pro and X/Ala carriers of the PPARG variant in a control and a high-NEFA setting. Only the clamp condition with a concomitant infusion of Intralipid solution, performed to raise NEFA levels, had unmasked striking differences in insulin secretion between PPARG genotypes [11]. However, no explanation could be given for the mechanism of action by that time. Meanwhile, the NEFA receptor FFAR1 has been established as an important stimulator of fatty-acid mediated insulin secretion [4] and genetic variation in FFAR1 has been shown to influence beta-cell function [9], [19]. Therefore, FFAR1 seemed to be a plausible link between PPARG and insulin secretion. By analyzing the previously described 7 FFAR1 tagging SNPs, we now found 2 SNPs, which exert a NEFA and PPARG-dependent effect on insulin secretion. The SNPs rs12462800 and rs10422744 are located 0.8 kb apart in an intergenic regulatory area between the FFAR1 (GPR40) and FFAR3 (GPR41) genes, 3.5 and 3.8 kb from the 3′ end of the single FFAR1 exon. These SNPs are more distal from the gene than the previously described FFAR1 SNP rs1573611 which directly interacts with fasting NEFA in association with insulin secretion [9]. The molecular mechanisms underlying the PPARG–FFAR1 interaction are still speculative. Although the literature is controversial, there is a wealth of data from basic science and clinical studies involving the use of PPARG agonists (thiazolidinediones) indicating that PPARG activation may have a positive impact on beta-cell function and beta-cell survival (reviewed by [20]). The PPARG–FFAR1 interaction, especially in light of the effect modification by NEFA levels, could possibly explain this still poorly understood link between PPARG action and beta-cell function. A recent study demonstrated that PPARG overexpression leads to an increased expression of FFAR1 in rat INS-1 cells and primary rat islets [10]. A possible interaction scenario could thus be a defective PPARG-induced transcriptional or translational activity of the FFAR1 gene in the presence of the FFAR1 minor allele variants, which would consecutively result in a limited compensatory potential to increase insulin secretion when fasting NEFA are elevated. The fundamental human phenotypic alterations associated with the Pro12Ala variant seem to involve lipolysis and its insulin-dependent inhibition [21], [22], [23]. Since FFAR1 is activated by medium and long-chained fatty acids [24], perturbations in NEFA levels or their composition as a consequence of altered PPARG action could modulate insulin secretion through FFAR1.