In the present study, we found for the first time that genetic polymorphisms of PPARD and NOS1AP may affect the therapeutic efficacy of nateglinide in Chinese patients with T2DM. We observed that, T2DM patients with at least one C allele of PPARD rs2016520 (T/C) or one C allele of NOS1AP rs12742393 (A/C) may be less responsive to treatment with nateglinide, indicating that the PPARD and NOS1AP genotype may serve as nateglinide response prognosticator. Therefore, we suggest that prior genotyping and individualized administration of nateglinide may be beneficial for those T2DM patients who require treatment with nateglinide. PPARD and NOS1AP are directly or indirectly involved in the regulation of β-cell function and insulin resistance, which suggests that genetic polymorphisms in the two genes may contribute to interindividual differences in nateglinide response [7,8,9, 16, 17]. Further pharmacogenetic and functional studies are necessary to investigate the potential mechanism and lay the foundation for Individualized administration for patients with T2DM.
Studies have reported that CYP2C9 and SLCO1B1 gene polymorphisms could affect the pharmacokinetic process of nateglinide, resulting in differences in drug concentrations in plasma and therapeutic efficacy [27,28,29,30]. Therefore, we selected patients with the same CYP2C9*1 and SLCO1B1 521TT genotype to avoid any possible changes in the pharmacokinetics and pharmacodynamics of nateglinide caused by OATP1B1 or CYP2C9 polymorphism. After the treatment with nateglinide for 8 consecutive weeks, serum FPG, PPG, HbA1c, TG and TC levels decreased significantly in patients with T2DM and FINS, PINS, HOMA-B and HDL-C levels increased markedly increased markedly. Also, patients with PPARD rs2016520 TC + CC genotypes had attenuated efficacy of nateglinide monotherapy with respect to PPG and HOMA-B compared with TT genotype carriers. Our results also showed that the NOS1AP rs12742393 (A/C) polymorphism was associated with an attenuated nateglinide effect in Chinese patients with T2DM, and that individuals with AC + CC genotypes showed a smaller increase in FINS and HOMA-B, but a smaller decrease in FPG and HOMA-IR levels as compared to individuals with the TT genotype.
PPARD encoding PPAR-δ, which is related to islet function and insulin resistance, might directly or indirectly participate in the pathogenesis of T2DM [9, 31,32,33]. In the present study, we preliminarily found that the polymorphism of PPARD affected the impact of nateglinide on insulin secretion in Chinese patients with T2DM, which may be attributed entirely to the role of PPAR-δ in insulin secretion, as measured by HOMA-B. The biological effect of PPAR-δ overlaps with the therapeutic mechanism of nateglinide to a certain extent, which can partly explain the mechanism of PPARD genetic polymorphism affecting the efficacy of nateglinide. However, the exact molecular mechanism remains to be further studied.
NOS1AP mainly regulates nNOS activity, and nNOS can inhibit intracellular Ca2+ level and thereby regulate insulin secretion [15, 18, 34]. In addition, lateral ventricular injection of nNOS inhibitors can affect insulin secretion and insulin sensitivity . In this study, we observed that subjects with at least one C allele of the NOS1AP rs12742393 showed a smaller decrease in FPG and HOMA-IR and more obvious increase in FINS and HOMA-B levels than those with the AA genotype, which suggested that the NOS1AP rs12742393 C allele confers the poor nateglinide response through improving insulin resistance, as measured by HOMA-IR. Animal studies have shown that knockout of mouse nNOS gene may induce insulin resistance in mice . Meanwhile, it has been reported that the dysfunction of nNOS in islet β cells is related to insulin secretion [15, 16]. Therefore, it is speculated that NOS1AP rs12742393 risk gene C affects the efficacy of nateglinide in patients with T2DM, which is at least partially associated with insulin resistance and islet β cell. However, the exact mechanism by which NOS1AP polymorphism affects the efficacy of nateglinide needs to be further investigated.
In interpreting the results of our study, several shortcomings must be addressed. First, our study focused only on the effect of variation in PPARD rs2016520 and NOS1AP rs12742393 on nateglinide efficacy. However, the possibility still exists that other susceptibility loci for T2DM may affect the therapeutic efficacy of nateglinide. Second, the sample size was relatively small, we may have missed some meaningful results. The duration of nateglinide therapy for 8 weeks is relatively short, since HbA1c reduction is better observed after 12 weeks of treatment. Further studies with a larger sample size and longer observation periods are required to confirm the effects of PPARD and NOS1AP polymorphisms on the therapeutic efficacy of nateglinide. Third, our study only investigated the effects of gene polymorphism on the efficacy of nateglinide. However, the mechanisms by which the two SNPs in PPARD and NOS1AP affect the therapeutic efficacy of nateglinide are not fully understood. In the future, more functional studies are needed to explore the mechanism by which PPARD and NOS1AP genetic polymorphisms affect drug efficacy.