In this study, the genetic polymorphism of MINR1B rsl0830963 potentially influenced the efficacy of nateglinide in Chinese patients with T2DM. We observed this in T2DM patients with G allele of MTNR1B rs10830963 decreased the efficacy of nateglinide. We also found that the risk G allelic frequency of MINR1B rsl0830963 was significantly higher in T2DM patients than healthy subjects (P < 0.05). Consequently, MTNR1B gene represents a susceptibility target for T2DM and affects the response to nateglinide.
A significant basis for clinical individualized drug delivery is provided by a relatively new subject called pharmacogenomics. Presently, the pharmacogenomics researches of oral hypoglycemic drugs mainly focus on the study of classic sulfonylurea oral hypoglycemic agents, thiazolidinedione insulin sensitizers and biguanide hypoglycemic drugs. There are few reports on the pharmacogenomics of the novel insulin secretagogues of glinide, but no evidence related to MTNR1B gene is found.
Studies conducted with the Chinese Han population have confirmed that single nucleotide polymorphisms (SNPs) of MTNR1B are associated with T2DM susceptibility.22, 23 Among the SNP sites involved in MTNR1B, the rs10830963 locus is a functional polymorphic locus and is closely related to glucose metabolism and islet β cell function. Further, it is highly correlated with the pathogenesis of T2DM. The variation of the MTNR1B gene is consistent with the FPG level; rs10830963 is the most relevant, and each G allele increases the FPG level by 0.07mmol/l. The homeostasis model assessment (HOMA-β) analysis showed impaired beta-cell function.15 In this study, we found that the risk G allelic frequency of MINR1B rsl0830963 was significantly higher in T2DM patients, when compared to the healthy subjects (P < 0.05) and remains consistent with previous studies.15, 16 The study had an estimated 80–92% power (for α = 0.05) to detect such a difference in allelic frequencies and genotypes distribution. Also, it is found that patients with T2DM carrying the GG genotype had higher FPG levels when compared with the CC and CG genotypes. The difference being statistically significant, suggest that the G allele has an association with the elevated FPG levels.
The pineal gland releases the circulating hormone melatonin (MLT) and its action is mediated by melatonin receptor 1 and 2 (MT1, MT2) respectively 13. MT2 is encoded by the MTNR1B gene and is expressed in the islet beta cells of both animals and human beings.13 Multiple GWAS studies conducted in European populations found that MTNR1B rs10830963 is associated with FPG, insulin secretion, and T2DM susceptibility.14, 15 Subsequently, it was also found that MTNR1B rs10830963 has an association with FPG and islet β-cell function in Chinese Han population.16, 17 However, the molecular mechanism by which the MTNR1B gene polymorphism increases T2DM susceptibility remains unclear. Studies have reported that after MLT activates MT2, MT2 gets coupled with the inhibitory G protein, mediating cAMP and cGMP signal transduction pathways and inhibits insulin release from islet beta cells.22, 23 In addition to MLT in MT2 knockout mice, islet β cells release insulin increases24 and therefore MTNR1B gene polymorphism increased T2DM susceptibility relating to its influence on insulin secretion.
Next to repaglinide, nateglinide is the new non-sulfonylurea oral hypoglycemic agent. It is more commonly used in clinical practices, but the difference in efficacy and adverse reactions is significant. The main mechanism of action of nateglinide is to close the ATP-dependent K+ channel on the islet β-cell membrane to cause the depolarization of the cell membrane and open the Ca2+ channel to lead to Ca2+ influx and thus promote insulin secretion.25 Therefore, the MTNR1B gene polymorphism plays a role in the hypoglycemic effect of nateglinide.
The purpose of this study was to analyze the effect of MTNR1B rs10830963 gene polymorphism on the efficacy of nateglinide in treating the newly diagnosed type 2 diabetes patients. Previous studies have reported that CYP2C9 and SLCO1B1 gene polymorphisms may affect the pharmacokinetics of nateglinide.26–29 Hence we decided to retain the same patients with the CYP2C9*1 and SLCO1B1 521TT genotypes as subjects to rule out interference. After 8 consecutive weeks of nateglinide monotherapy, patients with FPG, PPG, FINS, PINS, HOMA-IR, HOMA-β, HbA1c, and TC showed significant improvement. Thus indicating that nateglinide has a good therapeutic effect on patients with type 2 diabetes. There are literatures reporting the nateglinide effect on improving insulin resistance.10, 11 Our research results were found to be consistent with the literature results. But, there was no evidence to find the relationship between MTNR1B rs10830963 gene polymorphism and nateglinide efficacy. Therefore, in our study, we compared the difference between the clinical indicators before and after nateglinide treatment. The decrease of FPG and the increase of HOMA-β in MTNR1B rs10830963 risk gene G carriers were lower when compared with the CC genotype patients (P < 0.05). These results indicated that the risk gene G carriers had a worse response to nateglinide when compared with the CC genotype patients. Also, the clinical treatment showed that the GG genotype patient had poor nateglinide treatment. Prokopenko et al15 reported that calculation of islet beta-cell function using the homeostasis model showed that, MTNR1B rs10830963 risk gene G carriers had lower islet function. Lyssenko et al14 found GG genotype carriers, oral or intravenous glucose stimulation early-phase insulin release was impaired. Previous reports results were consistent with the results of this study. After nateglinide treatment, risk gene G may further reduce the efficacy of nateglinide by affecting FPG and HOMA-β. The exact mechanism by which the MTNR1B gene polymorphism affects the efficacy of nateglinide requires further investigation.
However, this study does have some shortcomings as the sample size is not large enough, and the frequency of MTNR1B rs10830963 GG genotype is low. Therefore this study might miss some meaningful results. Hence, we recommend further detailed study with expanded sample size. Glinide drugs are mealtime blood glucose regulators and are characterized by rapid but short-acting insulin secretion with weak hypoglycemic effect and good safety. Therefore, this study neither focused on the clinical adverse events during nateglinide monotherapy nor did it receive reports of adverse events in the subjects. T2DM is a multi-gene metabolic disease and in this study we found that the MTNR1B gene polymorphism has a certain effect on the efficacy of nateglinide. But the individual difference in the efficacy of hypoglycemic drugs is caused by the accumulation of multiple gene polymorphisms as well as the changes in the environmental factors and lifestyles. The results of a single genetic polymorphism study could not fully explain the individual differences in drug efficacy. Patients received only an 8-week course of nateglinide therapy, and optimal reduction in HbA1c levels occurs after 12 weeks of administration.30 Therefore, in order to apply this research results to clinical practice, it requires collaboration among researchers from different regions.
In summary, the results of this study suggest that the MTNR1B rs10830963 polymorphism is associated with the efficacy of nateglinide in the treatment of type 2 diabetes, and also has a certain role in promoting clinical individualized drug delivery. But, this study is only an exploratory trial of glinide pharmacogenomics research.
Finally, the statistical power of our study may be sufficient had we collected a relatively larger sample size.
We recommend exploration with more extensive and comprehensive clinical research along with an in-depth mechanism to confirm its relevance.