关键词: 利拉鲁肽, 2型糖尿病, 大麻素受体基因, 多态性, 疗效

Abstract: AIM: Recent studies have shown that the cannabinoid receptor 1 (CNR1) gene played an important role in diabetes and its complications development. And liraglutide was of positive therapeutic significance in patients with type 2 diabetes mellitus. This study was to investigate the influence of CNR1 genetic variation on the clinical outcomes of early stage type 2 diabetes mellitus treated with liraglutide. METHODS: From March 2016 to December 2018, a total of 230 patients with early stage type 2 diabetes mellitus were included as the research object in this study. The patients were treated with liraglutide, and the clinical outcomes were evaluated 16 weeks later. Additionally, peripheral blood and part of the patients with fresh peripheral blood specimens of the patients were collected for the genotyping of the genetic variation and CNR1 gene mRNA expression, respectively. The correlation between genetic polymorphism and other baseline characteristics was analyzed by chi square test and non-parametric test. The mRNA expression of CNR1 in different genotypes was analyzed by non-parametric test. RESULTS:All of the 230 diabetes mellitus patients were of available for efficacy evaluation. BMI, FPG, 2H PG and HbA1c of all patients decreased significantly after 16 weeks of treatment, and the difference was statistically significant compared with that before treatment (P<0.05). In terms of the CNR1 gene polymorphism analysis, only rs1049353 was found to be of clinical significance. The prevalence of rs1049353 among the 230 patients were as follows: GG genotype 188 cases (81.74%), GA genotype 39 cases (16.96%), AA genotype 3 cases (1.30%), the minor allele frequency is 0.10, The distribution of three genotypes were in accordance with Hardy-Weinberg Equilibrium (P=0.551). GA genotype and AA genotype patients were merged in the following analysis. The clinical outcomes analysis indicated that BMI index of GA/AA genotype patients decreased (3.4±0.9) kg/m2 on average, FPG index decreased (5.1±0.9) mmol/l on average, HbA1c decreased (2.7±0.5)%. And the BMI index of GG genotype patients decreased (3.0±1.5) kg/m2 on average, FPG index decreased (4.7±1.3) mmol/l on average, HbA1c decreased (2.6±0.5)%, respectively. There were statistically significant differences between the two genotypes. Additionally, of the 125 available specimens for CNR1 gene mRNA analysis, the results showed that the mRNA expression of CNR1 in the patients with GG genotypes were significantly higher than those of the GA/AA genotype patients［(4.2±1.3) vs. (2.8±1.2), P<0.001)］. In terms of adverse reactions, the incidence of adverse reactions during treatment was relatively low, and gradually disappeared after drug withdrawal, and there was no significant correlation with CNR1 gene rs1049353 polymorphism. CONCLUSION:It is safe and effective in early stage type 2 diabetes patients received liraglutide treatment. And the clinical outcomes of the patients received liraglutide treatment may be influenced by CNR1 rs1049353 through mediating the mRNA expression of CNR1.

Key words: liraglutide, type 2 diabetes, cannabinoid receptor 1, polymorphism, clinical outcome