大麻素受体1型基因多态性对利拉鲁肽治疗早期2型糖尿病患者临床疗效的影响研究

背景　利拉鲁肽在Ⅲ期临床试验中被证实可以有效降低糖尿病患者血糖水平，然而在临床应用过程中利拉鲁肽的降糖效果仍存在较大的个体差异。研究表明，基因多态性是造成众多药物出现个体差异的原因之一。目的　大麻素受体1型基因（CNR1）在糖尿病及其并发症中发挥重要作用，本研究旨在探讨CNR1多态性对利拉鲁肽治疗早期2型糖尿病（T2DM）患者临床疗效的影响。方法　选取2016年3月-2018年10月河南省直第三人民医院内分泌科收治的230例早期T2DM患者作为研究对象。患者均皮下注射利拉鲁肽进行治疗，治疗16周后测量体质指数（BMI）、空腹血糖（FPG）、餐后2 h血糖（2 hPG）和糖化血红蛋白（HbA1c）。另外，收集患者外周血及部分患者新鲜外周血标本分别用来进行CNR1基因1260G>A位点的基因分型及CNR1 mRNA的表达测定。结果　治疗16周后患者BMI、FPG、2 hPG、HbA1c水平均低于治疗前（P<0.05）。230例患者CNR1基因1260G>A位点的基因分型为：GG型188例（81.7%），GA型39例（17.0%），AA型3例（1.3%），最小等位基因频率为0.098，三种基因型分布频率符合哈迪温伯格平衡（P=0.550）。治疗16周后，GA/AA型患者BMI、FPG、HbA1c水平均低于GG型（P<0.05）。GG型和GA/AA型患者治疗16周后BMI、FPG、2 hPG、HbA1c水平均低于治疗前（P<0.05）。125例具有合适标本的CNR1 mRNA表达分析显示，GG型患者CNR1 mRNA表达水平高于GA/AA型患者（P<0.05）。不同基因型患者恶心呕吐、低血糖及总体不良反应发生率比较，差异均无统计学意义（P>0.05）。结论　利拉鲁肽在早期T2DM患者治疗中安全有效。CNR1基因1260G>A位点的GA/AA型可能通过影响该基因mRNA的表达进而影响利拉鲁肽对T2DM患者的疗效。

Influence of Cannabinoid Receptor 1 Gene Polymorphisms on the Clinical Outcomes of Early-stage Type 2 Diabetes Mellitus Treated with Liraglutide

Background　Liraglutide was proved to be effective in reducing the blood sugar level of patients with diabetes during a phase Ⅲ clinical trial.However，great individual difference of the hypoglycemic effect among patients treated with liraglutide has been found in clinical application.And studies have shown that gene polymorphism is one of the reasons for individual differences in actual effects of many drugs in humans.Objective　Cannabinoid Receptor 1（CNR1） gene plays an important role in diabetes and its complications.This study was to investigate the influence of CNR1 gene polymorphisms on the clinical outcomes of early-stage type 2 diabetes mellitus treated with liraglutide.Methods　Patients with early-stage type 2 diabetes mellitus from Department of Endocrinology，the No.3 Provincial People's Hospital of Henan Province from March 2016 to October 2018 were selected as study subjects.All of them were treated with subcutaneous injection of liraglutide，and the BMI，FPG，2 hPG and HbA1c were evaluated 16 weeks later.Additionally，peripheral venous blood specimens taken from all patients and fresh peripheral venous blood specimens from some of the patients were collected for measuring CNR1 1260G>A genotypes and CNR1 mRNA expression，respectively.Results　The mean levels of BMI，FPG，2 hPG and HbA1c decreased significantly after 16 weeks compared with baseline levels（P<0.05）.The prevalence of 1260G>A among the 230 patients was as follows： GG genotype was found in 188 cases（81.7%），GA genotype in 39 cases（17.0%），AA genotype in 3 cases（1.3%），and the minor allele frequency was 0.098.The distribution of three genotypes were in accordance with Hardy-Weinberg equilibrium（P=0.550）.The clinical outcomes analysis indicated that mean levels of BMI，FPG and HbA1c of GA/AA genotype patients decreased more significantly than GG genotype patients（P<0.05）.Mean levels of BMI，FPG，2 hPG and HbA1c of GA/AA and GG genotype patients decreased significantly compared with those before treatment（P<0.05）.Additionally，of the 125 available specimens for CNR1 mRNA analysis，the mean mRNA expression of CNR1 in patients with GG genotype was significantly higher than that of GA/AA genotype patients（P<0.05）.The incidence of nausea and vomiting，hypoglycemia and overall adverse reactions according to genotypes status was not significantly different（P>0.05）.Conclusion　Liraglutide is safe and effective in early-stage type 2 diabetes patients.And the clinical outcomes of the patients receiving liraglutide treatment may be influenced by CNR1 1260G>A GA/AA genotype through mediating the mRNA expression of CNR1.