2型糖尿病患者中有机阳离子转运体1变体与二甲双胍的胃肠道副作用
Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with Type 2 diabetes.
作者信息
Dujic T, Causevic A, Bego T, Malenica M, Velija-Asimi Z, Pearson E R, Semiz S
机构信息
Department of Biochemistry and Clinical Analysis, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
Clinic for Endocrinology, Diabetes and Metabolism Diseases, University Clinical Centre of Sarajevo, Sarajevo, Bosnia and Herzegovina.
出版信息
Diabet Med. 2016 Apr;33(4):511-4. doi: 10.1111/dme.13040. Epub 2015 Dec 24.
AIMS
Metformin is the most widely used oral anti-diabetes agent and has considerable benefits over other therapies, yet 20-30% of people develop gastrointestinal side effects, and 5% are unable to tolerate metformin due to the severity of these side effects. The mechanism for gastrointestinal side effects and their considerable inter-individual variability is unclear. We have recently shown the association between organic cation transporter 1 (OCT1) variants and severe intolerance to metformin in people with Type 2 diabetes. The aim of this study was to explore the association of OCT1 reduced-function polymorphisms with common metformin-induced gastrointestinal side effects in Type 2 diabetes.
METHODS
This prospective observational cohort study included 92 patients with newly diagnosed Type 2 diabetes, incident users of metformin. Patients were genotyped for two common loss-of-function variants in the OCT1 gene (SLC22A1): R61C (rs12208357) and M420del (rs72552763). The association of OCT1 reduced-function alleles with gastrointestinal side effects was analysed using logistic regression.
RESULTS
Forty-three patients (47%) experienced gastrointestinal adverse effects in the first 6 months of metformin treatment. Interestingly, the number of OCT1 reduced-function alleles was significantly associated with over two-fold higher odds of the common metformin-induced gastrointestinal side effects (odds ratio = 2.31, 95% confidence interval 1.07-5.01, P = 0.034).
CONCLUSIONS
In conclusion, we showed for the first time the association between OCT1 variants and common metformin-induced gastrointestinal side effects. These results confirm recent findings related to the role of OCT1 in severe metformin intolerance, and suggest that high inter-individual variability in mild/moderate and severe gastrointestinal intolerance share a common underlying mechanism. These data could contribute to more personalized and safer metformin treatment.
目的
二甲双胍是使用最广泛的口服抗糖尿病药物，与其他疗法相比有诸多益处，但20% - 30%的人会出现胃肠道副作用，5%的人因这些副作用的严重性而无法耐受二甲双胍。胃肠道副作用的机制及其显著的个体间差异尚不清楚。我们最近发现2型糖尿病患者中有机阳离子转运体1（OCT1）变体与对二甲双胍的严重不耐受之间存在关联。本研究的目的是探讨OCT1功能降低多态性与2型糖尿病患者中常见的二甲双胍诱导的胃肠道副作用之间的关联。
方法
这项前瞻性观察队列研究纳入了92例新诊断的2型糖尿病患者，他们均为二甲双胍的初用者。对患者进行OCT1基因（SLC22A1）中两个常见功能丧失变体的基因分型：R61C（rs12208357）和M420del（rs72552763）。使用逻辑回归分析OCT1功能降低等位基因与胃肠道副作用之间的关联。
结果
43例患者（47%）在二甲双胍治疗的前6个月出现胃肠道不良反应。有趣的是，OCT1功能降低等位基因的数量与常见的二甲双胍诱导的胃肠道副作用的发生率高出两倍以上显著相关（比值比 = 2.31，95%置信区间1.07 - 5.01，P = 0.034）。
结论
总之，我们首次表明OCT1变体与常见的二甲双胍诱导的胃肠道副作用之间存在关联。这些结果证实了最近关于OCT1在严重二甲双胍不耐受中作用的发现，并表明轻度/中度和严重胃肠道不耐受的高度个体间差异具有共同的潜在机制。这些数据可能有助于实现更个性化、更安全的二甲双胍治疗。
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