Variation in the Plasma Membrane Monoamine Transporter (PMAT) (Encoded by SLC29A4) and Organic Cation Transporter 1 (OCT1) (Encoded by SLC22A1) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: An IMI DIRECT Study
Variation in the Plasma Membrane Monoamine Transporter (PMAT) (Encoded by SLC29A4) and Organic Cation Transporter 1 (OCT1) (Encoded by SLC22A1) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: An IMI DIRECT Study
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DOI：
10.2337/dc18-2182
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发表时间：
2019-06-01
期刊：
影响因子：
16.2
通讯作者：
Pearson, Ewan R.
中科院分区：
文献类型：
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作者：
Dawed, Adem Y.;Zhou, Kaixin;Pearson, Ewan R.
二甲双胍治疗的2型糖尿病患者中有20-30%发生胃肠道不良反应，导致5-10%的病例提前停药。胃肠道不耐受可能反映了肠道中二甲双胍的局部高浓度。我们假设二甲双胍通过质膜单胺转运蛋白（PMAT）和有机阳离子转运蛋白1（OCT 1）的转运减少可能会增加严重胃肠道不良反应的风险。研究设计和方法该研究包括286名严重二甲双胍不耐受和1,128名二甲双胍耐受的个体，来自IMI DIRECT（创新药物倡议：关于患者分层的二甲双胍研究）财团。我们评估了患者特征、合并用药、SLC 29 A4和SLC 22 A1基因突变负荷与二甲双胍不耐受几率之间的关系，发现女性（P < 0.001）和老年人（P < 0.001）更容易发生二甲双胍不耐受。同时使用转运蛋白抑制药物增加了不耐受的几率（比值比[OR] 1.72，P < 0.001）。在校正的logistic回归模型中，rs3889348（SLC 29 A4）的G等位基因与胃肠道不耐受相关（OR 1.34，P = 0.005）。rs3889348是SLC 29 A4在肠道组织中的最高顺式表达数量性状基因座，其中G等位基因的携带者具有降低的表达。携带G等位基因的纯合子携带者接受转运蛋白抑制药物治疗的不耐受几率是不携带G等位基因且未接受抑制药物治疗的携带者的3倍多（OR 3.23，P < 0.001）。使用从rs3889348和SLC 22 A1变体衍生的遗传风险评分发现，与不携带风险等位基因的个体相比，携带三个或更多风险等位基因的个体的不耐受几率高出两倍多（或2.15，P = 0.01）结论：这些结果表明，肠道二甲双胍转运蛋白和合并用药在二甲双胍的胃肠道不良反应中起重要作用。二甲双胍。
OBJECTIVEGastrointestinal adverse effects occur in 20-30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5-10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects.RESEARCH DESIGN AND METHODSThe study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance.RESULTSWomen (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01).CONCLUSIONSThese results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.