Moazzami Reza, Mehrjardi Mohammad Yahya Vahidi, Miri Ali
Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
J Diabetes Metab Disord. 2024 Aug 28;23(2):2183-2190. doi: 10.1007/s40200-024-01486-4. eCollection 2024 Dec.
: Metformin, an oral hypoglycemic agent, is generally used as the first-line treatment in type 2 diabetes mellitus (T2DM) patients. The response to metformin varies between patients, and its mechanisms remain incompletely understood. Genetic variations in proteins involved in the pharmacodynamics and pharmacokinetics of metformin, like OCT1 transporter, are suspected to explain this difference. This study investigated the association of the response to metformin in T2DM patients with the presence of rs12208357 (R61C) variant in the gene.
We selected 100 patients who responded and 100 patients who did not respond to metformin monotherapy after 20 weeks according to their HbA1c level change. We investigated the effect of rs12208357 on the structure, function, and stability of OCT1 protein and its interaction with metformin by in silico tools. To determine the genotype of rs12208357 we used the ARMS-PCR technique.
The in silico study indicated that rs12208357 probably changes OCT1 stability, function, interaction site, and binding energy to metformin in the extracellular domain. ARMS-PCR also showed the frequency of T and C alleles were significantly different between responders and non-responders ( = 0.014), also there is a significant difference in CC and CT/TT genotype frequency between responders and non-responders ( = 0.023).
Based on the in silico study and ARMS-PCR experiment results, the CC genotype has a better response to metformin therapy and the carrier of the T allele (CT and TT genotype) probably has complications in glycemic control by metformin.
二甲双胍是一种口服降糖药，通常用作2型糖尿病（T2DM）患者的一线治疗药物。患者对二甲双胍的反应各不相同，其作用机制仍未完全明确。参与二甲双胍药效学和药代动力学的蛋白质的基因变异，如有机阳离子转运体1（OCT1），被怀疑是导致这种差异的原因。本研究调查了T2DM患者对二甲双胍的反应与基因中rs12208357（R61C）变异存在之间的关联。
根据糖化血红蛋白（HbA1c）水平变化，我们选择了100例对二甲双胍单药治疗20周后有反应的患者和100例无反应的患者。我们通过计算机模拟工具研究了rs12208357对OCT1蛋白的结构、功能和稳定性及其与二甲双胍相互作用的影响。为了确定rs12208357的基因型，我们使用了扩增阻滞突变系统聚合酶链反应（ARMS-PCR）技术。
计算机模拟研究表明，rs12208357可能会改变OCT1在细胞外结构域的稳定性、功能、相互作用位点以及与二甲双胍的结合能。ARMS-PCR还显示，反应者和无反应者之间T和C等位基因的频率存在显著差异（P = 0.014），反应者和无反应者之间CC与CT/TT基因型频率也存在显著差异（P = 0.023）。
基于计算机模拟研究和ARMS-PCR实验结果，CC基因型对二甲双胍治疗反应较好，而T等位基因携带者（CT和TT基因型）可能在二甲双胍血糖控制方面存在并发症。
