Begum Rokeya, Das Arindita, Alam Md Jahangir, Sultana Gazi Nurun Nahar
Genetic Engineering and Biotechnology Research Laboratory, Centre for Advanced Research in Sciences (CARS), University of Dhaka, Dhaka 1000, Bangladesh.
Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh.
Adv Pharmacol Pharm Sci. 2025 Jan 29;2025:8568658. doi: 10.1155/adpp/8568658. eCollection 2025.
Metformin is the most widely prescribed drug for the treatment of Type 2 diabetes mellitus (T2DM), but its response varies from person to person. This study aims to analyze the complete mutation spectrum of the gene in metformin poor responders and to explore the potential pathogenic effects of the identified mutations. Clinical features of 56 Bangladeshi T2DM patients (who showed altered response to metformin) were analyzed, and genomic DNA was extracted from their blood samples. Subsequently, the entire exons (1-11), along with flanking introns of the gene were amplified and sequenced. Molecular consequences of the identified mutations on OCT1 protein activity were determined through in silico analyses. In this study, 29 mutations of the gene were identified; among which 5 mutations (c.412-86G>T, c.970G>C, c.1386-3088_1386-3083delGAATCA, c.1498+66G>T, and c.1653C>A) were novel. It was found that nsSNPs c.181C>T, c.1022C>T, c.493G>T, c.1207A>G, and c.970G>C (novel) as well as frameshift deletions have potential deleterious effects on OCT1 protein stability and function. Some of these mutations also cause alternative splicing, as per the HSF tool. In addition, alteration of interatomic bonding in the OCT1 protein due to two high-risk mutations (c.181C>T and c.1022C>T) was found from web-based analysis. The mutations, as mentioned earlier, are the most probable causative factor of decreased metformin effectiveness and adverse side effects in T2DM patients who are poor responders. Understanding the gene variations of patients can help tailor treatment strategies for optimal metformin response or identify alternative medications.
二甲双胍是治疗2型糖尿病（T2DM）最常用的药物，但其疗效因人而异。本研究旨在分析二甲双胍疗效不佳者中该基因的完整突变谱，并探讨所鉴定突变的潜在致病作用。分析了56例孟加拉国T2DM患者（对二甲双胍反应改变）的临床特征，并从他们的血液样本中提取基因组DNA。随后，扩增并测序该基因的全部外显子（1 - 11）及其侧翼内含子。通过计算机分析确定所鉴定突变对OCT1蛋白活性的分子影响。在本研究中，鉴定出该基因的29个突变；其中5个突变（c.412 - 86G>T、c.970G>C、c.1386 - 3088_1386 - 3083delGAATCA、c.1498 + 66G>T和c.1653C>A）是新发现的。发现非同义单核苷酸多态性c.181C>T、c.1022C>T、c.493G>T、c.1207A>G和c.970G>C（新发现）以及移码缺失对OCT1蛋白稳定性和功能具有潜在有害影响。根据HSF工具，其中一些突变还会导致可变剪接。此外，基于网络分析发现两个高风险突变（c.181C>T和c.1022C>T）导致OCT1蛋白中原子间键的改变。如前所述，这些突变是T2DM疗效不佳患者中二甲双胍疗效降低和出现不良反应的最可能原因。了解患者的该基因变异有助于制定治疗策略以实现最佳二甲双胍反应或确定替代药物。
