SAINS MALAYSIANA

Sains Malaysiana 54(8)(2025): 2007-2020

http://doi.org/10.17576/jsm-2025-5408-11

Implication of MATE2, OCT2 and ATM Genes Polymorphism and Their Association with Metformin Efficacy and Glycemic Control in Type 2 Diabetes Mellitus Patients

(Implikasi Polimorfisme Gen MATE2, OCT2 dan ATM serta Perkaitannya dengan Keberkesanan Metformin dan Kawalan Glukosa dalam Kalangan Pesakit Diabetes Mellitus Jenis 2)

MUHAMMAD KASHIF RAZA^1,2,3, AZIZ-UL-HASAN AAMIR^4,5, DURR-E- SHAHWAR², USAMA², LAMJED MANSOUR⁶, ZAHID KHAN², AKTAR ALI¹ & MUHAMMAD IMRAN^2,*

¹Warren Center for Drug Discovery Research, Department of Biochemistry and Chemistry, University of Notre Dame, Indiana 46556, USA

²Biochemistry Section, Institute of Chemical Sciences, University of Peshawar, Peshawar 25120 KP, Pakistan

³Department of Chemistry, Shaheed Benazir Bhutto University, Sheringal Dir Upper 18050 KP, Pakistan

⁴Department of Diabetes and Endocrinology, Hayatabad Medical Complex, Peshawar 25120 KP, Pakistan

⁵Department of Endocrinology, Peshawar General Hospital, Peshawar 25120, KP, Pakistan

⁶Department of Zoology, College of Science, King Saud University, Riyadh 2455, 11451, Saudi Arabia

Diserahkan: 28 Januari 2025/Diterima: 30 Mei 2025

Abstract

In type 2 diabetes mellitus (T2DM) patients, metformin, the drug of choice, exhibits variable therapeutic response attributed to gene polymorphism. The current study aimed to investigate the association of MATE2 rs12943590, OCT2 rs7757336, and ATM rs11212617, which are hotspot single-nucleotide polymorphisms (SNPs), with metformin efficacy and glycemic control in T2DM patients. A total of 417 study subjects were enrolled, consisting of 217 newly diagnosed and drug-naive T2DM patients, while 200 individuals were healthy controls. Patients were further divided into two subgroups: metformin responsive and metformin-non-responsive individuals. Study patients were kept on exclusive metformin monotherapy for three successive months. Patients' basic parameters like age, fasting glucose, HbA1c, LDL, HDL, Cholesterol, and BMI were recorded. Real-time PCR involving melt curve analysis and subsequent agarose gel electrophoresis with Sanger sequencing was employed for genotype analysis. MATE2 (SLC47A2) rs12943590 GA genotype (OR 0.44, CI 95% 0.23-0.86, p = 0.01), OCT2 (SLC22A2) rs7757336 GG genotype (OR 5.82, 95% CI 1.40-24.24, p = 0.01), and G allele (OR 2.21, CI 95% 1.18-4.14, p = 0.01) were significantly associated with metformin response and glucose-lowering effect. No significant association (p > 0.05) was observed for ATM rs11212617.

Keywords: Association studies; diabetes mellitus; gene polymorphism; glycemic control; metformin

Abstrak

Metformin sebagai ubat pilihan untuk pesakit diabetes mellitus jenis 2 (T2DM) menunjukkan respons terapeutik yang berbeza-beza yang dikaitkan dengan polimorfisme gen. Penyelidikan ini bertujuan untuk mengkaji hubungan antara MATE2 rs12943590, OCT2 rs7757336 dan ATM rs11212617 yang merupakan polimorfisme nukleotida tunggal (SNP) titik panas dan hubungan mereka dengan keberkesanan metformin dan kawalan glisemik pada pesakit T2DM. Sebanyak 417 individu subjek kajian telah disertakan, terdiri daripada 217 pesakit T2DM yang baru didiagnosis dan tidak pernah menjalani rawatan, manakala 200 individu merupakan kumpulan kawalan sihat. Pesakit dibahagikan kepada dua kumpulan sub, iaitu individu yang responsif terhadap metformin dan individu yang tidak responsif terhadap metformin. Pesakit kajian diberikan monoterapi metformin eksklusif selama tiga bulan berturut-turut. Parameter asas pesakit seperti umur, glukosa puasa, HbA1c, LDL, HDL, kolesterol dan BMI dicatat. PCR masa nyata yang melibatkan analisis lengkung lebur dan elektroforesis gel agarosa seterusnya dengan penjujukan Sanger digunakan untuk analisis genotip. Genotip MATE2 (SLC47A2) rs12943590 GA (OR 0.44, CI 95% 0.23-0.86, p = 0.01), genotip OCT2 (SLC22A2) rs7757336 GG (OR 5.82, CI 95% 1.40-24.24, p = 0.01) dan alel G (OR 2.21, CI 95% 1.18-4.14, p = 0.01) didapati secara signifikan berkaitan dengan respons metformin dan kesan penurunan glukosa. Tiada hubungan signifikan (p > 0.05) yang diperhatikan untuk ATM rs11212617.

Kata kunci: Diabetes mellitus; kajian hubungan; kawalan glisemik; metformin; polimorfisme gen

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