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Background <p>The solute carrier (SLC) gene family encodes membrane transporters critical for drug disposition. Among these, SLC22A1 (OCT1) and SLC22A2 (OCT2) are central to the pharmacogenomics of type 2 diabetes mellitus (T2DM). OCT1 mediates hepatic uptake of metformin, while OCT2 regulates renal clearance. Genetic polymorphisms in these transporters may alter drug absorption and elimination, contributing to variability in glycemic response to oral hypoglycemic agents (OHAs).</p> Objective <p>To investigate the association between SLC22A1 and SLC22A2 polymorphisms and glycemic outcomes in patients with T2DM from an Indian cohort.</p> Methods <p>The present study was a cross-sectional analytical clinical study involving 144 patients with type 2 diabetes mellitus. Patients receiving OHAs were genotyped for selected SNPs in SLC22A1 and SLC22A2. Glycemic control was assessed using HbA1c and classified as good and poor responders. Associations between genotypes and drug response were analyzed across metformin, sulfonylureas, thiazolidinediones (TZDs), DPP4 inhibitors, and meglitinides.</p> Results <p>SLC22A1 polymorphisms were associated with differences in metformin response. Heterozygous variants at rs12657366 (<i>p</i> = 0.0281), rs41897827 (<i>p</i> = 0.027), and rs11588695 (<i>p</i> = 0.040) appeared more frequently among patients with good glycemic control, whereas homozygous mutations were associated with poor metformin response. SLC22A2 variants (rs35638327) were associated with sulfonylurea efficacy, with heterozygous correlating with better glycemic outcomes. TZDs and DPP4 inhibitors showed minimal genotype‑related differences, consistent with their mechanisms of action, while meglitinide response was unaffected.</p> Conclusion <p>SLC22A1 polymorphisms strongly predict metformin efficacy, and SLC22A2 variants may modulate sulfonylurea response. These findings highlight transporter genetics as key determinants of OHA effectiveness and suggest a possible heterozygote advantage. Incorporating pharmacogenomic profiling into diabetes care could enable personalized therapy, optimize glycemic outcomes, and reduce treatment failure.</p>

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Pharmacogenetic insights into SLC22A1 and SLC22A2 polymorphisms affecting glycemic response to oral hypoglycemic agents

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Ipseeta Ray Mohanty,
  • Shouvik Ganguly,
  • Sandeep Rai

摘要

Background

The solute carrier (SLC) gene family encodes membrane transporters critical for drug disposition. Among these, SLC22A1 (OCT1) and SLC22A2 (OCT2) are central to the pharmacogenomics of type 2 diabetes mellitus (T2DM). OCT1 mediates hepatic uptake of metformin, while OCT2 regulates renal clearance. Genetic polymorphisms in these transporters may alter drug absorption and elimination, contributing to variability in glycemic response to oral hypoglycemic agents (OHAs).

Objective

To investigate the association between SLC22A1 and SLC22A2 polymorphisms and glycemic outcomes in patients with T2DM from an Indian cohort.

Methods

The present study was a cross-sectional analytical clinical study involving 144 patients with type 2 diabetes mellitus. Patients receiving OHAs were genotyped for selected SNPs in SLC22A1 and SLC22A2. Glycemic control was assessed using HbA1c and classified as good and poor responders. Associations between genotypes and drug response were analyzed across metformin, sulfonylureas, thiazolidinediones (TZDs), DPP4 inhibitors, and meglitinides.

Results

SLC22A1 polymorphisms were associated with differences in metformin response. Heterozygous variants at rs12657366 (p = 0.0281), rs41897827 (p = 0.027), and rs11588695 (p = 0.040) appeared more frequently among patients with good glycemic control, whereas homozygous mutations were associated with poor metformin response. SLC22A2 variants (rs35638327) were associated with sulfonylurea efficacy, with heterozygous correlating with better glycemic outcomes. TZDs and DPP4 inhibitors showed minimal genotype‑related differences, consistent with their mechanisms of action, while meglitinide response was unaffected.

Conclusion

SLC22A1 polymorphisms strongly predict metformin efficacy, and SLC22A2 variants may modulate sulfonylurea response. These findings highlight transporter genetics as key determinants of OHA effectiveness and suggest a possible heterozygote advantage. Incorporating pharmacogenomic profiling into diabetes care could enable personalized therapy, optimize glycemic outcomes, and reduce treatment failure.