Can Known Genetic Polymorphisms Guide Personalized Therapy Approach in Type 2 Diabetes?

Summary

This project explores the potential for pharmacogenetic-guided personalised therapy in the management of type 2 diabetes (T2DM), a chronic metabolic disease affecting over 1 in 9 adults worldwide. It focuses on a key challenge in type 2 diabetes treatment, that is, inter-individual variability in drug response, often arising from genetic polymorphisms in genes that may affect drug metabolism, transporters or target binding. These genetic variants can significantly impact how well a patient responds to a particular medication.

The project focuses on three commonly prescribed antidiabetic drugs - Metformin, Liraglutide and Empagliflozin - selected for their distinct drug class and mechanism of action. Through a review of peer-reviewed literature and pharmacogenomic databases such as PharmGKB, several key single nucleotide polymorphisms (SNPs) were identified and compared to evaluate how each influences glycemic outcomes, particularly by lowering HbA1c levels.

For Metformin, the most well-studied variant is rs622342 in the SLC22A1 gene, which affects the OCT1 transporter critical for hepatic uptake and is associated with improved glycemic response. In the case of Liraglutide, two SNPs in the GLP1R gene - rs3765467 and rs10305420 - have shown associations with significantly better HbA1c reduction in individuals carrying the GG and TT genotypes respectively. In contrast, although Empagliflozin targets the SGLT2 protein encoded by the SLC5A2 gene, current evidence does not support any clinically relevant polymorphism that significantly impacts glycemic response.

Overall, the findings suggested that there is a growing role of pharmacogenetics in guiding treatment selection for T2DM. However, the clinical implementation of these insights still requires validation through large-scale, multi ethnic studies. Further research is essential to ensure that personalised diabetes therapies based on genetic profiling are effective and broadly applicable.

Figure: Mechanism of action of GLP-1 receptor agonist Liraglutide in enhancing insulin secretion via cAMP signaling.

(Figure representation created by the author: Iraj Gupta)

Shortlisted genes related to targets, enzymes, and transporters of Empagliflozin, Liraglutide, and Metformin for investigating potential pharmacogenomic polymorphisms.

(Figure representation created by the author: Iraj Gupta)

Genetic polymorphisms associated with drug response in metformin, liraglutide, and empagliflozin. Variants listed have been supported by published literature and curated pharmacogenomic data.
(Data sourced from PharmGKB. Figure/representation created by the author:Iraj Gupta)

Video Presentation

Impact Statement

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Hello! I’m Iraj Gupta, a student at Global Indian International School, Singapore. Through this program, I gained a deeper understanding of how our body functions at a molecular level and how various drugs interact , covering everything from absorption and metabolism to receptor binding and elimination. One area that especially fascinated me was pharmacogenetics, how genetic differences affect individual responses to medications. With the guidance of my mentor, this concept became the foundation of my project on pharmacogenetics-guided therapy for type 2 diabetes mellitus (T2DM). Throughout the project, I developed essential research skills, such as learning how to interpret and analyse clinical data. I also learned how to interpret pharmacokinetic and pharmacodynamic principles and apply them to real-world treatment decisions, which gave me a strong foundation for future scientific research. Overall, through this program and with the guidance of my mentor I not only deepened my interest in medicine but gained the confidence and tools to pursue more advanced research in the field.

Student Reflection

By: Iraj Gupta. The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of Elio Academy.

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