Transcriptome analysis of Newly Diagnosed Type 2 Diabetes Subjects identifies genes to predict Metformin drug Response

Aims: Metformin is a widely used, primary drug of choice to treat individuals with type 2 diabetes (T2D). Clinically, inter-individual variability of drug response is of significant concern. The targets and precise mechanisms of action for metformin is still under interrogation. In the present study, a whole transcriptome analysis was performed with an intent to identify predictive biomarkers of metformin response in T2D individuals. Methods: Twenty drug naïve individuals with T2D and ten healthy controls were enrolled. T2D individuals were administrated with metformin monotherapy and were defined as responders and non-responders based on the changes in their glycated haemoglobin (HbA1c) over a period of three months. Poly(A) RNA Seq was performed using Ion Torrent Proton platform and differentially expressed genes were identified from the transcriptome profiles. The gene prioritization, enrichment analysis, drug-gene interactions, disease gene association analysis were performed using various tools and databases. A correlation analysis was also performed between gene expression and change in HbA1c levels after 3 months of metformin therapy. Results: The expression analysis highlighted differentially expressed genes in metformin responders, non-responders and healthy individuals. The gene prioritization and enrichment analysis highlighted potential targets for predicting metformin response (n=35) as well as T2D disease (n=14). The drug-gene interactions did not show any direct association with diabetes drugs. However, the expression of GDF15, TWISTNB and RPL36A genes showed maximum correlation with change in HbA1c levels after 3 months of metformin therapy. The disease gene association analysis highlighted rs113805659 in MAGI2 gene to be linked with T2D in African Americans. Conclusion: The results of the present study provide evidence for the perturbed transcriptome and pathways associated with metformin drug response in T2D individuals. Whole transcriptome profile of 20 drug naïve individuals with T2D and 10 healthy controls was generated for total RNA isolated from whole blood using Ion Torrent Proton