Summary of - Implications of genetic variations, differential gene expression, and allele-specific expression on metformin response in drug-naïve type 2 diabetes

Document Type

Article

Abstract

The current study explored the variability in metformin response among drug-naive individuals with type 2 diabetes mellitus (T2DM). By combining genetic and transcriptomic analysis, identified potential biomarkers associated with response to metformin treatment. These findings suggest a link between genetic variations, gene expression patterns, and individual response to metformin, opening doors for personalized medicine approaches in T2DM treatment.

Aim of the study:

This research investigates why some people with type 2 diabetes respond better to metformin treatment than others. The study focused on individuals who had never taken metformin before (drug-naive) and used genetic and gene expression analysis to identify potential markers that could predict how well someone would respond to the drug.

Methods:

  • Type: Prospective study - follows participants forward in time.
  • Participants:

192 individuals with drug-naive T2DM (never taken metformin before).

223 control individuals (healthy).

  • Treatment: T2DM group received metformin monotherapy (only metformin) for 3 months.
  • Response Classification: Based on the change in glycated hemoglobin (HbA1c) after 3 months, participants were classified as responders (HbA1c improved) or non-responders (HbA1c didn't improve).
  • Final Analysis: Only data from 146 T2DM individuals was used due to sample loss during follow-up.
  • Validation: Selected variations and gene expression levels were validated using TaqMan assays.

Additional Analysis: Tools and databases were used to prioritize genes, identify enriched pathways, analyze drug-gene interactions, and explore disease-gene associations.

Correlation analysis: Looked for relationships between gene expression and changes in HbA1c.

Results and Discussion

rs1050152 and rs272893 in SLC22A4 were associated with improved response to metformin. The copy number loss was observed in PPARGC1A in the non-responders. The expression analysis highlighted potential differentially expressed targets for predicting metformin response (n = 35) and T2DM (n = 14). The expression of GDF15, TWISTNB, and RPL36A genes showed a maximum correlation with the change in HbA1c levels. The disease-gene association analysis highlighted MAGI2 rs113805659 to be linked with T2DM.

Conclusion

This study offers valuable insights into the genes and gene activity of treatment-naive T2DM patients. While variations in the SLC22A4 gene show promise for predicting metformin response, larger studies are needed for confirmation. The identified gene expression markers warrant further investigation to understand their role in both T2DM susceptibility and individual response to metformin.

Citation to this article - Vohra M, Sharma AR, Mallya S, Prabhu NB, Jayaram P, Nagri SK, Umakanth S, Rai PS. Implications of genetic variations, differential gene expression, and allele-specific expression on metformin response in drug-naïve type 2 diabetes. J Endocrinol Invest. 2023 Jun;46(6):1205-1218. doi: 10.1007/s40618-022-01989-y. Epub 2022 Dec 18. PMID: 36528847; PMCID: PMC10185588.

Publication date

18 December 2022

Publication Date

2022

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