# Initial Insights into the Genetic Variation Associated with Metformin Treatment Failure in Youth with Type 2 Diabetes

## TL;DR

This study explores genetic factors linked to metformin treatment failure in young people with type 2 diabetes.

## Contribution

The study provides initial evidence of genetic variation associated with metformin response in youth with type 2 diabetes.

## Key findings

- Several genetic variants showed a suggestive association with metformin response, though none reached genome-wide significance.
- The ATRNL1 variant rs76195229 was linked to worse metformin response in a replication cohort.
- Higher β-cell polygenic scores were associated with reduced β-cell function over time.

## Abstract

Metformin is the first-line treatment for type 2 diabetes (T2D) in youth but with limited sustained glycemic response. To identify common variants associated with metformin response, we used a genome-wide approach in 506 youth from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study and examined the relationship between T2D partitioned polygenic scores (pPS), glycemic traits, and metformin response in these youth. Several variants met a suggestive threshold (P < 1 × 10−6), though none including published adult variants reached genome-wide significance. We pursued replication of top nine variants in three cohorts, and rs76195229 in ATRNL1 was associated with worse metformin response in the Metformin Genetics Consortium (n = 7,812), though statistically not being significant after Bonferroni correction (P = 0.06). A higher β-cell pPS was associated with a lower insulinogenic index (P = 0.02) and C-peptide (P = 0.047) at baseline and higher pPS related to two insulin resistance processes were associated with increased C-peptide at baseline (P = 0.04, 0.02). Although pPS were not associated with changes in glycemic traits or metformin response, our results indicate a trend in the association of the β-cell pPS with reduced β-cell function over time. Our data show initial evidence for genetic variation associated with metformin response in youth with T2D.