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

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 ( $P<1\times {10}^{-6}$ ), 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.