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

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.