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

Authors

Shylaja Srinivasan
Ling Chen
Miriam Udler
Jennifer Todd
Megan M Kelsey
Morey W Haymond
Silva Arslanian
Philip Zeitler
Rose Gubitosi-Klug
Kristen J Nadeau
Katherine Kutney
Neil H White
Josephine H Li
James A Perry
Varinderpal Kaur
Laura Brenner
Josep M Mercader
Adem Dawed
Ewan R Pearson
Sook-Wah Yee
Kathleen M Giacomini
Toni Pollin
Jose C Florez

Publication Date

1-1-2023

Journal

Pediatric Diabetes

DOI

10.1155/2023/8883199

PMID

38590442

PMCID

PMC11000826

PubMedCentral® Posted Date

4-8-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Adult, Humans, Adolescent, Metformin, Diabetes Mellitus, Type 2, C-Peptide, Treatment Failure, Genetic Variation, Blood Glucose, Hypoglycemic Agents

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.