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

Language

English

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

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.

Keywords

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

Published Open-Access

yes

Recommended Citation

Srinivasan, Shylaja; Chen, Ling; Udler, Miriam; et al., "Initial Insights into the Genetic Variation Associated with Metformin Treatment Failure in Youth with Type 2 Diabetes" (2023). Faculty, Staff and Students Publications. 3543.
https://digitalcommons.library.tmc.edu/baylor_docs/3543