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

TY - JOUR

T1 - Initial Insights into the Genetic Variation Associated with Metformin Treatment Failure in Youth with Type 2 Diabetes

AU - Srinivasan, Shylaja

AU - Chen, Ling

AU - Udler, Miriam

AU - Todd, Jennifer

AU - Kelsey, Megan M.

AU - Haymond, Morey W.

AU - Arslanian, Silva

AU - Zeitler, Philip

AU - Gubitosi-Klug, Rose

AU - Nadeau, Kristen J.

AU - Kutney, Katherine

AU - White, Neil H.

AU - Li, Josephine H.

AU - Perry, James A.

AU - Kaur, Varinderpal

AU - Brenner, Laura

AU - Mercader, Josep M.

AU - Dawed, Adem

AU - Pearson, Ewan R.

AU - Yee, Sook Wah

AU - Giacomini, Kathleen M.

AU - Pollin, Toni

AU - Florez, Jose C.

N1 - Publisher Copyright: © 2023 Shylaja Srinivasan et al.

PY - 2023/5/24

Y1 - 2023/5/24

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85176251487

U2 - 10.1155/2023/8883199

DO - 10.1155/2023/8883199

M3 - Article

C2 - 38590442

AN - SCOPUS:85176251487

SN - 1399-543X

VL - 2023

JO - Pediatric Diabetes

JF - Pediatric Diabetes

M1 - 8883199

ER -