{"doi":"10.1155/2023/8883199","title":"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 ( <a:math xmlns:a=\"http://www.w3.org/1998/Math/MathML\" id=\"M1\"> <a:mi>P</a:mi> <a:mo>&lt;</a:mo> <a:mn>1</a:mn> <a:mo>×</a:mo> <a:msup> <a:mrow> <a:mn>10</a:mn> </a:mrow> <a:mrow> <a:mo>−</a:mo> <a:mn>6</a:mn> </a:mrow> </a:msup> </a:math> ), 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 ( <c:math xmlns:c=\"http://www.w3.org/1998/Math/MathML\" id=\"M2\"> <c:mi>P</c:mi> <c:mo>=</c:mo> <c:mn>0.06</c:mn> </c:math> ). A higher β-cell pPS was associated with a lower insulinogenic index ( <e:math xmlns:e=\"http://www.w3.org/1998/Math/MathML\" id=\"M3\"> <e:mi>P</e:mi> <e:mo>=</e:mo> <e:mn>0.02</e:mn> </e:math> ) and C-peptide ( <g:math xmlns:g=\"http://www.w3.org/1998/Math/MathML\" id=\"M4\"> <g:mi>P</g:mi> <g:mo>=</g:mo> <g:mn>0.047</g:mn> </g:math> ) at baseline and higher pPS related to two insulin resistance processes were associated with increased C-peptide at baseline ( <i:math xmlns:i=\"http://www.w3.org/1998/Math/MathML\" id=\"M5\"> <i:mi>P</i:mi> <i:mo>=</i:mo> <i:mn>0.04</i:mn> <i:mo>,</i:mo> <i:mn>0.02</i:mn> </i:math> ). 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.","journal":"Pediatric Diabetes","year":2023,"id":407654,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":335190,"name":"Ling Chen","orcid":"0009-0001-6225-2516","position":1,"is_corresponding":false},{"id":7372,"name":"Miriam S. 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Giacomini","orcid":"0000-0001-8041-5430","position":20,"is_corresponding":false},{"id":16093,"name":"Toni I. Pollin","orcid":"0000-0002-6402-746X","position":21,"is_corresponding":false},{"id":1150,"name":"José C. Florez","orcid":"0000-0002-1730-9325","position":22,"is_corresponding":false},{"id":645953,"name":"Shylaja Srinivasan","orcid":"0000-0002-8049-6370","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T01:21:10.867368Z","pmid":"38590442","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}