{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:36:00Z","timestamp":1785411360644,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,28]]},"group-title":"Endocrinology (including Diabetes Mellitus and Metabolic Disease)","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"award":["ZIADK075133"],"award-info":[{"award-number":["ZIADK075133"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Institute of Health, Clinical Center Bench to Bedside Award","award":["381469"],"award-info":[{"award-number":["381469"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,28]]},"abstract":"ABSTRACT<\/jats:title>\n \n Aims\/Hypothesis<\/jats:title>\n \n Behavioral and phenotypic characteristics do not fully explain variability in African Americans with youth-onset type 2 diabetes (Y-T2D) treated with metformin with or without liraglutide. We hypothesized that biological heterogeneity, including genetic variation in the metformin transporter\n OCT1,<\/jats:italic>\n influences metformin pharmacokinetics and hepatic glucose flux. Therefore, we sought to characterize metformin pharmacokinetics in Y-T2D and evaluate genetic variants known to modulate metformin efficacy in adults to determine the mechanisms underlying variation in treatment response.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We evaluated genetic variants related to metformin transport and mechanisms of action in 30 Y-T2D using a candidate-gene approach to evaluate the association of pharmacogenetic variants with fasting glucose and gluconeogenesis. In a subset of Y-T2D randomized to 3 months of metformin (n=11) or metformin and liraglutide (n=8), we constructed a metformin population pharmacokinetic model and evaluated gene variant associations.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A one-compartment first-order absorption and elimination pharmacokinetic model provided the optimal fit. Metformin pharmacokinetic parameters were similar by group and not related to glycemia. The rs628031_\n OCT1<\/jats:italic>\n A allele was associated with greater metformin clearance. The rs622342_\n OCT1<\/jats:italic>\n C allele was associated with lower post-treatment fractional gluconeogenesis (\u03b2 [95% CI] = -8.8 [-14.13, -3.47] %, Adjusted R\n 2<\/jats:sup>\n = 0.56,\n P<\/jats:italic>\n = 0.003). The rs7903146_\n TCF7L2<\/jats:italic>\n T allele was associated with greater reductions in fasting glucose among those treated with metformin + liraglutide (\u03b2 = -1.32 [-2.42, -0.22] mmol\/L, Adjusted R\n 2<\/jats:sup>\n = 0.8,\n P<\/jats:italic>\n <0.002), but baseline glucose and gluconeogenesis (\n P<\/jats:italic>\n <0.0001) were the strongest predictors of post-treatment glycemia.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion\/interpretation<\/jats:title>\n \n In Y-T2D,\n OCT1<\/jats:italic>\n gene variants rs628031 and rs622342 were associated with metformin clearance and gluconeogenesis, respectively.\n TCF7L2<\/jats:italic>\n variant rs7903146 may contribute to differences in glycemic response in youth treated with metformin and liraglutide. These findings suggest genetic variants may be important for understanding variable metformin response in Y-T2D.\n <\/jats:p>\n <\/jats:sec>\n \n RESEARCH IN CONTEXT<\/jats:title>\n \n What is already known about this subject?<\/jats:title>\n \n \n Metformin is the first-line therapeutic approach for management of youth-onset type-2 diabetes (Y-T2D); however, 65% of African American (AA) youth require additional medication within 2 years, and the biological drivers of variability remain unclear<\/jats:p>\n <\/jats:list-item>\n \n Y-T2D has a distinct pathophysiology from adult-onset T2D, characterized by rapid beta-cell failure, high rates of gluconeogenesis, and glomerular hyperfiltration that may influence metformin action and clearance, especially among AA Y-T2D.<\/jats:p>\n <\/jats:list-item>\n \n \n Genetic variants in the OCT1 (\n SLC22A1<\/jats:italic>\n ) metformin transporter have been associated with metformin clearance and glycemic response in adults, but there are no pharmacokinetic-pharmacogenetic models of metformin in Y-T2D\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>\n \n What is the key question?<\/jats:title>\n \n \n Among AA Y-T2D, how do genetic variants associated with adult-onset T2D affect metformin pharmacokinetic profiles and glycemic response?<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>\n \n What are the new findings?<\/jats:title>\n \n \n Metformin pharmacokinetics in AA Y-T2D were best described by a one-compartment first-order absorption and elimination model<\/jats:p>\n <\/jats:list-item>\n \n \n The\n OCT1<\/jats:italic>\n variant rs628031 A allele was associated with \u223c40% greater metformin clearance\n <\/jats:p>\n <\/jats:list-item>\n \n \n The\n OCT1<\/jats:italic>\n variant rs622342 C allele was associated with \u223c8% lower rates of fractional gluconeogenesis after treatment\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>\n \n How might this impact on clinical practice in the foreseeable future?<\/jats:title>\n \n \n \n Identifying\n OCT1<\/jats:italic>\n variants that modulate gluconeogenic flux, together with a novel pharmacokinetic profile, could help reshape evaluation of metformin response in Y-T2D and facilitate mechanistically informed, genotype-guided strategies to distinguish patients who can be safely managed on metformin from those who need early combination therapy\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>\n <\/jats:sec>","DOI":"10.64898\/2026.05.27.26354152","type":"posted-content","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T22:10:14Z","timestamp":1780006214000},"source":"Crossref","is-referenced-by-count":0,"title":["OCT1<\/i>\n Variants Are Associated with Metformin Clearance and Gluconeogenesis: Mechanistic Insights for Youth-Onset Type 2 Diabetes in the MIGHTY 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