OCT1 Variants Are Associated with Metformin Clearance and Gluconeogenesis: Mechanistic Insights for Youth-Onset Type 2 Diabetes in the MIGHTY Study.

内容摘要

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 OCT1, 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. 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. 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_ OCT1 A allele was associated with greater metformin clearance. The rs622342_ OCT1 C allele was associated with lower post-treatment fractional gluconeogenesis (&#x3b2; [95% CI] = -8.8 [-14.13, -3.47] %, Adjusted R 2 = 0.56, P = 0.003). The rs7903146_ TCF7L2 T allele was associated with greater reductions in fasting glucose among those treated with metformin + liraglutide (&#x3b2; = -1.32 [-2.42, -0.22] mmol/L, Adjusted R 2 = 0.8, P <0.002), but baseline glucose and gluconeogenesis ( P <0.0001) were the strongest predictors of post-treatment glycemia. In Y-T2D, OCT1 gene variants rs628031 and rs622342 were associated with metformin clearance and gluconeogenesis, respectively. TCF7L2 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. What is already known about this subject?: 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 unclearY-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. Genetic variants in the OCT1 ( SLC22A1 ) 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 What is the key question?: Among AA Y-T2D, how do genetic variants associated with adult-onset T2D affect metformin pharmacokinetic profiles and glycemic response?What are the new findings?: Metformin pharmacokinetics in AA Y-T2D were best described by a one-compartment first-order absorption and elimination model The OCT1 variant rs628031 A allele was associated with &#x223c;40% greater metformin clearance The OCT1 variant rs622342 C allele was associated with &#x223c;8% lower rates of fractional gluconeogenesis after treatment How might this impact on clinical practice in the foreseeable future?: Identifying OCT1 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.