OCT1 Variants Are Associated with Metformin Clearance and Gluconeogenesis: Mechanistic Insights for Youth-Onset Type 2 Diabetes in the MIGHTY Study
Abstract
ABSTRACT:
Aims/Hypothesis: 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.
Methods: 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.
Results: 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 (β [95% CI] = -8.8 [-14.13, -3.47] %, Adjusted R 2 = 0.56, P = 0.003). The…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 11 participants or records.
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