The population-specific Thr44Met OCT3 coding variant affects metformin pharmacokinetics with subsequent effects on insulin sensitivity in C57Bl/6J mice – published online 18/10/2024

Qian Wang, Megan P. Leask, Kate Lee, Jagdish Jaiswal, Prasanna Kallingappa, Waruni Dissanayake, Chris Puli’uvea, Conor O’Sullivan, Huti Watson, Phillip Wilcox, Rinki Murphy, Troy L. Merry, Peter R. Shepherd

Precision medicine approaches using genetic markers have been biased towards populations where the most genomic studies have been undertaken. Therefore, results may not be fully translatable to genetically diverse ethnic populations. In this issue, Wang et al (https://doi.org/10.1007/s00125-024-06287-1) find that the SLC22A3 rs8187715 variant (p. Thr44Met) is essentially unique to Māori and Pacific peoples of Polynesia: it exhibits a relatively high minor allele frequency (MAF=15.4%). SLC22A3 encodes the organic cation transporter 3 (OCT3) monoamine transporter, which transports many drugs, including metformin. Using an orthologous knock-in mouse model, the authors demonstrated that this variant increases metformin uptake into tissues and enhances insulin sensitivity acutely. However, with longer term treatment the efficacy of metformin in lowering blood glucose and weight loss was lost. The authors conclude that these findings suggest this variant could be used as a population-specific pharmacogenetic marker to guide metformin use in people of Māori and Pacific ancestry.