Wang, QianLeask, Megan PLee, KateJaiswal, JagdishKallingappa, PrasannaDissanayake, WaruniPuli’uvea, ChrisO’Sullivan, ConorWatson, HutiWilcox, PhillipMurphy, RinkiMerry, Troy LShepherd, Peter R2025-04-152025-04-152024-10-18Diabetologia, ISSN: 0012-186X (Print); 1432-0428 (Online), Springer Science and Business Media LLC, 68(3), 537-548. doi: 10.1007/s00125-024-06287-10012-186X1432-0428http://hdl.handle.net/10292/19071Aims/hypothesis: Metformin is an important first-line treatment for type 2 diabetes and acts by increasing the body’s ability to dispose of glucose. Metformin’s efficacy can be affected by genetic variants in the transporters that regulate its uptake into cells. The SLC22A3 gene (also known as EMT; EMTH; OCT3) codes for organic cation transporter 3 (OCT3), which is a broad-specificity cation transporter that also transports metformin. Most SLC22A3 variants reduce the rate of metformin transport but the rs8187715 variant (p.Thr44Met) is reported to increase uptake of metformin in vitro. However, the impact of this on in vivo metformin transport and efficacy is unknown. Very few carriers of this variant have been reported globally, but, notably, all were of Pacific Island descent. Therefore, this study aims to understand the prevalence of this variant in Polynesian peoples (Māori and Pacific peoples) and to understand its impact on metformin transport and efficacy in vivo. Methods: rs8187715 was genotyped in 310 individuals with Māori and Pacific ancestry recruited in Aotearoa New Zealand. To study this variant in a physiological context, an orthologous knockin mouse model with C57BL/6J background was used. Pharmacokinetic analysis compared uptake rate of metformin into tissues. Plasma growth/differentiation factor 15 (GDF-15) was also measured as a marker of metformin efficacy. Glucose and insulin tolerance was assessed after acute or sustained metformin treatment in knockin and wild-type control mice to examine the impact of the variant on metformin’s glycaemic control. Results: The minor allele frequency of this variant in the Māori and Pacific participants was 15.4%. There was no association of the variant with common metabolic parameters including diabetes status, BMI, blood pressure, lipids, or blood glucose and HbA1c. However, in the orthologous knockin mouse model, the rate of metformin uptake into the blood and tissues was increased. Acute metformin dosing increased insulin sensitivity in variant knockin mice but this effect was lost after longer-term metformin treatment. Metformin’s effects on GDF-15 levels were also lost in variant knockin mice with longer-term metformin treatment. Conclusions/interpretation: These data provide evidence that the SLC22A3 rs8187715 variant accelerates metformin uptake rate in vivo. While this acutely improves insulin sensitivity, there was no increased effect of metformin with longer-term dosing. Thus, our finding of a high prevalence of this variant specifically in Māori and Pacific peoples identifies it as a potential population-specific pharmacogenetic marker with potential to guide metformin therapy in these peoples.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/SLC22A3DiabetesGDF-15Insulin sensitivityMetforminPharmacogeneticsPrecision medicine32 Biomedical and Clinical Sciences3202 Clinical SciencesDiabetesGenetics2.1 Biological and endogenous factorsMetabolic and endocrine1103 Clinical Sciences1114 Paediatrics and Reproductive Medicine1117 Public Health and Health ServicesEndocrinology & Metabolism3202 Clinical sciences4206 Public healthMetforminAnimalsMiceMice, Inbred C57BLInsulin ResistanceHumansHypoglycemic AgentsMaleOrganic Cation Transport ProteinsFemaleDiabetes Mellitus, Type 2GenotypeMiddle AgedBlood GlucoseAnimalsMice, Inbred C57BLHumansMiceDiabetes Mellitus, Type 2Insulin ResistanceMetforminBlood GlucoseOrganic Cation Transport ProteinsHypoglycemic AgentsGenotypeMiddle AgedFemaleMaleMetforminAnimalsMiceMice, Inbred C57BLInsulin ResistanceHumansHypoglycemic AgentsMaleOrganic Cation Transport ProteinsFemaleDiabetes Mellitus, Type 2GenotypeMiddle AgedBlood GlucoseJournal ArticleOpenAccess10.1007/s00125-024-06287-1