The population-specific Thr44Met OCT3 coding variant affects metformin pharmacokinetics with subsequent effects on insulin sensitivity in C57Bl/6J mice
Abstract
AIMS/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…
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