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Metformin Regulates TRPM6, a Potential Explanation for Magnesium Imbalance in Type 2 Diabetes Patients

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Metformin Regulates TRPM6, a Potential Explanation for Magnesium Imbalance in Type 2 Diabetes Patients

Hacene Bouras et al. Can J Physiol Pharmacol.

Abstract

Metformin therapy is associated with lower serum magnesium (Mg2+) levels in type 2 diabetes (T2D) patients. The TRPM6 channel determines the fine-tuning of Mg2+ (re)absorption in intestine and kidney. Therefore, we aimed to investigate the short- and long-term effects of metformin on TRPM6. Patch clamp recordings and biotinylation assays were performed upon 1h of incubation with metformin in TRPM6-transfected HEK293 cells. Additionally, 24h treatment of mDCT15 kidney and hCaco-2 colon cells with metformin was applied to measure the effects on endogenous TRPM6 expression by RT-qPCR. To assess Mg2+ absorption, 25Mg2+ uptake measurements were performed using ICP-MS. Short-term effects of metformin significantly increased TRPM6 activity and its cell surface trafficking. In contrast, long-term effects significantly decreased TRPM6 mRNA expression and 25Mg2+ uptake. Metformin lowered TRPM6 mRNA levels independently of insulin- and AMPK-mediated pathways. Moreover, in T2D patients, metformin therapy was associated with lower plasma Mg2+ concentrations and fractional excretion of Mg2+. Thereby, short-term metformin treatment increases TRPM6 activity explained by enhanced cell surface expression. Conversely, long-term metformin treatment results in downregulation of TRPM6 gene expression in intestine and kidney cells. This long-term effect translated in an inverse correlation between metformin and plasma Mg2+ concentration in T2D patients.

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