Metformin regulates TRPM6, a potential explanation for magnesium imbalance in type 2 diabetes patients.

Metformin therapy is associated with lower serum magnesium (Mg) levels in type 2 diabetes patients. The TRPM6 channel determines the fine-tuning of Mg (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 1 h of incubation with metformin in TRPM6-transfected HEK293 cells. Additionally, 24 h of treatment of mDCT15 kidney and hCaco-2 colon cells with metformin was applied to measure the effects on endogenous expression by quantitative real-time PCR. To assess Mg absorption, Mg uptake measurements were performed using inductively coupled plasma mass spectrometry. Short-term effects of metformin significantly increased TRPM6 activity and its cell surface trafficking. In contrast, long-term effects significantly decreased mRNA expression and Mg uptake. Metformin lowered mRNA levels independently of insulin- and AMPK-mediated pathways. Moreover, in type 2 diabetes patients, metformin therapy was associated with lower plasma Mg concentrations and fractional excretion of Mg. Thereby, short-term metformin treatment increases TRPM6 activity explained by enhanced cell surface expression. Conversely, long-term metformin treatment results in downregulation of gene expression in intestine and kidney cells. This long-term effect translated in an inverse correlation between metformin and plasma Mg concentration in type 2 diabetes patients.