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- Title
Metformin regulates TRPM6, a potential explanation for magnesium imbalance in type 2 diabetes patients.
- Authors
Bouras, Hacene; Roig, Sara R.; Kurstjens, Steef; Tack, Cees J.J.; Kebieche, Mohamed; de Baaij, Jeroen H.F.; Hoenderop, Joost G.J.
- Abstract
Metformin therapy is associated with lower serum magnesium (Mg2+) levels in type 2 diabetes 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 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 TRPM6 expression by quantitative real-time PCR. To assess Mg2+ absorption, 25Mg2+ 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 TRPM6 mRNA expression and 25Mg2+ uptake. Metformin lowered TRPM6 mRNA levels independently of insulin- and AMPK-mediated pathways. Moreover, in type 2 diabetes 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 type 2 diabetes patients.
- Subjects
HYPOMAGNESEMIA; MAGNESIUM ions; INDUCTIVELY coupled plasma mass spectrometry; TYPE 2 diabetes; PEOPLE with diabetes; METFORMIN
- Publication
Canadian Journal of Physiology & Pharmacology, 2020, Vol 98, Issue 6, p400
- ISSN
0008-4212
- Publication type
Article
- DOI
10.1139/cjpp-2019-0570