Increased NEFA levels reduce blood Mg(2+) in hypertriacylglycerolaemic states via direct binding of NEFA to Mg(2+)

AIMS/HYPOTHESIS: The blood triacylglycerol level is one of the main determinants of blood Mg(2+) concentration in individuals with type 2 diabetes. Hypomagnesaemia (blood Mg(2+) concentration <0.7 mmol/l) has serious consequences as it increases the risk of developing type 2 diabetes and accelerates progression of the disease. This study aimed to determine the mechanism by which triacylglycerol levels affect blood Mg(2+) concentrations. METHODS: Using samples from 285 overweight individuals (BMI >27 kg/m(2)) who participated in the 300-Obesity study (an observational cross-sectional cohort study, as part of the Human Functional Genetics Projects), we investigated the association between serum Mg(2+) with laboratory variables, including an extensive lipid profile. In a separate set of studies, hyperlipidaemia was induced in mice and in healthy humans via an oral lipid load, and blood Mg(2+), triacylglycerol and NEFA concentrations were measured using colourimetric assays. In vitro, NEFAs harvested from albumin were added in increasing concentrations to several Mg(2+)-containing solutions to study the direct interaction between Mg(2+) and NEFAs. RESULTS: In the cohort of overweight individuals, serum Mg(2+) levels were inversely correlated with triacylglycerols incorporated in large VLDL particles (r = −0.159, p ≤ 0.01). After lipid loading, we observed a postprandial increase in plasma triacylglycerol and NEFA levels and a reciprocal reduction in blood Mg(2+) concentration both in mice (Δ plasma Mg(2+) −0.31 mmol/l at 4 h post oral gavage) and in healthy humans (Δ plasma Mg(2+) −0.07 mmol/l at 6 h post lipid intake). Further, in vitro experiments revealed that the decrease in plasma Mg(2+) may be explained by direct binding of Mg(2+) to NEFAs. Moreover, Mg(2+) was found to bind to albumin in a NEFA-dependent manner, evidenced by the fact that Mg(2+) did not bind to fatty-acid-free albumin. The NEFA-dependent reduction in the free Mg(2+) concentration was not affected by the presence of physiological concentrations of other cations. CONCLUSIONS/INTERPRETATION: This study shows that elevated NEFA and triacylglycerol levels directly reduce blood Mg(2+) levels, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. We show that blood NEFA level affects the free Mg(2+) concentration, and therefore, our data challenge how the fractional excretion of Mg(2+) is calculated and interpreted in the clinic. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00125-018-4771-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.