Increased NEFA levels reduce blood Mg2+ in hypertriacylglycerolaemic states via direct binding of NEFA to Mg2+

Abstract

Aims/hypothesisThe blood triacylglycerol level is one of the main determinants of blood Mg2+ concentration in individuals with type 2 diabetes. Hypomagnesaemia (blood Mg2+ 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 Mg2+ concentrations.MethodsUsing samples from 285 overweight individuals (BMI >27 kg/m2) 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 Mg2+ 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 Mg2+, triacylglycerol and NEFA concentrations were measured using colourimetric assays. In vitro, NEFAs harvested from albumin were added in increasing concentrations to several Mg2+-containing solutions to study the direct interaction between Mg2+ and NEFAs.ResultsIn the cohort of overweight individuals, serum Mg2+ 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 Mg2+ concentration both in mice (Δ plasma Mg2+ −0.31 mmol/l at 4 h post oral gavage) and in healthy humans (Δ plasma Mg2+ −0.07 mmol/l at 6 h post lipid intake). Further, in vitro experiments revealed that the decrease in plasma Mg2+ may be explained by direct binding of Mg2+ to NEFAs. Moreover, Mg2+ was found to bind to albumin in a NEFA-dependent manner, evidenced by the fact that Mg2+ did not bind to fatty-acid-free albumin. The NEFA-dependent reduction in the free Mg2+ concentration was not affected by the presence of physiological concentrations of other cations.Conclusions/interpretationThis study shows that elevated NEFA and triacylglycerol levels directly reduce blood Mg2+ levels, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. We show that blood NEFA level affects the free Mg2+ concentration, and therefore, our data challenge how the fractional excretion of Mg2+ is calculated and interpreted in the clinic.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4771-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Low extracellular magnesium does not impair glucose-stimulated insulin secretion

“…Given the conflicting literature and our data showing that acute changes in extracellular Mg 2+ do not inhibit insulin secretion in both pancreatic islets and INS-1 cells, we postulate that hypomagnesemia does not exert its effect primarily on insulin secretion. Based on recent large studies in animals and patients, other factors such as lipid metabolism may be more important in determining the interaction between hypomagnesemia and progression of type 2 diabetes [4, 25, 26].…”

Evaluation of serum free fatty acids in chronic renal failure: evidence from a rare case with undetectable serum free fatty acids and population data

“…In terms of serum electrolytes, we only found that Cl − was inversely correlated with FFAs. Interestingly, a recent study has proved that elevated FFAs and triacylglycerol levels directly reduced blood Mg 2+ levels in metabolic disorders [27].…”

Association of hemoglobin A1C with circulating metabolites in Dutch with European, African Surinamese and Ghanaian background

“…The study population was composed of three ethnic groups in the Dutch population. In particular, 217 African Surinamese and 255 Ghanaian were from the HELIUS (HEalthy Life In an Urban Setting) study 34,35 , and 301 European Dutch were from the 300-Obesity cohort 36 from the Human Functional Genomics Project 37 .…”