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Diabetologia. 2018 Nov 13. doi: 10.1007/s00125-018-4771-3. [Epub ahead of print]

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

Author information

1
Department of Physiology (286), Radboud Institute for Molecular Life Sciences, Radboud university medical center, P. O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
2
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
3
Department of Internal Medicine, Radboud university medical center, Nijmegen, the Netherlands.
4
Department of Internal Medicine, Center for Diabetes and Vascular Medicine, Franciscus Gasthuis Rotterdam, Rotterdam, the Netherlands.
5
Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
6
Department of Physiology (286), Radboud Institute for Molecular Life Sciences, Radboud university medical center, P. O. Box 9101, 6500 HB, Nijmegen, the Netherlands. joost.hoenderop@radboudumc.nl.

Abstract

AIMS/HYPOTHESIS:

The 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.

METHODS:

Using 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.

RESULTS:

In 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/INTERPRETATION:

This 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.

KEYWORDS:

Albumin; Hypertriacylglycerolaemia; Hypomagnesaemia; Magnesium; Magnesium deficiency; Non-esterified fatty acid; Obesity; Triacylglycerols

PMID:
30426168
DOI:
10.1007/s00125-018-4771-3

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