Chapter 7 160 causing increased cellular glucose utilization. In Chapter 2, we additionally studied the association of NMR-measured plasma ionized magnesium with the risk of developing T2D in a large population-based cohort study free of T2D at baseline (n=5747). Here, we observed that lower plasma ionized magnesium was associated with a higher risk of developing T2D in women (HR: 1.80 per 0.1 mmol/L decrease in plasma magnesium; 95% CI: 1.20–2.70 mmol/L), independent of T2D risk factors, including C-reactive protein. This association was, however, not observed in men. Our study is the first to report an interaction by sex for the association between plasma magnesium and incident T2D. While the underlying mechanism remains to be determined, we hypothesize that sex steroids, such as estrogens, may play a role. In fact, several studies have shown that estrogen substitution therapy in postmenopausal women reduces urinary magnesium excretion 16, and that estrogen increases renal expression of transient receptor potential melastatin 6 (TRPM6) 17. In line with previous observational studies 18,19, our study demonstrates a potential role of magnesium in the development of T2D. These findings, including the female-specific association should be further investigated preferable in large RCTs focusing on magnesium intake and risk of T2D. Magnesium in erythrocytes Magnesium is, after potassium, the second most abundant intracellular cation in the human body. Magnesium regulates many cellular functions, including ion channels, metabolic cycles and signaling pathways 20. Numerous methods for the assessment of cellular magnesium concentrations have been evaluated, including the assessment of magnesium in leukocytes. An alternative method to assess cellular magnesium concentrations is the assessment of magnesium in erythrocytes. This can be done with direct and indirect methods. For direct methods, erythrocytes must be isolated from whole blood, and magnesium concentrations are subsequently measured in the isolated erythrocytes. Indirect methods calculate intra-erythrocyte magnesium concentrations based on whole blood and plasma magnesium concentrations, while accounting for hematocrit. Although direct methods to assess intra-erythrocyte magnesium have been suggested to be more accurate, these methods are labor-intensive and costly, mainly because of extensive sample preparation. An indirect method to obtain intraerythrocyte magnesium concentrations was previously evaluated in a small sample 21. In Chapter 3, we aimed to validate the previously proposed indirect method to obtain intra-erythrocyte magnesium concentrations using a large population-based cohort study. For calculation of the intra-erythrocyte magnesium concentrations, we used the following formula:
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