Chapter 1 12 level is highly regulated. Although it poorly represents total body magnesium, many observational studies have focused on the plasma or serum total concentration and found weak to moderate associations with CVD and hypertension 25,26. The impact of magnesium deficiency, a state in which whole body magnesium content is low, may therefore be grossly underestimated 24. Magnesium and health outcomes Type 2 diabetes (T2D) The global prevalence of T2D is rapidly growing. In fact, it was estimated in 2019 that approximately 460 million (19.3%) adults aged 20-79 years suffered from T2D 27. Patients with T2D have a two-fold higher risk of CVD mortality 28. Since 1947, T2D has been linked to the incidence of hypomagnesaemia 29, which is defined as a plasma magnesium concentration below 0.70 mmol/L. Although T2D has been associated with low plasma magnesium concentrations, subjects with T2D do not necessarily consume less magnesium than subjects without T2D 30. Hyperglycemia, on the other hand, leads to increased urinary magnesium loss, which in turn can result in decreased plasma magnesium concentrations. Because of this, magnesium supplementation is sometimes recommended in T2D patients with magnesium deficiency 25,31. Although hypomagnesaemia may be a consequence of T2D, several studies have suggested that hypomagnesaemia might also be a risk factor for developing T2D 32,33, in which the mechanistic pathway may at least in part be mediated through insulin resistance. In this respect, these studies investigated the prospective association of total serum/ plasma magnesium with T2D. To date, prospective associations of ionized plasma magnesium, the biologically active fraction, with risk of developing T2D have been poorly documented. Blood pressure Hypertension is currently one of the strongest risk factors for CVD. Hypertension, defined as a systolic blood pressure of ≥ 140 mmHg and/or a diastolic blood pressure of ≥ 90 mmHg, is a global public health problem, being responsible for 12.8% of all deaths worldwide 34. Risk factors for hypertension include, among others, age, race, family history of hypertension, obesity, physical inactivity, smoking, excessive intake of sodium, as well as insufficient dietary intake of potassium and magnesium 35–37. Epidemiological studies reported dose-response associations between dietary magnesium intake and risk of hypertension 26. In a large prospective cohort study, Joosten et al. showed a
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