Antonio Galioto

Role of magnesium in insulin action, diabetes and cardio-metabolic syndrome X

Magnesium (Mg) is one of the most abundant ions present in living cells and its plasma concentration is remarkably constant in healthy subjects. Plasma and intracellular Mg concentrations are tightly regulated by several factors. Among them, insulin seems to be one of the most important. In vitro and in vivo studies have demonstrated that insulin may modulate the shift of Mg from extracellular to intracellular space. Intracellular Mg concentration has also been shown to be effective in modulating insulin action (mainly oxidative glucose metabolism), offset calcium-related excitation-contraction coupling, and decrease smooth cell responsiveness to depolarizing stimuli. A poor intracellular Mg concentration, as found in noninsulin-dependent diabetes mellitus (NIDDM) and in hypertensive patients, may result in a defective tyrosine-kinase activity at the insulin receptor level and exaggerated intracellular calcium concentration. Both events are responsible for the impairment in insulin action and a worsening of insulin resistance in noninsulin-dependent diabetic and hypertensive patients. By contrast, in NIDDM patients daily Mg administration, restoring a more appropriate intracellular Mg concentration, contributes to improve insulin-mediated glucose uptake. The benefits deriving- from daily Mg supplementation in NIDDM patients are further supported by epidemiological studies showing that high daily Mg intake are predictive of a lower incidence of NIDDM. In conclusion, a growing body of studies suggest that intracellular Mg may play a key role in modulating insulin-mediated glucose uptake and vascular tone. We further suggest that a reduced intracellular Mg concentration might be the missing link helping to explain the epidemiological association between NIDDM and hypertension.

Oral magnesium supplementation improves vascular function in elderly diabetic patients.

Magnesium (Mg) ions directly influence vascular tone and responsiveness and are cofactors for acetylcholine-induced endothelium-dependent relaxation. Alterations in extracellular Mg are able to modify the formation and release of nitric oxide (NO), altering arterial smooth muscle tone. Previous in vivo studies in humans have shown that parenteral or oral Mg supplementation increase endothelial-dependent vasodilation. The aim of the present study was to evaluate the effects of Mg oral supplementation on endothelial function in elderly diabetic and hypertensive subjects. Sixty elderly (≥ 65 years) diabetic patients were recruited (mean age: 71.1 ± 6.1 years; M/F: 35/25). Endothelial function, evaluated by non-invasive flow-mediated dilatation of the brachial artery, as well as anthropometric and laboratory data, including ionized Mg (Mg-ion), were measured in all patients before and after one-month. Thirty patients underwent oral Mg supplementation with 4.5 g/day of Mg pidolate (368 mg/day of Mg ion), while the rest were used as a control group. The usual management of diabetes and hypertension was not changed during the month of study participation for all the patients. In the group of patients that underwent Mg supplementation, Mg-ion concentration significantly increased from 0.42 ± 0.05 mmol/L to 0.49 ± 0.06 mmol/L; p < 0.05. Mg intervention resulted in a significant improvement of the post-ischemic endothelial-dependent flow-mediated dilation (from 3.3 ± 3.6% to 8.4 ± 3.9%; p < 0.05). No significant differences were found, either in ion-Mg or endothelial function, in the control group. In conclusion, the present study suggests that oral Mg improves endothelial function in diabetic elderly subjects.

Age, homocysteine, and oxidative stress: relation to hypertension and type 2 diabetes mellitus.

Objectives: Hyperhomocysteinemia and oxidative stress are independent risk factors for cardiovascular events, which occur more frequently in old age. We evaluated these parameters in relation to age and the presence of hypertension and type 2 diabetes mellitus. Methods: Two hundred eighty-two subjects (female/male: 142/140; 141 were >65 years and 141 were <65 years; mean age 73.9 ± 6.6 years and 52.5 ± 8.2 years, respectively) were randomly recruited from those attending our institution. Blood pressure, anthropometric parameters, oxidative stress parameters (reactive oxygen species [ROS] and malondialdehyde [MDA]), and homocysteine levels were evaluated in participants. Results: Homocysteine (2.9 ± 0.06 vs. 2.3 ± 0.03 µmol/L, p < 0.001) and oxidative stress (ROS: 10.8 ± 0.3 vs. 8.1 ± 0.3 mmol/L, p < 0.001; MDA: 1.62 ± 0.05 vs. 1.21 ± 0.05 nmol/mL, p < 0.001) were significantly higher in older vs. younger subjects without hypertension or diabetes. However, homocysteine and MDA were not significantly different in older vs. younger hypertensive subjects (homocysteine: 3.0 ± 0.03 vs. 2.9 ± 0.04 µmol/L, p  =  NS; MDA: 1.7 ± 0.07 vs. 1.4 ± 0.06 nmol/mL, p  =  NS) and in older vs. younger diabetic hypertensive subjects (homocysteine: 3.02 ± 0.05 vs. 2.9 ± 0.05 µmol/L, p  =  NS; ROS: 10.7 ± 0.7 vs. 9.7 ± 0.8 mmol/L, p  =  NS; MDA: 1.6 ± 0.10 vs. 1.5 ± 0.12 nmol/mL, p  =  NS). Conclusions: Aging is accompanied by elevated homocysteine and oxidative stress levels similar to those observed in younger subjects with hypertension or diabetes mellitus, independent of age. Hence, these conditions appear to accelerate the age-dependent increase in homocysteine and oxidative stress.

MAGNESIUM METABOLISM IN INSULIN RESISTANCE, METABOLIC SYNDROME, AND TYPE 2 DIABETES MELLITUS

Magnesium plays a key role in regulating insulin action, insulin-mediated glucose uptake, and vascular tone. Intracellular magnesium depletion may result in a defective tyrosine—kinase activity at the insulin receptor level, in a postreceptorial impairment in insulin action, and clinically in a worsening of insulin resistance. Intra- and extracellular alterations of magnesium metabolism have been identified in clinical states characterized by insulin resistance, such as metabolic syndrome, hypertension, altered glucose tolerance, type 2 diabetes, and aging. Several studies, from our and other’s groups, have confi rmed the clinical relevance of alterations of magnesium homeostasis in these conditions and have highlighted the importance of an accurate definition of the magnesium status. While measurements of total serum magnesium levels have been proven inadequate for this purpose because important magnesium depletions are required before total serum level decreases, two technologies, 31P nuclear magnetic resonance (31P-NMR) spectroscopy and magnesium-specifi c ion-selective electrodes, that, respectively, measure intracellular and extracellular free levels of magnesium, have a higher sensitivity in detecting magnesium deficits. A number of evidences have confirmed that magnesium supplementation is indicated in conditions associated with magnesium deficit, although well-designed therapeutic trials with oral magnesium supplements to study the beneficial effects in metabolic syndrome and in type 2 diabetes are needed.