Mario Barbagallo

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.

Hypertension, diabetes mellitus, and insulin resistance : The role of intracellular magnesium

Magnesium is one of the most abundant ions present in living cells and its plasma concentration is remarkably constant in healthy subjects. Plasma and intracellular magnesium concentrations are tightly regulated by several factors. Among them, insulin seems to be one of the most important. In fact, in vitro and in vivo studies have demonstrated that insulin may modulate the shift of magnesium from extracellular to intracellular space. Intracellular magnesium concentration has also been shown to be effective on modulating insulin action (mainly oxidative glucose metabolism), offset calcium-related excitation-contraction coupling, and decrease smooth cell responsiveness to depolarizing stimuli, by stimulating Ca2+-dependent K+ channels. A poor intracellular magnesium concentration, as found in non-insulin-dependent diabetes mellitus (NIDDM) and in hypertensive (HP) 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 non-insulin-dependent diabetic and hypertensive patients. By contrast, in NIDDM patients daily magnesium administration, restoring a more appropriate intracellular magnesium concentration, contributes to improve insulin-mediated glucose uptake. Similarly, in HP patients magnesium administration may be useful in decreasing arterial blood pressure and improving insulin-mediated glucose uptake. The benefits deriving from daily magnesium supplementation in NIDDM and HP patients are further supported by epidemiological studies showing that high daily magnesium intake to be predictive of a lower incidence of NIDDM and HP. In conclusion, a growing body of studies suggest that intracellular magnesium may play a key role on modulating insulin-mediated glucose uptake and vascular tone. We further suggest that a reduced intracellular magnesium concentration might be the missing link helping to explain the epidemiological association between NIDDM and hypertension.

Sex hormones and hemostatic risk factors for coronary heart disease in men with hypertension.

Objective and design: It has been hypothesized that risk factors for coronary heart disease in men are linked and that the underlying factor linking them may be an alteration in the sex hormone milieu. As a test of this hypothesis, sex hormones and fibrinogen, factor VII and plasminogen activator inhibitor (PAI-1), hemostatic factors recently shown to be risk factors for myocardial infarction, were measured in men with hypertension and in healthy control subjects. Results: The fasting serum testosterone and free testosterone levels were decreased and the plasma factor VII and PAI-1 levels increased in the men with hypertension. Conclusion: These findings are consistent with the stated hypothesis.

Effects of Vitamin E and Glutathione on Glucose Metabolism: Role of Magnesium

Vitamin E is an antioxidant that has been demonstrated to improve insulin action. Glutathione, another natural antioxidant, may also be important in blood pressure and glucose homeostasis, consistent with the involvement of free radicals in both essential hypertension and diabetes mellitus. Our group has recently suggested that the effects of reduced glutathione on glucose metabolism may be mediated, at least in part, by intracellular magnesium levels (Mg([i])). Recent evidence suggests that vitamin E enhances glutathione levels and may play a protective role in magnesium deficiency-induced cardiac lesions. To directly investigate the effects of vitamin E supplementation on insulin sensitivity in hypertension, in relation to the effects on circulating levels of reduced (GSH) and oxidized (GSSG) glutathione and on Mg([i]), we performed a 4-week, double-blind, randomized study of vitamin E administration (600 mg/d) versus placebo in 24 hypertensive patients and measured whole-body glucose disposal (WBGD) by euglycemic glucose clamp, GSH/GSSG ratios, and Mg([i]) before and after intervention. The relationships among WBGD, GSH/GSSG, and Mg([i]) in both groups were evaluated. In hypertensive subjects, vitamin E administration significantly increased WBGD (25.56+/-0.61 to 31.75+/-0.53 micromol/kg of fat-free mass per minute; P<0.01), GSH/GSSG ratio (1.10+/-0.07 to 1.65+/-0.11; P<0.01), and Mg([i]) (1.71+/-0.042 to 1.99+/-0.049 mmol/L; P<0.01). In basal conditions, WBGD was significantly related to both GSH/GSSG ratios (r=0.58, P=0.047) and Mg([i]) (r=0.78, P=0.003). These data show a clinical link between vitamin E administration, cellular magnesium, GSH/GSSG ratio, and tissue glucose metabolism. Further studies are needed to explore the cellular mechanism(s) of this association.

Magnesium homeostasis and aging

Aging is very often associated with magnesium (Mg) deficit. Total plasma magnesium concentrations are remarkably constant in healthy subjects throughout life, while total body Mg and Mg in the intracellular compartment tend to decrease with age. Dietary Mg deficiencies are common in the elderly population. Other frequent causes of Mg deficits in the elderly include reduced Mg intestinal absorption, reduced Mg bone stores, and excess urinary loss. Secondary Mg deficit in aging may result from different conditions and diseases often observed in the elderly (i.e. insulin resistance and/or type 2 diabetes mellitus) and drugs (i.e. use of hypermagnesuric diuretics). Chronic Mg deficits have been linked to an increased risk of numerous preclinical and clinical outcomes, mostly observed in the elderly population, including hypertension, stroke, atherosclerosis, ischemic heart disease, cardiac arrhythmias, glucose intolerance, insulin resistance, type 2 diabetes mellitus, endothelial dysfunction, vascular remodeling, alterations in lipid metabolism, platelet aggregation/thrombosis, inflammation, oxidative stress, cardiovascular mortality, asthma, chronic fatigue, as well as depression and other neuropsychiatric disorders. Both aging and Mg deficiency have been associated to excessive production of oxygen-derived free radicals and low-grade inflammation. Chronic inflammation and oxidative stress are also present in several age-related diseases, such as many vascular and metabolic conditions, as well as frailty, muscle loss and sarcopenia, and altered immune responses, among others. Mg deficit associated to aging may be at least one of the pathophysiological links that may help to explain the interactions between inflammation and oxidative stress with the aging process and many age-related diseases.

Type 2 diabetes mellitus and Alzheimer's disease.

Epidemiological and biological evidences support a link between type 2 diabetes mellitus (DM2) and Alzheimers disease (AD). Persons with diabetes have a higher incidence of cognitive decline and an increased risk of developing all types of dementia. Cognitive deficits in persons with diabetes mainly affect the areas of psychomotor efficiency, attention, learning and memory, mental flexibility and speed, and executive function. The strong epidemiological association has suggested the existence of a physiopathological link. The determinants of the accelerated cognitive decline in DM2, however, are less clear. Increased cortical and subcortical atrophy have been evidenced after controlling for diabetic vascular disease and inadequate cerebral circulation. Most recent studies have focused on the role of insulin and insulin resistance as possible links between diabetes and AD. Disturbances in brain insulin signaling mechanisms may contribute to the molecular, biochemical, and histopathological lesions in AD. Hyperglycemia itself is a risk factor for cognitive dysfunction and dementia. Hypoglycemia may also have deleterious effects on cognitive function. Recurrent symptomatic and asymptomatic hypoglycemic episodes have been suggested to cause sub-clinical brain damage, and permanent cognitive impairment. Future trials are required to clarify the mechanistic link, to address the question whether cognitive decline may be prevented by an adequate metabolic control, and to elucidate the role of drugs that may cause hypoglycemic episodes.

Vascular Effects of Progesterone: Role of Cellular Calcium Regulation

Vascular actions of progesterone have been reported, independently of estrogen, affecting both blood pressure and other aspects of the cardiovascular system. To study possible mechanisms underlying these effects, we examined the effects of P in vivo in intact rats and in vitro in isolated artery and vascular smooth muscle cell preparations. In anesthetized Sprague-Dawley rats , bolus intravenous injections of P (100 &mgr;g/kg) significantly decreased pressor responses to norepinephrine (0.3 &mgr;g/kg). In vitro, progesterone (10−8 to 10−5 mmol/L) produced a significant, dose-dependent relaxation of isolated helical strips, both of rat tail artery precontracted with KCl (60 mmol/L) or arginine vasopressin (3 nmol/L), and of rat aorta precontracted with KCl (60 mmol/L) or norepinephrine (0.1 &mgr;mol/L). In isolated vascular smooth muscle cells, progesterone (5×10−7 mol/L) reversibly inhibited KCl (30 mmol/L) -induced elevation of cytosolic-free calcium by 64.1±5.5% (P <0.05), and in whole-cell patch-clamp experiments, progesterone (5×10−6 mol/L) reversibly and significantly blunted L-type calcium channel inward current, decreasing peak inward current to 65.7±4.3% of the control value (P <0.05). Our results provide evidence that progesterone is a vasoactive hormone, inhibiting agonist-induced vasoconstriction. The data further suggest that progesterone effects on vascular tissue may, at least in part, be mediated by modulation of the L-type calcium channel current activity and, consequently, of cytosolic-free calcium content.

Magnesium and muscle performance in older persons: the InCHIANTI study

BACKGROUND The role of magnesium in maintaining muscle integrity and function in older adults is largely unknown. OBJECTIVE We aimed to investigate the relation between serum magnesium concentrations and muscle performance in older subjects. DESIGN Data are from the baseline examination conducted between September 1998 and March 2000 of the InCHIANTI (aging in the Chianti area) study, a prospective epidemiologic survey of risk factors for late-life disability. From among 1453 randomly selected community residents completing a home interview, 1138 men (46%) and women (aged 66.7 +/- 15.2 y; x +/- SD) with complete data on muscle performance and serum magnesium who were not severely cognitively compromised and had no evidence of kidney disease or hypercalcemia were included in the analysis. Muscle performance was evaluated by grip strength, lower-leg muscle power, knee extension torque, and ankle extension isometric strength and was normalized for age and body mass index (BMI) within each sex. RESULTS After adjustment for age, sex, BMI, laboratory variables, presence of chronic diseases, muscle area, muscle density, and physical activity level, serum magnesium concentrations were significantly associated with indexes of muscle performance, including grip strength (beta = 2.0 +/- 0.5, P = 0.0002), lower-leg muscle power (beta = 8.8 +/- 2.7, P = 0.001), knee extension torque (beta = 31.2 +/- 7.9, P < 0.0001), and ankle extension strength (beta = 3.8 +/- 0.5, P < 0.0001). CONCLUSIONS The serum magnesium concentration is an independent correlate of muscle performance in older persons. Whether magnesium supplementation improves muscle function remains to be shown.

Curcumin, inflammation, ageing and age-related diseases

A Symposium regarding the Pathophysiology of Successful and Unsuccessful Ageing was held in Palermo, Italy between April 7 and 8th 2009. Here the lecture by Sikora with some input from the chairpersons Scapagnini and Barbagallo is summarized. Ageing is manifested by the decreasing health status and increasing probability to acquire age-related disease such as cancer, Alzheimers disease, atherosclerosis, metabolic disorders and others. They are likely caused by low grade inflammation driven by oxygen stress and manifested by the increased level of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α, encoded by genes activated by the transcription factor NF-κB. It is believed that ageing is plastic and can be slowed down by caloric restriction as well as by some nutraceuticals. Accordingly, slowing down ageing and postponing the onset of age-related diseases might be achieved by blocking the NF-κB-dependent inflammation. In this review we consider the possibility of the spice curcumin, a powerful antioxidant and anti-inflammatory agent possibly capable of improving the health status of the elderly.

Extra virgin olive oil improves learning and memory in SAMP8 mice.

Polyphenols are potent antioxidants found in extra virgin olive oil (EVOO); antioxidants have been shown to reverse age- and disease-related learning and memory deficits. We examined the effects of EVOO on learning and memory in SAMP8 mice, an age-related learning/memory impairment model associated with increased amyloid-β protein and brain oxidative damage. We administered EVOO, coconut oil, or butter to 11 month old SAMP8 mice for 6 weeks. Mice were tested in T-maze foot shock avoidance and one-trial novel object recognition with a 24 h delay. Mice which received EVOO had improved acquisition in the T-maze and spent more time with the novel object in one-trial novel object recognition versus mice which received coconut oil or butter. Mice that received EVOO had improve T-maze retention compared to the mice that received butter. EVOO increased brain glutathione levels suggesting reduced oxidative stress as a possible mechanism. These effects plus increased glutathione reductase activity, superoxide dismutase activity, and decreased tissue levels of 4-hydroxynoneal and 3-nitrotyrosine were enhanced with enriched EVOO (3 × and 5 × polyphenols concentration). Our findings suggest that EVOO has beneficial effects on learning and memory deficits found in aging and diseases, such as those related to the overproduction of amyloid-β protein, by reversing oxidative damage in the brain, effects that are augmented with increasing concentrations of polyphenols in EVOO.