Magnesium mediates insulin resistance, diabetes risk

Magnesium, insulin resistance and diabetesMagnesium is required for hundreds crucial functions, not least of which are its calming, parasympathetic nervous system supporting and anti-inflammatory effects. Patients in our practice are also informed that a good magnesium level is necessary for insulin receptor function, further evidence for which has just been published in the journal Diabetologia. The results of this study demonstrate a causal role for low magnesium in diabetes and prediabetes, especially through insulin receptor resistance.

Magnesium and diabetes

An association with diabetes has long been observed, but questions have remained regarding whether this is a cause or an effect. For this reason the authors investigated its role in prediabetes.

“Previous studies have found an association between serum magnesium and incident diabetes; however, this association may be due to reverse causation, whereby diabetes may induce urinary magnesium loss. In contrast, in prediabetes (defined as impaired fasting glucose), serum glucose levels are below the threshold for urinary magnesium wasting and, hence, unlikely to influence serum magnesium levels. Thus, to study the directionality of the association between serum magnesium levels and diabetes, we investigated its association with prediabetes. We also investigated whether magnesium-regulating genes influence diabetes risk through serum magnesium levels. Additionally, we quantified the effect of insulin resistance in the association between serum magnesium levels and diabetes risk.”

 Prediabetes and insulin resistance

They examined data from 8555 subjects for an association with prediabetes/diabetes, and further sought to determine if genes influence diabetes risk through serum magnesium levels. They also aimed to determine how much of the effect is mediated through insulin resistance  by HOMA-IR). Their data show a robust role in regulating insulin receptor function and effect on diabetes risk.

A 0.1 mmol/l decrease in serum magnesium level was associated with an increase in diabetes risk (HR 1.18 [95% CI 1.04, 1.33]), confirming findings from previous studies. Of interest, a similar association was found between serum magnesium levels and prediabetes risk (HR 1.12 [95% CI 1.01, 1.25]). Genetic variation…significantly influenced diabetes risk and for CNNM2, FXYD2, SLC41A2 and TRPM6 this risk was completely mediated by serum magnesium levels.”

Condensing these results they state:

“In this large population-based cohort, we found that over a median follow-up of almost 6 years, low serum magnesium levels are associated with an increased risk of prediabetes, with comparable risk estimates to that of diabetes. Furthermore, we found that common genetic variants in magnesium-regulating genes influence diabetes risk and that this risk is mediated through serum magnesium levels.”

In the clinic

Practitioners are aware of two well-known facts: serum magnesium is a poor, insensitive biomarker for sufficiency; and clinical insufficiency is extremely common. (Even RBC membrane levels are not as dependable as the EXA test—see under ‘Useful Links’.) Thus when serum magnesium is suboptimal it should be diligently attended to by the clinician.

The authors conclude:

“…we found that low serum magnesium levels are associated with an increased risk of prediabetes, with similar effect estimates as compared with diabetes. The effect of serum magnesium on prediabetes and diabetes risk is partly mediated through insulin resistance. Furthermore, common genetic variation in magnesium regulating genes TRPM6, CLDN19, SLC41A2, CNNM2 and FXYD2 significantly modify the risk of diabetes through serum magnesium levels. Both findings support a potential causal role of magnesium in the development of diabetes...”

Calcium supplementation may increase risk for dementia

NeurologyCalcium supplementation continues to come under scrutiny as evidence accumulates that it can increase the risk of inflammatory disorders, most notably cerebrovascular disease, likely by opposing the anti-inflammatory effects of magnesium. A study just published in the journal Neurology offers evidence that supplementation can increase the risk for dementia in women with cardiovascular disease. The authors set out to…

“…determine whether calcium supplementation is associated with the development of dementia in women after a 5-year follow-up.”

700 dementia-free women aged 70–92 years were examined at baseline and at follow-up 5 years later with comprehensive neuropsychiatric and physical examinations. 447 underwent CT scans at baseline. Dementia was diagnosed according to DSM-III-R criteria, and this was correlated with information on the use and dosage of calcium supplements.

Calcium supplementation dramatically increased the risk for dementia

Neurology 2The risk more was increased almost 7 times for the subset of women with a history of stroke, and tripled for those with white matter lesions, in comparison to similar subjects who did not supplement:

Women treated with calcium supplements (n = 98) were at a higher risk of developing dementia (odds ratio [OR] 2.10) and the subtype stroke-related dementia (vascular dementia and mixed dementia) (OR 4.40) than women not given supplementation (n = 602)….supplementation was associated with the development of dementia in groups with a history of stroke (OR 6.77) or presence of white matter lesions (OR 2.99), but not in groups without these conditions.”

Correspondence with previous studies

This was a relatively small study, but the findings correspond to earlier evidence that supplementation can increase the burden of systemic inflammation (some have been written about here). It opposes the absorption and action of magnesium, a likely mechanism accounting for these observations. Recall that osteoporosis is not a calcium deficiency disorder, rather a failure to maintain the protein matrix of bone to which the minerals attach. Though it was only subjects with a history of cerebrovascular disease or white matter lesions for whom the risk of dementia was markedly increased, clinicians should consider very carefully before recommending supplementation. The authors conclude:

Calcium supplementation may increase the risk of developing dementia in elderly women with cerebrovascular disease.”

Magnesium protects against preeclampsia seizures

Pregnancy HypertensionPreeclampsia includes among its afflictions a tendency for seizures. A study just published in the journal Pregnancy Hypertension demonstrates magnesium raises the threshold for seizures in preeclampsia by reducing neuroinflammation. The authors state:

“The mechanism by which MgSO4 [magnesium sulfate] provides seizure prophylaxis in women with preeclampsia (PE) remains unclear, and may be multifaceted. Here, we investigated the effect of MgSO4 on seizure threshold, blood-brain barrier (BBB) permeability and neuroinflammation in a rat model of PE.”

Neuroinflammation and BBB permeability are both increased in preeclampsia

They subjected their pregnant (P) and preeclampsia (PE) study animals to seizures by infusions of pentylenetetrazol (PTZ) and while recorrding EEGs and the amount of PTZ required to elicit a seizure compared to a subset treated with magnesium. They measured blood brain barrier (BBB) permeability by quantifying passage of infused sodium fluorescein (NaFl) into the brain. Microglial activation was their metric for neuroinflammation, done by immunostaining for ionized calcium binding adapter molecule. This revealed a specific benefit of magnesium in preeclampsia:

“Seizure threshold was lower in PE compared to P rats that was reversed by MgSO4. BBB permeability was increased in PE, with more NaFl passing into the brain compared to P rats that was unaffected by MgSO4. PE rats had neuroinflammation, characterized by activated microglia that was reversed by MgSO4.”

Magnesium reduces neuroinflammation

Magnesium increases seizure threshold by reducing activation of microglia in preeclampsia.

Magnesium increases seizure threshold by reducing activation of microglia in preeclampsia.

Among its many virtues, this preeclampsia model highlights the ability of magnesium to reduce neuroinflammation, calming the brain’s immune cells (microglia). Also relevant for preeclampsia is magnesium’s benefit for hypertension. Alert practitioners note that suboptimal levels of magnesium are ubiquitous. The authors conclude:

“PE was associated with lower seizure threshold, potentially due to increased BBB permeability and neuroinflammation. MgSO4 increased seizure threshold in PE rats through a quiescent effect on microglia without affecting BBB permeability.”

Magnesium prevents high blood pressure in pregnancy

Gynecology and ObstetricsHere we can appreciate a study demonstrating that magnesium supplementation also prevents hypertension in the last weeks of pregnancy that was published in Gynecology and Obstetrics. The authors conducted a randomized placebo controlled trial by giving 300 mg magnesium as citrate or placebo from pregnancy week 25 in a randomised double-blind setup to a cohort of pregnant primagravida women with a marked result:

In the magnesium-supplemented group, the average diastolic blood pressure at week 37 was significantly lower than in the placebo group. The number of women with an increase in diastolic blood pressure of ≥15 mmHg was significantly lower in the magnesium group compared with the women who received placebo. There was an inverse relation between the urinary excretion of magnesium during pregnancy and the diastolic blood pressure.”

Preeclampsia: seizures and hypertension controlled by magnesium

Taken together this and similar data in the literature argue in favor of clinicians diligently considering magnesium supplementation for every pregnant woman at risk for preeclampsia. It’s hard to argue against this point, particularly considering the low cost and practically absent risk. The authors of the latter study conclude:

Magnesium supplementation prevented an increase in diastolic blood pressure during the last weeks of pregnancy. The relation between diastolic blood pressure and urinary excretion of magnesium suggests that magnesium is involved in the regulation of blood pressure and that the increase in diastolic blood pressure in pregnancy could be due to a lack of magnesium.”

Stroke risk reduced by magnesium

StrokeStroke risk is reduced by higher plasma magnesium levels according to data from 32,826 women in the Nurses’ Health Study presented in a paper just published in the journal Stroke. The authors note:

Lower plasma magnesium levels may be associated with higher blood pressure and endothelial dysfunction, but sparse prospective data are available for stroke.”

So they compared plasma magnesium in stroke cases with controls matched for age, race/ethnicity, smoking status, date of blood draw, fasting status, menopausal status, and hormone use. Women with magnesium levels* that I see in lab reports had a signficantly increased risk for stroke:

“Conditional on matching factors, women in the lowest magnesium quintile had a relative risk of 1.34 for total ischemic stroke compared with women in the highest quintile. Additional adjustment for risk factors and confounders did not substantially alter the risk estimates for total ischemic stroke. Women with magnesium levels <0.82 mmol/L* had significantly greater risk of total ischemic stroke (multivariable relative risk, 1.57) and thrombotic stroke (multivariable relative risk, 1.66) compared with women with magnesium levels ≥0.82 mmol/L. No significant effect modification was observed by age, body mass index, hypertension, or diabetes mellitus.”

Magnesium is an anti-inflammatory agent

Clinical key  point: Cardiovascular and cerebrovascular disease have a well-known inflammatory component. Besides lowering blood pressure and promoting healthy endothelial function, magnesium is ‘nature’s anti-inflammatory mineral’ that supports parasympathetic nervous system function with a calming, anti-spasmodic effect.

* Plasma magnesium <0.82 mmol/L = 2.0 mg/dL.

The authors conclude:

Lower plasma magnesium levels may contribute to higher risk of ischemic stroke among women.”

Magnesium, inflammation and endothelial function

American Journal of Clinical NutritionRegarding additional mechanisms by which magnesium status is linked to stroke and cardiovascular disease, a study published in the American Journal of Clinical Nutrition provides evidence that magnesium is important for endothelial (blood vessel lining) health:

“We conducted a cross-sectional study of 657 women from the Nurses’ Health Study cohort who were aged 43-69 y and free of cardiovascular disease, cancer, and diabetes mellitus when blood was drawn in 1989 and 1990. Plasma concentrations of C-reactive protein (CRP), interleukin 6 (IL-6), soluble tumor necrosis factor alpha receptor 2 (sTNF-R2), E-selectin, soluble intercellular adhesion molecule 1 (sICAM-1), and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured. Estimates from 2 semiquantitative food-frequency questionnaires, administered in 1986 and 1990, were averaged to assess dietary intakes.”

E-selectin recruits white blood cells to engage in the endothelial inflammatory process. The authors demonstrated a  role for magnesium significant for stroke:

“…magnesium intake was inversely associated with plasma concentrations of CRP, E-selectin, and sICAM-1. After further adjustment for physical activity, smoking status, alcohol use, postmenopausal hormone use, and body mass index, dietary magnesium intake remained inversely associated with CRP and E-selectin. Multivariate-adjusted geometric means for women in the highest quintile of dietary magnesium intake were 24% lower for CRP and 14% lower for E-selectin than those for women in the lowest quintile.”

Magnesium reduces CRP

Archives of Medical ResearchA recent study published in Archives of Medical Research also shows anti-inflammatory effect of magnesium in lowering CRP:

“It has been suggested that magnesium deficiency is associated with the triggering of acute phase response, which may contribute to type 2 diabetes and cardiovascular disease risk. We undertook this study to determine whether oral magnesium supplementation modifies serum levels of high-sensitivity C-reactive protein (hsCRP) in apparently healthy subjects with prediabetes and hypomagnesemia.”

The authors examined the effect of magnesium supplementation on 62 men and non-pregnant women aged 18–65 years who were newly diagnosed with prediabetes and hypomagnesemia (serum magnesium levels <0.74 mmol/L/1.8 mg/dL) for the effects of daily supplementation with magnesium in a double-blind placebo-controlled trial, leading to their conclusion…

Oral magnesium supplementation decreases hsCRP levels in apparently healthy subjects with prediabetes and hypomagnesemia.”

Magnesium supplementation improves insulin resistance

Diabetes, Obesity and MetabolismInsulin resistance is benefited by magnesium supplementation according to mounting evidence. A study published in the journal Diabetes, Obesity and Metabolism documents significant improvements in insulin resistance by supplementation even when the subjects’ magnesium levels appeared normal (normomagnesemic). The authors state:

The incidence of insulin resistance and metabolic syndrome correlates with the availability of magnesium (Mg). We studied the effect of oral Mg supplementation on insulin sensitivity and other characteristics of the metabolic syndrome in normomagnesemic, overweight, insulin resistant, non-diabetic subjects.”

After collecting data on insulin sensitivity, plasma glucose, serum insulin, blood pressure and lipid profiles subjects were randomized to receive either a magnesium supplement or placebo for 6 months.The results offered strong evidence for the ability of magnesium supplementation to improve insulin resistance:

“Mg supplementation resulted in a significant improvement of fasting plasma glucose and some insulin sensitivity indices (ISIs) compared to placebo. Blood pressure and lipid profile did not show significant changes. The results provide significant evidence that oral Mg supplementation improves insulin sensitivity even in normomagnesemic, overweight, non-diabetic subjects emphasizing the need for an early optimization of Mg status to prevent insulin resistance and subsequently type 2 diabetes.”

Magnesium, insulin resistance and cardiovascular risk reduction

Medical Science MonitorIn another study published in Medical Science Monitor that included subjects with  hypertension, magnesium supplementation improved both insulin resistance and blood fats:

“Epidemiological studies have associated low dietary Mg2+ intake with insulin resistance (IR) and increased risk for metabolic syndrome…This study aimed to investigate the effects of oral Mg2+ supplementation on insulin sensitivity (IS) and serum lipids.”

Forty-eight patients were divided into a magnesium supplementation with lifestyle recommendations and a lifestyle only group, with measurements of fasting glucose and insulin levels, serum lipids and other standard laboratory tests, as well as an oral glucose tolerance test (OGTT) for insulin sensitivity were made at the beginning and after 12 weeks. Data for the magnesium supplementation group showed numerous improvements not present in the controls:

In the Mg2+ supplementation group the OGTT-derived IS indices of Stumvoll, Matsuda and Cedercholm in were increased between baseline baseline and study-end. In contrast, none of these parameters were changed in the control group. Reductions in total cholesterol, LDL-cholesterol and triglyceride levels, along with a parallel increase in HDL-cholesterol levels, were evident at study-end in the intervention group, but not in the control group.”

Clinical note: Magnesium supplementation should be a routine consideration to lower cardiovascular risk in patients with hypertension, especially with insulin resistance. The authors conclude:

“This study suggests that oral Mg2+ supplementation improves IS and lipid profile in mildly hypertensive patients. These potential beneficial effects of Mg2+ on associated metabolic factors could be helpful for patients with hypertension in terms of overall cardiovascular risk reduction.

Magnesium improves metabolism with normal weight but insulin resistance

Archives of Medical ResearchAnd a study recently published in Archives of Medical Research showed similar improvements in insulin resistance and metabolism with magnesium supplementation in a randomized placebo-controlled trial with metabolically obese, normal-weight (MONW) individuals.

“A total of 47 MONW individuals with hypomagnesemia were enrolled in clinical a randomized double-blind placebo-controlled trial. Individuals in the intervention group received 30 mL of MgCl2 5% solution (equivalent to 382 mg of magnesium) and individuals in the control group 30 mL of placebo solution, once daily during 4 months. In the absence of obesity or overweight, the presence of fasting glucose levels ≥100 mg/dL, HOMA-IR index ≥3, triglyceride levels ≥150 mg/dL and/or systolic and diastolic blood pressure ≥140 and 90 mmHg defined the presence of the MONW phenotype. Hypomagnesemia was defined by serum magnesium concentration ≤1.8 mg/dL.”

Clinical note: Even with a cut-off point of 2.0 mg/dL serum magnesium is a ‘blunt’ indicator that misses many if not most cases needing supplementation. Practitioners should be alert to clinical manifestations of suboptimal magnesium levels. Objective verification when necessary can be reliably obtained with the Exa Test.

Consonant with other studies magnesium supplementation showed a distinct benefit:

“At basal conditions there were no significant differences between groups. At the end of follow-up, changes in the mean of systolic (–2.1 vs. 3.9% mmHg, p <0.05) and diastolic (–3.8 vs. 7.5% mmHg, p <0.05) blood pressures, HOMA-IR index (–46.5 vs. –5.4%, p <0.0001), fasting glucose (–12.3 vs. –1.8% mg/dL, p <0.05) and triglyceride levels (–47.4% vs. 10.1% mg/dL, p <0.0001) were significantly lower in the subjects who received MgCl2 compared with individuals in the control group.”

The authors’ conclusion supports the practice of starting early (while weight is normal) with magnesium supplementation to address adverse metabolic changes:

“Oral magnesium supplementation improves the metabolic profile and blood pressure of MONW individuals.”

Clinical note: Magnesium may be the element most commonly insufficient universally. Critical to hundreds of metabolic pathways, it is ‘nature’s calming, antiinflammatory mineral’ and supports parasympathetic nervous system function. Deficiency should be highly suspect in the presence of muscle cramps.

Magnesium: insulin, brain, heart and inflammation

PLOS ONEMagnesium may be the critical nutrient most commonly drained by modern environmental stress to suboptimal levels. It seems to be commonly overlooked in clinical practice, even for muscle cramps and spasms for which it is often effective (if given at an adequate dose), and is a prime parasympathetic nervous system support. Recent studies add evidence to its indication for insulin resistance, diabetes, cognitive impairment, atrial fibrillation, cardiovascular disease, and neurogenic inflammation. A recent study published in PLOS One (Public Library of Science) confirms an association of lower levels of magnesium with diabetes and diabetic complications:

“The effect of magnesium (Mg) deficiency on the prevalence of diabetes and diabetic complications has received a great attention. The present study investigated the association of Mg level in the serum or urine of the patients, lived in the Northeast areas of China, with either pre-diabetes or diabetes with and without complications.”

The authors examined data for patients with type 1 diabetes (T1D), type 2 diabetes (T2D), impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), along with the incidence of nephropathy, retinopathy or peripheral neuropathy in associateion with serum and urinary magnesium (Mg) levels…

Serum Mg levels in the patients with IGT, IFG, T2D, and T1D were significantly lower than that of control. The urinary Mg levels were significantly increased only in T2D and T1D patients compared to control.”

Importantly, they revealed evidence that statins can contribute to magnesium deficiency:

“There was an early study that showed a reduction trend of serum Mg in the T2D patients treated with 4-month simvastatin treatment compared to T2D patients treated with placebo. In the present study, we found no reduction of serum Mg, but significant reduction of urinary Mg in the T2D patients treated with simvastatin…The above findings suggest that there was a risk for reducing either serum Mg or urinary Mg. Since we have appreciated, based on the above discussion, that Mg appears to play a vital function in the prevention of insulin resistance, diabetes and diabetic complications; In addition, Mg has been also reported to have anti-inflammatory and statin-like effect as well as the stimulating effect of Mg at physiological level on the statin passive diffusion into hepatocytes and their pharmacological actions on cholesterol biosynthesis. Therefore, combination of statin administration with supplementation of certain amount of Mg may be required to avoid the reduction of the Mg level either in the blood or urine caused by supplementation with statin alone. In fact, the combination of Mg with a statin has been recently suggested as a potential and seemingly-promising avenue to reduce cholesterol, C-reactive protein, and cardiovascular disorders.”

The authors sonclude:

“By directly measuring serum and urinary Mg here we demonstrated the significantly low serum Mg level not only in T2D, but also in IFG, IGT, and T1D…In the present study, we demonstrated for the first time that T1D patients also exhibited a significant low of serum Mg level compared to control…We also demonstrated the increase secretion of Mg in urine for both T1D and T2D patients…Therefore, the potential impact of Mg in metabolic syndrome, diabetes and diabetes-related or no-related cardiovascular disorders needs to be received special attention.”

 

NutrientsThese findings were echoed in another study recently published in the journal Nutrients showing that dietary magnesium improves insulin resistance in subjects with metabolic syndrome, and the need for adequate magnesium may not be met through diet. The authors state:

“Many cross-sectional studies show an inverse association between dietary magnesium and insulin resistance, but few longitudinal studies examine the ability to meet the Recommended Dietary Allowance (RDA) for magnesium intake through food and its effect on insulin resistance among participants with metabolic syndrome (MetS). The dietary intervention study examined this question in 234 individuals with MetS.”

They assessed magnesium intake, along with fasting glucose, insulin and insulin resistance estimated by the standard homeostasis model assessment (HOMA-IR) for 234 individuals with MetS at baseline, 6, and 12 months. Clinicians really need to bear in mind what their data reveals:

“Baseline magnesium intake was 287 ± 93 mg/day, and HOMA-IR, fasting glucose and fasting insulin were 3.7 ± 3.5, 99 ± 13 mg/dL, and 15 ± 13 μU/mL, respectively. At baseline, 6-, and 12-months, 23.5%, 30.4%, and 27.7% met the RDA for magnesium. After multivariate adjustment, magnesium intake was inversely associated with metabolic biomarkers of insulin resistance. Further, the likelihood of elevated HOMA-IR (>3.6) over time was 71% lower in participants in the highest quartile of magnesium intake than those in the lowest quartile. For individuals meeting the RDA for magnesium, the multivariate-adjusted OR for high HOMA-IR over time was 0.37.”

In other words, magnesium from diet alone just doesn’t cut it for most people in regard to insulin resistance. The authors conclude:

“These findings indicate that dietary magnesium intake is inadequate among non-diabetic individuals with MetS and suggest that increasing dietary magnesium to meet the RDA has a protective effect on insulin resistance…Since this population has a higher risk of cardiovascular disease and type 2 diabetes, dietary behaviors that have the ability to impact insulin resistance can have far-reaching clinical implications.”

 

The Journal of Neuroscience 33(19)Of premiere importance is the role that magnesium plays in neuroplasticity and protects against loss of cognitive function. A study published recently in The Journal of Neuroscience provides evidence for the benefit of magnesium in Alzheimer’s disease:

“Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer’s disease (AD) and might underlie memory impairment. Our previous work demonstrated that the magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we investigated whether elevation of brain magnesium by the use of a recently developed compound, magnesium-l-threonate (MgT), can ameliorate the AD-like pathologies and cognitive deficits…”

They examined the effect of magnesium levels on AD-like pathologies in the brains of their study subjects (a a transgenic (Tg) mouse model of Alzheimer’s disease), including Aβ (amyloid beta) plaque formation, molecules necessary for neuronal energy metabolism, and influence on signaling pathways involved in synaptic plasticity and density. Their data showed a remarkable correlation:

MgT treatment reduced Aβ plaque and prevented synapse loss and memory decline in the Tg mice. Strikingly, MgT treatment was effective even when given to the mice at the end stage of their AD-like pathological progression… In the Tg mice, the NMDAR/CREB/BDNF signaling was downregulated, whereas calpain/calcineurin/Cdk5 neurodegenerative signaling and β-secretase (BACE1) expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression, and reduced soluble APPβ and β-C-terminal fragments in the Tg mice. At the molecular level, elevation of extracellular magnesium prevented the high-Aβ-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices.”

Reduction of amyloid plaque by magnesiumIn other words, the magnesium treatment profoundly ameliorated neuronal damage and memory loss. The authors note some fascinating observations:

“Our studies demonstrate that an increase in magnesium intake enhances memory in young rats, reverses memory decline in aged rats (Slutsky et al., 2010), and prevents memory deterioration a mouse model of AD (the present study). However, it is intriguing that after long-term magnesium supplementation, the Mg2+ concentration in the CSF only increased by 15% (Slutsky et al., 2010) and the total magnesium in brain increased by 30%. Can small increases in [Mg2+]CSF have major impact on synapse density? In a separate study, we found that increasing extracellular Mg2+ by 15% led to an ∼50% increase in synapse density in cultured hippocampal synapses (unpublished observations). These data suggest that hippocampal synapse density might be very sensitive to small changes in extracellular Mg2+ concentrations. Under normal physiological conditions, whole-body magnesium is tightly regulated by kidney function. Daily fluctuation of plasma magnesium associated with food intake is <0.1 mm above a baseline of 0.7 mm (Witkowski et al., 2011). Brain magnesium is supposed to be more stable because the blood–brain barrier isolates the brain from daily fluctuations in blood magnesium. Therefore, despite the high sensitivity of the synapses to Mg2+ concentration, synapse density is likely to be stable under physiological conditions. Conversely, if brain magnesium is reduced under pathological conditions, this might have a profound impact on synapse density and memory function. Interestingly, in the hippocampus of AD patients, the total magnesium level is reduced by 18% (Andrási et al., 2005).”

They conclude:

“Therefore, restoration/elevation of brain magnesium in AD patients might be beneficial for ameliorating the cognitive deficits of AD. Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of AD and may have therapeutic potential for treating AD in humans.”

 

The Journal of NutritionOf course there is an abundance of evidence for the importance of magnesium in cardiovascular disease. A paper just published in The Journal of Nutrition links magnesium intake with death from all causes in people at high cardiovascular risk. The authors state:

“The relation between dietary magnesium intake and cardiovascular disease (CVD) or mortality was evaluated in several prospective studies, but few of them have assessed the risk of all-cause mortality, which has never been evaluated in Mediterranean adults at high cardiovascular risk. The aim of this study was to assess the association between magnesium intake and CVD and mortality risk in a Mediterranean population at high cardiovascular risk with high average magnesium intake.”

They examined data for 7216 men and women assigned to one of two Mediterranean diets (supplemented with nuts or olive oil) or advice on a low-fat control diet and, in particular, assessed the associations between yearly repeated measurements of magnesium intake and mortality…

“After a median follow-up of 4.8 y, 323 total deaths, 81 cardiovascular deaths, 130 cancer deaths, and 277 cardiovascular events occurred. Energy-adjusted baseline magnesium intake was inversely associated with cardiovascular, cancer, and all-cause mortality. Compared with lower consumers, individuals in the highest tertile of magnesium intake had a 34% reduction in mortality risk. Dietary magnesium intake was inversely associated with mortality risk in Mediterranean individuals at high risk of CVD.”

 

PACEAs expected when considering the critical role of magnesium in neuromuscular excitability, magnesium should be considered in case management of cardiac arrhythmias. The authors of a paper published on magnesium and atrial fibrillation in the journal PACE (Pacing And Electrical Physiology) state:

“Magnesium (Mg) is an important intracellular ion with cardiac metabolism and electrophysiologic properties. A large percentage of patients with arrhythmias have an intracellular Mg deficiency, which is out of line with serum Mg concentrations, and this may explain the rationale for Mg’s benefits as an atrial antiarrhythmic agent.”

They further note:

“A current limitation of antiarrhythmic therapy is that the potential for cardiac risk offsets some of the benefits of therapy. Mg enhances the balance of benefits to harms by enhancing atrial antiarrhythmic efficacy and reducing antiarrhythmic proarrhythmia potential as well as providing direct antiarrhythmic efficacy when used as monotherapy in patients undergoing cardiothoracic surgery.”

 

American Journal of Clinical NutritionIschemic heart disease (IHD) is also influenced by magnesium sufficiency as documented in a study published in the American Journal of Clinical Nutrition. The authors set out to…

“…investigate whether urinary magnesium excretion and plasma magnesium are associated with IHD risk.”

To do so they examined 7664 subjects without for urinary magnesium excretion as measured in 2 baseline 24-h urine collections and found that…

“Mean ± SD urinary magnesium excretion was 4.24 ± 1.65 mmol/24 h for men and 3.54 ± 1.40 mmol/24 h for women. During a median follow-up of 10.5 y, 462 fatal and nonfatal IHD events occurred. After multivariable adjustment, urinary magnesium excretion had a nonlinear relation with IHD risk. The lowest sex-specific quintile (men: <2.93 mmol/24 h; women: <2.45 mmol/24 h) had an increased risk of fatal and nonfatal IHD (multivariable HR: 1.60) compared with the upper 4 quintiles of urinary magnesium excretion. A similar increase in risk of the lowest quintile was observed for mortality related to IHD (HR: 1.70). No associations were observed between circulating magnesium and risk of IHD.”

This interesting study demonstrates two clinically significant points: (1) magnesium status is indeed associated with the risk of ischemic heart disease, and (2) serum magnesium is a very poor indicator of magnesium status (a fact that all experienced clinicians should be aware of). The authors conclude:

Low urinary magnesium excretion was independently associated with a higher risk of IHD incidence. An increased dietary intake of magnesium, particularly in those with the lowest urinary magnesium, could reduce the risk of IHD.”

 

Heart Failure ReviewsPerhaps of premiere importance is the fact that suboptimal magnesium promotes neurogenic inflammation that can contribute to not only cardiovascular disease but any inflammatory disease, and be a contributing factor in the progression of intestinal permeability. This is presented in a paper published in Heart Failure Reviews:

“Magnesium is a micronutrient essential for the normal functioning of the cardiovascular system, and Mg deficiency (MgD) is frequently associated in the clinical setting with chronic pathologies such as CHF, diabetes, hypertension, and other pathologies. Animal models of MgD have demonstrated a systemic pro-inflammatory/pro-oxidant state, involving multiple tissues/organs including neuronal, hematopoietic, cardiovascular, and gastrointestinal systems; during later stages of MgD, a cardiomyopathy develops which may result from a cascade of inflammatory events. In rodent models of dietary MgD, a significant rise in circulating levels of proinflammatory neuropeptides such as substance P (SP) and calcitonin gene-related peptide among others, was observed within days (1–7) of initiating the Mg-restricted diet, and implicated a neurogenic trigger for the subsequent inflammatory events; this early “neurogenic inflammation” phase may be mediated in part, by the Mg-gated N-methyl-D-aspartate (NMDA) receptor/channel complex.”

Of the greatest importance for clinical case management…

“Deregulation of the NMDA receptor may trigger the abrupt release of neuronal SP from the sensory-motor C-fibers to promote the subsequent pro-inflammatory changes: elevations in circulating inflammatory cells, inflammatory cytokines, histamine, and PGE2 levels, as well as formation of nitric oxide, reactive oxygen species, lipid peroxidation products, and depletion of key endogenous antioxidants.”

Recall that sensory-motor C-fibers are also involved in chronic pain. And of great interest to practitioners managing autoimmunity and gastrointestinal infection:

“Concurrent elevations of tissue CD14, a high affinity receptor for lipopolyssacharide, suggest that intestinal permeability may be compromised leading to endotoxemia. If exposure to these early (1–3 weeks MgD) inflammatory/pro-oxidant events becomes prolonged, this might lead to impaired cardiac function, and when co-existing with other pathologies, may enhance the risk of developing chronic heart failure.”

 

Clinical note: Suboptimal magnesium levels are so common, and involved in so many pathophysiological processes (only a fraction of which have been described here)—that so often go unrecognized in clinical practice—I urge practitioners to keep this in mind.

Breast cancer risk doubles with calcium channel blockers for hypertension

JAMA Internal MedicineBreast cancer risk assessment must take into consideration chronic inflammation, which comes to the fore in light of a study just published in JAMA Internal Medicine (formerly Archives of Internal Medicine) offering evidence that use use of calcium channel blockers double the risk for breast cancer. The authors observe:

“Antihypertensive agents are the most commonly prescribed class of medications in the United States. Evidence regarding the relationship between different types of antihypertensives and breast cancer risk is sparse and inconsistent…”

So they investigated different types of blood pressure medication for an association with invasive breast cancers among a group of 2,763 postmenopausal women in the Seattle area. Their data for the risk of invasive ductal and invasive lobular breast cancers shows a strong link to calcium-channel blockers:

“Current use of calcium-channel blockers for 10 or more years was associated with higher risks of ductal breast cancer (odds ratio [OR], 2.4; 95% CI, 1.2-4.9) and lobular breast cancer (OR, 2.6; 95% CI, 1.3-5.3). This relationship did not vary appreciably by type of calcium-channel blocker used (short-acting vs long-acting, dihydropyridines vs non-dihydropyridines). In contrast, use of diuretics, β-blockers, and angiotensin II antagonists were not associated with risk.”

That’s a 240% and 260% (more than double) increase in risk for ductal and lobular breast cancer respectively.

Clinical note: Neuromuscular excitability, including innervation of the smooth muscles that line the arteries, is controlled by the balance of calcium and magnesium ions. Hyperexcitability results with an excess of calcium in relation to magnesium can result in vasoconstriction that increases blood pressure. Calcium-channel blockers diminish the effect of calcium on the blood vessel but without increasing the relative deficit of magnesium (‘nature’s calcium-channel blocker’ and one of the most common deficiencies). Magnesium also supports the parasympathetic nervous system’s anti-inflammatory effect. A number of studies have associated suboptimal magnesium with chronic inflammation, and the link between the increased risk factor for cardiovascular disease with calcium supplementation is thought to be associated with calcium’s opposition to magnesium. It would be prudent to not only avoid calcium-channel blockers in the treatment of hypertensive postmenopausal women, but to carefully assess them for evidence of suboptimal magnesium levels.

Migraine: most patients should be taking magnesium

Journal of Neural TransmissionMagnesium plays a key role in hundreds of physiological processes and is very commonly depleted to suboptimal levels by common stresses. A paper recently published in the Journal of Neural Transmission is a good reminder that magnesium supplementation should be considered for all patients suffering from migraine. The authors state:

Magnesium, the second most abundant intracellular cation, is essential in many intracellular processes and appears to play an important role in migraine pathogenesis.”

It’s important for clinicians to be aware that tissue magnesium status is not reliably reflected by serum, or even red blood cell membrane, levels…*

Routine blood tests do not reflect true body magnesium stores since <2 % is in the measurable, extracellular space, 67 % is in the bone and 31 % is located intracellularly.”

The depredations of magnesium insufficiency are legion…

Lack of magnesium may promote cortical spreading depression, hyperaggregation of platelets, affect serotonin receptor function, and influence synthesis and release of a variety of neurotransmitters.”

Suboptimal levels of magnesium are ubiquitous, and circumstances that deplete magnesium resulting in the need to increase supplementation are common. They include alcohol consumption and long haul air travel. Moreover…

“Migraine sufferers may develop magnesium deficiency due to genetic inability to absorb magnesium, inherited renal magnesium wasting, excretion of excessive amounts of magnesium due to stress, low nutritional intake, and several other reasons.”

Regarding migraine specifically:

There is strong evidence that magnesium deficiency is much more prevalent in migraine sufferers than in healthy controls. Double-blind, placebo-controlled trials have produced mixed results, most likely because both magnesium deficient and non-deficient patients were included in these trials. This is akin to giving cyanocobalamine in a blinded fashion to a group of people with peripheral neuropathy without regard to their cyanocobalamine levels. Both oral and intravenous magnesium are widely available, extremely safe, very inexpensive and for patients who are magnesium deficient can be highly effective.”

The authors’ point about the critical flaws in many, if not most, studies on nutrient supplementation should be borne in mind by practitioners and the public alike: treating with an agent like magnesium or cyanocobalamine (a form of vitamin B12) will not yield a beneficial result if the subject is not deficient to begin with. The authors conclude:

“Considering these features of magnesium, the fact that magnesium deficiency may be present in up to half of migraine patients, and that routine blood tests are not indicative of magnesium status, empiric treatment with at least oral magnesium is warranted in all migraine sufferers.”

* Clinician’s note: The Exa Test® does provide reliable tissue levels of magnesium and other minerals analytical scanning electron microscopy (ASEM) and elemental X-ray analysis (fluorescence) performed on easily obtained buccal epithelial cells.

Colorectal tumor risk is reduced by magnesium

Functional deficiencies in magnesium are common and known to play a role in chronic inflammation and insulin resistance, both of which are tumor promoters. A study just published in The American Journal of Clinical Nutrition offers evidence that higher intakes of magnesium reduce colorectal tumor risk. The authors observe:

“Dietary magnesium might be related to colorectal tumor risk through the pivotal roles of magnesium in cellular metabolism, insulin resistance, and systemic inflammation.”

The compared the dietary intake of magnesium of 768 subjects with colorectal adenomas in comparison to 709 polyp-free control subjects. In addition they conducted a meta-analysis of 3 colorectal adenoma studies and 6 carcinoma studies. The association was apparent for individuals with a BMI equal to or greater than 24 or over age 55, or those with a more advanced colorectal tumor:

“The case-control study showed a nonsignificant inverse association between dietary magnesium intake and risk of colorectal adenomas. However, inverse associations were observed only in subjects with BMI (in kg/m2) ≥25, in subjects aged ≥55 y, and for advanced adenomas. Associations did not vary by the calcium-to-magnesium intake ratio. In the meta-analysis, every 100-mg/d increase in magnesium intake was associated with 13% lower risk of colorectal adenomas.”

The authors conclude:

“Our findings support the hypothesis that higher intakes of dietary magnesium are associated with lower risk of colorectal tumors. The consumption of magnesium-rich foods may be a new avenue to explore further in the search for cancer-prevention strategies.”

Since blood tests for minerals are very poor indicators (99% of magnesium is in the tissues, only 1% in the blood where it regulated differently) and hair analysis is completely unreliable for the purpose, what is the best way to objectively measure the tissue magnesium level? The ExaTest, analytical scanning electron microscopy (ASEM) and Elemental X-ray analysis, is a non-invasive and affordable method that measures the mineral content in buccal epithelial cells. This reliably correlates with mineral levels, including magnesium, in deep organ tissues.

Oral magnesium helps asthma in children—reduces inflammation, supports glutathione

Asthma is a disease of chronic inflammation and magnesium is known to have anti-inflammatory effects. A rigorous trial published in the European Journal of Clinical Nutrition offers evidence that oral magnesium helps relieve asthma in children. The authors set out to…

“…investigate the long-term effect of oral magnesium supplementation on clinical symptoms, bronchial reactivity, lung function and allergen-induced skin responses in children and adolescents with moderate persistent asthma.”

They staged a double-blind randomized parallel placebo-controlled study randomizing 37 patients aged 7–19 years into two groups. One got 300 mg/day of magnesium and the rest placebo over 2 months. The primary outcome was bronchial reactivity which was evaluated by a methacholine challenge test (PC20). The data showed a significant benefit from magnesium:

“After a follow-up of 2 months, the methacholine PC20 for testing bronchial reactivity has augmented significantly in the magnesium group only. The skin responses to recognized antigens have also decreased in patients treated with magnesium. The forced vital capacity (FVC), the forced expiratory volume at first second (FEV1), the forced expiratory flow at 25–75 and the FEV1/FVC ratio were similar in both groups. The magnesium group presented fewer asthma exacerbations and used less salbutamol compared to the placebo group.”

The magnesium clearly produced a welcome anti-inflammatory effect. The authors conclude:

Oral magnesium supplementation helped to reduce bronchial reactivity to methacholine, to diminish their allergen-induced skin responses and to provide better symptom control in pediatric patients with moderate persistent asthma treated with inhaled fluticasone.”

It’s very interesting that magnesium reduced inflammation in both the lung mucosa and skin. Besides the antiinflammatory effect of increasing parasympathetic tone (see posts on heart rate variability and others on magnesium and calcium), a striking paper published in the journal Inflammation Research shows that magnesium also supports the glutathione redox system, an extremely important factor in autoimmunity and allergy. The authors conducted their randomized, double-blind, placebo-controlled study to…

“…investigate the effects of 12-week oral magnesium (Mg) supplementation on the RBC redox system in stable, persistent, moderately asthmatic children.”

They examined oxidized glutathione (GSSG) and reduced (GSH) glutathione, oxyhaemoglobin, methaemoglobin (metHb), hemichrome and bilirubin levels before and after treatment with magnesium and GSH stability in 40 kids aged 4-16 (24 boys, 16 girls). There was a clear benefit from the magnesium:

“The GSH concentration was significantly higher in the Mg-treated than in the placebo-treated patients after the treatment period. There was a positive correlation between the decreased plasma metHb and hemichrome levels and the decreased plasma haemoglobin concentrations in the Mg-treated patients at the end of the study.”

Clinicians who case manage autoimmunity please note: impairment of the glutathione redox system is a major contributor to the loss of self-tolerance. Evidence that magnesium, a benign and inexpensive agent, can significantly help to improve glutathione activity is valuable. The authors conclude:

Mg in the given doses exerts antioxidant activity and influences the glutathione redox system.”