Insulin resistance increases cardiovascular disease

Insulin resistance (IR), resistance of the insulin receptor due to overstimulation, elicits a rise of insulin levels to overcome the reduced receptor sensitivity. The resulting elevated insulin levels damage tissues throughout the body, and are a major contributing cause of cardiovascular disease. This is well known to many practitioners, so it was disturbing to read an article in the New York Times describing endocrinologists who are baffled by the fact that medications for type 2 diabetes that increase insulin levels worsen the risk for cardiovascular disease. The wealth of scientific evidence has been accumulating for a long time.

Insulin resistance and coronary artery disease

Insulin resistance and CADA study published in 1996 in the journal Diabetologia described the strong connection between CAD (coronary artery disease) and insulin resistance with its consequent hyperinsulinemia.

“The purpose of the present study was to quantitate insulin-mediated glucose disposal in normal glucose tolerant patients with angiographically documented coronary artery disease (CAD) and to define the pathways responsible for the insulin resistance.”

Of particular interest is that all the study subjects, both those with CAD and controls, had a normal oral glucose tolerance test. HOWEVER…

Fasting plasma insulin concentration and area under the plasma insulin curve following glucose ingestion were increased in CAD vs control subjects. Insulin-mediated whole body glucose disposal was significantly decreased in CAD subjects and this was entirely due to diminished non-oxidative glucose disposal. The magnitude of insulin resistance was positively correlated with the severity of CAD.”

It is hard to over emphasize the importance to clinicians of being vigilant in recognizing insulin resistance in the presence of normal glucose levels.

“In the CAD subjects basal and insulin-mediated rates of glucose and lipid oxidation were normal and insulin caused a normal suppression of hepatic glucose production. In conclusion, subjects with angiographically documented CAD are characterized by moderate-severe insulin resistance and hyperinsulinaemia and should be included in the metabolic and cardiovascular cluster of disorders that comprise the insulin resistance syndrome or ’syndrome X’.

Hypertension, Dyslipidemia, and Atherosclerotic Cardiovascular Disease

In 1991 a paper published in Diabetes Care described how insulin resistance promotes multiple factors that cause atherosclerosis.

“Diabetes mellitus is commonly associated with systolic/diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive control subjects, a heightened plasma insulin response to a glucose challenge is consistently found.”


“…insulin resistance…correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth muscle cells.”

It is also well-known that IR with its hyperinsulinemia cause elevated lipid levels.

Insulin resistance and hyperinsulinemia are also associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate-density and low-density lipoproteins, both of which are atherogenic.”

And elevated insulin directly fosters atherosclerosis:

“Last, insulin, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of various growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.”


Controlling insulin resistance more important than glucose or LDLA more recent study in Diabetes Care presents striking data demonstrating the massive impact reduction in heart attacks that would occur by preventing insulin resistance. In setting out to determine what portion of coronary artery disease is caused by IR, the authors used data from the National Health and Nutrition Examination Survey 1998–2004 to simulate a population representative of young adults in the U.S. They applied the Archimedes model was to estimate the proportion of heart attacks that would be prevented by maintaining insulin resistance at healthy levels. Their data painted a dramatic picture:

“In young adults, preventing insulin resistance would prevent ∼42% of myocardial infarctions. The next most important determinant of CAD is systolic hypertension, prevention of which would reduce myocardial infarctions by ∼36%. Following systolic blood pressure, the most important determinants are HDL cholesterol (31%), BMI (21%), LDL cholesterol (16%), triglycerides (10%), fasting plasma glucose and smoking (both ∼9%), and family history (4%).”

Preventing insulin resistance beat the pants off controlling LDL cholesterol and smoking! Interestingly, they found that the effects were especially important for women:

“The effects of insulin resistance are also affected by sex. Today’s young men face a higher rate of myocardial infarctions than today’s young women: 55 vs. 32%. However, insulin resistance plays a larger relative role in women than in men, with normalization of insulin resistance reducing the myocardial infarction rate ∼57% for women (from 32 to 14%), compared with ∼29% (from 55 to 39%) for men.”

Preventing insulin resistance carries more weight than controlling glucose

In their conclusion the authors make points that are crucial for clinicians to bear in mind:

“Of the risk factors that we believe are sufficiently well studied to permit quantitative analysis, insulin resistance is the most important single risk factor for CAD. Our results indicate that insulin resistance is responsible for approximately 42% of myocardial infarctions. Its effect on CAD is indirect, mediated through its effects on other variables such as SBP, HDL cholesterol, triglycerides, glucose, and apoB.”

Effect of insulin resistance on myocardial infarction

In comparing their results with other research, the authors highlight the critical error made by depending on medications that increase insulin to control glucose:

“Our results are not directly comparable with those of clinical trials, where the effects of glucose lowering on CAD were either much smaller or null. The reason is that in the clinical trials, the focus was on lowering blood glucose—not preventing or curing insulin resistance. The drugs used in the trials either lowered glucose without affecting insulin resistance (e.g., sulfonylureas and insulin) or lowered insulin resistance to some extent but did not eliminate it (e.g., metformin and rosiglitazone). Furthermore, we normalized insulin resistance over the entire lifetimes of the subjects, whereas the treatments in the trials were given only after individuals had developed diabetes and were given only for the limited durations of the studies. Thus, the results of the trials do not represent the full eff

ect of normalizing insulin resistance and are actually consistent with our results.”

Note the implication that cardiovascular damage by IR occurs long before losing glucose control and crossing the border into diabetes territory.

Insulin resistance without diabetes causes cardiovascular disease

Investigators publishing in PLoS One make the same point about cardiovascular damage caused by IR well before diabetes sets in.

“To enable a comparison between cardiovascular disease risks for glucose, insulin and HOMA-IR, we calculated pooled relative risks per increase of one standard deviation…We included 65 studies (involving 516,325 participants) in this meta-analysis. In a random-effect meta-analysis the pooled relative risk of CHD (95% CI; I2) comparing high to low concentrations was 1.52 (1.31, 1.76; 62.4%) for glucose, 1.12 (0.92, 1.37; 41.0%) for insulin and 1.64 (1.35, 2.00; 0%) for HOMA-IR. The pooled relative risk of CHD per one standard deviation increase was 1.21 (1.13, 1.30; 64.9%) for glucose, 1.04 (0.96, 1.12; 43.0%) for insulin and 1.46 (1.26, 1.69; 0.0%) for HOMA-IR.”

They concluded that insulin resistance (HOMA-IR) was the leading culprit:

“The relative risk of cardiovascular disease was higher for an increase of one standard deviation in HOMA-IR compared to an increase of one standard deviation in fasting glucose or fasting insulin concentration.”

The authors also demonstrate that IR is a much better biomarker than fasting insulin:

 “The present meta-analyses showed that fasting glucose, fasting insulin and HOMA-IR were all associated with incident cardiovascular disease in individuals without diabetes. In a standardized meta-analysis we found that coronary heart disease risk increased with 46% for an increase of one standard deviation in HOMA-IR concentration compared to an increase of 21% for fasting glucose concentration and an increase of 4% for fasting insulin concentration.”

Insulin resistance causes fat expansion and vascular endothelial damage

An excellent paper published in Arteriosclerosis, Thrombosis, and Vascular Biology details how IR causes cardiovascular disease beyond abnormal glucose, lipids, hypertension, and its proinflammatory effects.

“…insulin’s action directly on vascular endothelium, atherosclerotic plaque macrophages, and in the heart, kidney, and retina has now been described, and impaired insulin signaling in these locations can alter progression of cardiovascular disease in the metabolic syndrome and affect development of microvascular complications.”

The authors describe how IR causes vascular inflammation and atherosclerosis:

“Insulin action directly on vascular endothelial cells affects endothelial function beyond regulating blood flow or capillary recruitment. Conditional knockout of the insulin receptor in endothelial cells causes a 2- to 3-fold increase in the atherosclerotic lesion size in apolipoprotein E–null mice…the increased atherogenesis in this model can be attributed to insulin action directly on endothelial cells rather than effects mediated through systemic parameters. The accelerated atherosclerosis in mice with endothelial cell insulin receptor knockout is preceded by a dramatic increase in leukocyte rolling and adhesion to endothelium and an increase in expression of vascular cell adhesion molecule-1…insulin signaling independent of NO is responsible for this effect.”

They state that IR promotes the necrotic core at the heart of vulnerable plaque:

Insulin resistance in macrophages, however, promotes formation of a necrotic core in atherosclerotic plaques by enhancing macrophage apoptosis. This is an important event in advanced atherosclerosis because exposure of the necrotic core to circulating blood in the event of plaque rupture can precipitate thrombosis, leading to unstable angina pectoris, transitory cerebral ischemia, stroke, or myocardial infarction.”

Regarding cardiomyocyte function…

“…it is likely that the changes in metabolic substrate inflexibility and increased mitochondrial production of oxidants caused by cardiomyocyte insulin resistance can contribute to development of heart failure in the metabolic syndrome.”

The authors conclude with important clinical points:

“Research on insulin receptor signaling using tissue–specific gene manipulation in mice as well as other methods has provided important insights into insulin action and revealed insulin effects in tissues that a decade or 2 ago were considered nonresponsive to insulin….insulin sensitizers would theoretically have better profiles of action if they improved insulin resistance in tissues regulating glucose and lipid metabolism, as well as in the endothelium and other vascular tissues where impaired insulin signaling is proatherosclerotic independent of metabolic effects. Second, insulin analogues should be carefully evaluated for deleterious effects on insulin signaling pathways which are not affected by insulin resistance, such as those pathways which promote dyslipidemia or increase vascular expression of endothelin-1.”

Insulin resistance promotes advanced plaque progression

A paper published in Cell Metabolism details additional mechanisms by which IR promotes atherosclerosis. The authors note that…

“…the pathophysiological processes involved in the initiation and progression of early lesions are quite different from those that cause the formation of clinically dangerous plaques,…advanced plaque progression is influenced primarily by processes that promote plaque necrosis and thinning of a collagenous “scar” overlying the lesion called the fibrous cap… and distinguishing the effects of insulin resistance and hyperglycemia on these processes is critically important.”

They echo other investigators who point out the crucial fact that insulin resistance does damage before glucose control is lost:

“There is ample clinical evidence that insulin resistance increases the risk for coronary artery disease (CAD) even in the absence of hyperglycemia. Insulin resistance syndromes can promote both atherogenesis and advanced plaque progression, and the mechanisms likely involve both systemic factors that promote these processes, particularly dyslipidemia but also hypertension and a proinflammatory state, as well as the effect of perturbed insulin signaling at the level of the intimal cells that participate in atherosclerosis, including endothelial cells, vascular smooth muscle cells, and macrophages.”

They highlight the critical clinical implication that insulin resistance also entails overstimulation of various tissues by insulin elevated in compensation for receptor resistance or by insulin-elevating medications:

“…“insulin resistance” can mean either defective insulin receptor signaling or, ironically, overstimulation of insulin receptor pathways caused by hyperinsulinemia.”

They also note the difference between ‘ordinary’ atherosclerosis and the lesions, vulnerable plaque, that actually cause heart attacks and ischemic strokes.

“Most importantly, the primary objective of this study was to address an entirely different question, namely, the effect of myeloid IR deficiency on advanced lesional macrophage apoptosis and plaque necrosis. Recall that most atherosclerotic lesions in humans do not cause acute coronary artery disease, because they undergo outward remodeling of the arterial wall, which preserves lumen patency, and do not undergo plaque rupture or erosion and thus do not trigger acute lumenal thrombosis. The small percentage of lesions that do cause acute vascular disease are distinguished by the presence of large areas of necrosis and thin fibrous caps, which promote plaque disruption, acute lumenal thrombosis, and tissue infarction. This concept is particularly important for the topic of this review, because advanced atherosclerotic lesions in diabetic subjects are characterized by large necrotic cores when compared with similarly sized lesions from nondiabetic individuals”

In their conclusion the authors state the role of insulin resistance over hyperglycemia:

“These studies have provided evidence that insulin resistance in macrophages and endothelial cells may play important roles in both atherogenesis and clinically relevant advanced plaque progression. Hyperglycemia, on the other hand, appears to primarily promote early stages of lesion formation…”

Insulin resistance inhibits nitric oxide synthase

An interesting paper published in the Italian journal Panminerva Medica further elucidates key mechanisms, including the damage by IR to nitric oxide regulation done by increasing asymmetric dimethylarginine, which inhibits nitric oxide synthase. The author includes this under the rubric ‘insulin resistance syndrome’.

“…the more insulin resistant an individual, the more insulin they must secrete in order to prevent the development of type 2 diabetes. However, the combination of insulin resistance and compensatory hyperinsulinemia increases the likelihood that an individual will be hypertensive, and have a dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration….Several other clinical syndromes are now known to be associated with insulin resistance and compensatory hyperinsulinemia. For example, polycystic ovary syndrome appears to be secondary to insulin resistance and compensatory hyperinsulinemia. More recently, studies have shown that the prevalence of insulin resistance/hyperinsulinemia is increased in patients with nonalcoholic fatty liver disease, and there are reports that certain forms of cancer are more likely to occur in insulin resistant/hyperinsulinemic persons. Finally, there is substantial evidence of an association between insulin resistance/hyperinsulinemia, and sleep disordered breathing. Given the rapid increase in the number of clinical syndromes and abnormalities associated with insulin resistance/hyperinsulinemia, it seems reasonable to suggest that the cluster of these changes related to the defect in insulin action be subsumed under the term of the insulin resistance syndrome.”

Specifically in regard to cardiovascular disease…

“…in addition to a high TG and a low HDL-C, the atherogenic lipoprotein profile in insulin resistant/hyperinsulinemic individuals also includes the appearance of smaller and denser low density lipoprotein particles, and the enhanced postprandial accumulation of remnant lipoproteins; changes identified as increasing risk of CVD. Elevated plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be associated with increased CVD, and there is evidence of a significant relationship between PAI-1 and fibrinogen levels and both insulin resistance and hyperinsulinemia. Evidence is also accumulating that sympathetic nervous system (SNS) activity is increased in insulin resistant, hyperinsulinemic individuals, and, along with the salt sensitivity associated with insulin resistance/hyperinsulinemia, increases the likelihood that these individuals will develop essential hypertension.”


“The first step in the process of atherogenesis is the binding of mononuclear cells to the endothelium, and mononuclear cells isolated from insulin resistant/hyperinsulinemic individuals adhere with greater avidity. This process is modulated by adhesion molecules produced by endothelial cells, and there is a significant relationship between degree of insulin resistance and the plasma concentration of the several of these adhesion molecules. Further evidence of the relationship between insulin resistance and endothelial dysfunction is the finding that asymmetric dimethylarginine, an endogenous inhibitor of the enzyme nitric oxide synthase, is increased in insulin resistant/hyperinsulinemic individuals. Finally, plasma concentrations of several inflammatory markers are elevated in insulin resistant subjects.”


A paper published in Diabetes Metabolism Research and Reviews draws this point further.

“In recent years, it has become clear that insulin resistance and endothelial dysfunction play a central role in the pathogenesis of atherosclerosis. Much evidence supports the presence of insulin resistance as the fundamental pathophysiologic disturbance responsible for the cluster of metabolic and cardiovascular disorders, known collectively as the metabolic syndrome. Endothelial dysfunction is an important component of the metabolic or insulin resistance syndrome and this is demonstrated by inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries in response to stimuli that release nitric oxide (NO). Deficiency of endothelial-derived NO is believed to be the primary defect that links insulin resistance and endothelial dysfunction. NO deficiency results from decreased synthesis and/or release, in combination with exaggerated consumption in tissues by high levels of reactive oxygen (ROS) and nitrogen (RNS) species, which are produced by cellular disturbances in glucose and lipid metabolism.”

And a vicious cycle ensues…

“Endothelial dysfunction contributes to impaired insulin action, by altering the transcapillary passage of insulin to target tissues. Reduced expansion of the capillary network, with attenuation of microcirculatory blood flow to metabolically active tissues, contributes to the impairment of insulin-stimulated glucose and lipid metabolism. This establishes a reverberating negative feedback cycle in which progressive endothelial dysfunction and disturbances in glucose and lipid metabolism develop secondary to the insulin resistance. Vascular damage, which results from lipid deposition and oxidative stress to the vessel wall, triggers an inflammatory reaction, and the release of chemoattractants and cytokines worsens the insulin resistance and endothelial dysfunction.”

In their conclusion the authors state:

“…endothelial dysfunction and insulin resistance commonly occur together and can be detected early in the pathogenesis of atherosclerosis. Insulin resistance can be inferred by the presence of a cluster of metabolic and cardiovascular abnormalities known collectively as the metabolic syndrome or by direct measurement of impaired insulin-stimulated glucose and lipid metabolism . Endothelial dysfunction can be documented by the demonstration of inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries. Lack of endothelial-derived NO may provide the link between insulin resistance and endothelial dysfunction.”

Plea to clinicians

Many resources are available for practitioners to apply a functional medicine model of objectively targeted treatment to resuscitate insulin receptor function and address lifestyle issues, especially diet, for the management of type 2 diabetes that minimizes the use of agents that lower glucose by increasing insulin, and therefore insulin resistance. It is my sincere wish that not only endocrinologists, but all clinicians, recall the mechanisms by which medications that promote insulin resistance increase cardiovascular disease, and act accordingly to protect their patients.

Insulin resistance is a huge topic, and there are numerous posts here pertaining to IR an conditions as diverse as Alzheimer’s disease and breast cancer that can be viewed by using the search box. They include the earlier post on the correlation of IR with blood vessel damage leading to heart attack and stroke.

Brain blood flow reduction associated with kidney function

Journal of the American Society of NephrologyBrain health requires adequate cerebral blood flow. A study just published in the Journal of the American Society of Nephrology demonstrates that impairments in kidney function consistent with mild CKD (chronic kidney disease) are associated with reduced blood flow in the brain. The authors state:

“CKD is linked with various brain disorders. Whereas brain integrity is dependent on cerebral perfusion, the association between kidney function and cerebral blood flow has yet to be determined.”

So they examined data from the population–based Rotterdam Study that included 2645 participants with an average age of 56.6 years, roughly half men and women. They used eGFR (calculated rate of kidney filtration) and the albumin-to-creatinine ratio to assess kidney function and phase–contrast magnetic resonance imaging of the basilar and carotid arteries to measure cerebral blood flow. The albumin-to-creatinine ratio didn’t pan out when subjected to adjustment for cardiovascular risk factors, but every decrease in eGFR was associated with reduced brain blood flow:

“Participants had an average (SD) eGFR of 86.3 (13.4) ml/min per 1.73 m2 and a median (interquartile range) albumin-to-creatinine ratio of 3.4 (2.2–6.1) mg/g. In age- and sex-adjusted models, a higher albumin-to-creatinine ratio was associated with lower cerebral blood flow level (difference in cerebral blood flow [milliliters per minute per 100 ml] per doubling of the albumin-to-creatinine ratio, −0.31… The association was not present after adjustment for cardiovascular risk factors (P=0.10). Each 1 SD lower eGFR was associated with 0.42 ml/min per 100 ml lower cerebral blood flow (95% confidence interval, 0.01 to 0.83) adjusted for cardiovascular risk factors.”

Implications for blood pressure management

This applies to the general population without overt kidney disease, and clinicians should bear in mind the importance of maintaining adequate cerebral blood flow when managing hypertension and the evidence documenting worse outcomes when blood pressure is medicated too aggressively. According to the authors’ conclusion, even mild CKD may heighten the risk of adverse events such as cognitive impairment, falls and dizziness due to impairments of brain perfusion when blood pressure is forced too low.

“Thus, in this population-based study, we observed that lower eGFR is independently associated with lower cerebral blood flow.”

CKD (chronic kidney disease) expected for 50% over age 30

American Journal of Kidney DiseasesChronic kidney disease (CKD) is rising steeply and projected to affect more than half of those aged 30 to 64 years in the coming twenty years according to a study just published in the American Journal of Kidney Diseases. The authors state:

“Awareness of chronic kidney disease (CKD), defined by kidney damage or reduced glomerular filtration rate, remains low in the United States, and few estimates of its future burden exist…We used the CKD Health Policy Model to simulate the residual lifetime incidence of CKD and project the prevalence of CKD in 2020 and 2030. The simulation sample was based on nationally representative data from the 1999 to 2010 National Health and Nutrition Examination Surveys.”

More than half of people aged 30 to 64 years likely to be affected

The authors’ data showed that…

For US adults aged 30 to 49, 50 to 64, and 65 years or older with no CKD at baseline, the residual lifetime incidences of CKD are 54%, 52%, and 42%, respectively. The prevalence of CKD in adults 30 years or older is projected to increase from 13.2% currently to 14.4% in 2020 and 16.7% in 2030.”

Currently one in seven adults is affected by chronic kidney disease. The public health consequences are enormous. The authors conclude:

“For an individual, lifetime risk of CKD is high, with more than half the US adults aged 30 to 64 years likely to develop CKD. Knowing the lifetime incidence of CKD may raise individuals’ awareness and encourage them to take steps to prevent CKD.”

Prevention: Metabolic syndrome and chronic kidney disease

Current Opinion in Nephrology and HypertensionComponents of metabolic syndrome (MetS) including insulin resistance, hypertension, dyslipidemia and inflammation are particularly rough on the kidneys. A review published in Current Opinion in Nephrology and Hypertension highlights the connection:

“The association of the metabolic syndrome (MetS) with cardiovascular risk, mortality, type 2 diabetes mellitus, stroke, nonfatty liver disease and gout is well known. However, the association of the MetS with chronic kidney disease (CKD) is now emerging…Studies show that patients with MetS have a 2.5-fold higher risk of developing CKD. The risk of microalbuminuria is also increased two-fold in the MetS. Renal dysfunction becomes apparent long before the appearance of hypertension or diabetes in MetS. Compared with healthy controls, patients with MetS have increased microvascular disease-tubular atrophy, interstitial fibrosis, arterial sclerosis and global and segmental sclerosis.”

Clinicians should especially note that metabolic syndrome is contributing to chronic kidney disease well before it evolves into diabetes and the development of hypertension. Regarding potential mechanisms:

“Studies suggest that the renal fibrosis seen in MetS might be caused by a constellation of insulin resistance, hypertension, dyslipidemias and inflammation, and result in a heightened expression of adipocytokines, angiotensin and inflammatory cytokines such as interleukin-6 and tumour necrosis factor-alpha.”

World Journal of NephrologyThe author of a paper published in the World Journal of Nephrology states:

“Despite the ambiguous definition of MetS, it has been clearly associated with chronic kidney disease markers including reduced glomerular filtration rate, proteinuria and/or microalbuminuria, and histopathological markers such as tubular atrophy and interstitial fibrosis. However, the etiological role of MetS in chronic kidney disease (CKD) is less clear. The relationship between MetS and CKD is complex and bidirectional, and so is best understood when CKD is viewed as a common progressive illness along the course of which MetS, another common disease, may intervene and contribute. Possible mechanisms of renal injury include insulin resistance and oxidative stress, increased proinflammatory cytokine production, increased connective tissue growth and profibrotic factor production, increased microvascular injury, and renal ischemia.

PLOS ONEThe authors of a study published in PLOS One on the relation between metabolic syndrome and chronic kidney disease in an adult Korean population came to the conclusion:

“The strength of association between MS [metabolic syndrome] and the development of CKD increase as the number of components increased from 1 to 5. In sub-analysis by men and women, MS and its each components were a significant determinant for CKDMS and its individual components can predict the risk of prevalent CKD for men and women.”

Moreover, they excluded patients with diabetes to more clearly isolate contribution of metabolic syndrome to CKD.

Cardiology Research and PracticeCommenting on the link between metabolic syndrome and chronic kidney disease in the development of cardiovascular disease in a paper published in Cardiology Research and Practice the authors note:

Microalbuminuria has been described as the earliest manifestation of MetS-associated kidney damage and diabetic nephropathy, and it is associated with insulin resistance independent of diabetes. MetS is often accompanied by increased plasma renin activity, angiotensinogen, angiotensin-converting enzyme activity, and angiotensin II (renin-angiotensin-aldosterone system) and with renal sympathetic activity. Hyperinsulinemia, insulin resistance, and increased plasma angiotensin II levels are potent activators of expression of transforming growth factor-β1, a fibrogenic cytokine that contributes to glomerular injury.”

Insulin resistance, of course, spurs chronic inflammation:

“The hallmark of MetS is insulin resistance. Inflammatory mediators, including tumor necrosis factor (TNF)-α, have been shown to mediate insulin resistance. Adipokines, including TNF-α, IL-6, and resistin, are cytokines secreted by adipose tissue, and their plasma concentrations are elevated in patients with MetS, whereas their plasma adiponectin levels are reduced. These findings may contribute to insulin resistance, and insulin resistance promotes chronic inflammation.”

Sugar versus salt in hypertension and chronic kidney disease

Open HeartA striking paper just published in the journal Open Heart (British Cardiovascular Society) identifying sugar as a worse culprit than salt for hypertension and cardiometabolic disease further links metabolic syndrome and chronic kidney disease. The authors note:

“Cardiovascular disease is the leading cause of premature mortality in the developed world, and hypertension is its most important risk factor. Controlling hypertension is a major focus of public health initiatives, and dietary approaches have historically focused on sodium. While the potential benefits of sodium-reduction strategies are debatable, one fact about which there is little debate is that the predominant sources of sodium in the diet are industrially processed foods.”

But processed foods are high in sugar as well as salt, and it may be unwise to aggressively change sodium consumption…

‘Strategies to lower dietary sodium intake focus (implicitly if not explicitly) on reducing consumption of processed foods: the predominant sources of sodium in the diet…Nonetheless, the mean intake of sodium in Western populations is approximately 3.5–4 g/day. Five decades worth of data indicates that sodium intake has not changed from this level across diverse populations and eating habits, despite population-wide sodium-reduction efforts and changes in the food supply.Such stability in intake suggests tight physiologic control, which if indeed the case, could mean that lowering sodium levels in the food supply could have unintended consequences. Because processed foods are the principal source of dietary sodium, if these foods became less salty, there could be a compensatory increase in their consumption to obtain the sodium that physiology demands.

Highly refined carbohydrates, the fuel for metabolic syndrome, worse than salt

This includes fructose:

“Coincidentally, processed foods happen to be major sources of not just sodium but of highly refined carbohydrates: that is, various sugars, and the simple starches that give rise to them through digestion. Compelling evidence from basic science, population studies, and clinical trials implicates sugars, and particularly the monosaccharide fructose, as playing a major role in the development of hypertension. Moreover, evidence suggests that sugars in general, and fructose in particular, may contribute to overall cardiovascular risk through a variety of mechanisms. Lowering sodium levels in processed foods could lead to an increased consumption of starches and sugars and thereby increase in hypertension and overall cardiometabolic disease.”

Hypertensive mechanisms of fructose. NO, nitric oxide; RAS, renin-angiotensin system; RNS, reactive nitrogen species; ROS, reactive oxygen species.

Hypertensive mechanisms of fructose. NO, nitric oxide; RAS, renin-angiotensin system; RNS, reactive nitrogen species; ROS, reactive oxygen species.

 “Although high intakes of either fructose alone or sucrose may lead to insulin resistance, it is fructose that has been implicated as the sugar responsible for reducing sensitivity of adipose tissue to insulin.Insulin stimulates the SNS and hyperinsulinaemia may lead to hypertension, with the degree of insulin resistance in peripheral tissues directly correlated with hypertension severity. Reducing insulin resistance may lead to a reduction in blood pressure, and hyperinsulinaemia seems more related to fructose than glucose.”

The authors make a distinction between fructose added to foods and that found naturally in whole fruit as stated in their conclusion:

“While naturally occurring sugars in the form of whole foods like fruit are of no concern, epidemiological and experimental evidence suggest that added sugars (particularly those engineered to be high in fructose) are a problem and should be targeted more explicitly in dietary guidelines to support cardiometabolic and general health…Evidence from epidemiological studies and experimental trials in animals and humans suggests that added sugars, particularly fructose, may increase blood pressure and blood pressure variability, increase heart rate and myocardial oxygen demand, and contribute to inflammation, insulin resistance and broader metabolic dysfunction. Thus, while there is no argument that recommendations to reduce consumption of processed foods are highly appropriate and advisable, the arguments in this review are that the benefits of such recommendations might have less to do with sodium—minimally related to blood pressure and perhaps even inversely related to cardiovascular risk—and more to do with highly-refined carbohydrates. It is time for guideline committees to shift focus away from salt and focus greater attention to the likely more-consequential food additive: sugar.”

Quoted in Medscape Medical News, Richard Krasuski, MD, from the Cleveland Clinic in Ohio commented on the study:

“”It is a little bit frightening that we have been focusing on salt for so long.”…The conclusion that sugar represents a greater danger to the heart than salt, Dr Krasuski said, was an “eye opener.” He acknowledged, though, that he should have anticipated it. He and other cardiologists have noticed that the recommendations to increasingly lower salt intake have not resulted in the expected positive cardiovascular outcomes.”

Bottom line for chronic kidney disease

CKD incidence is rising steeply and projected to affect half the population aged 30 to 64. Key causal factors are metabolic syndrome with insulin resistance and hypertension. These are made worse by added sugars than by salt. Appropriate diet, objective determination of individual genetic and circumstantial needs for supplementation, regular exercise, not smoking, stress management and addressing sleep disordered breathing are common sense preventive and remedial measures.

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.”

Blood pressure forced too low and cognitive impairment

JAMA Internal MedicineBlood pressure treatment should relieve hypertension without attempting to achieve ‘perfect’ levels which can harm by impairing brain perfusion resulting in cognitive impairment. A study just published JAMA Internal Medicine adds to the body of evidence indicating that blood pressure management in the elderly must allow adequate pressure to maintain circulation to the periphery (which includes the brain). The authors set out to…

“…assess whether office blood pressure, ambulatory blood pressure monitoring, or the use of antihypertensive drugs (AHDs) predict the progression of cognitive decline in patients with overt dementia and mild cognitive impairment (MCI).”

Daytime systolic blood pressure equal or less than 128 mm Hg

They analyzed data for 172 patients whose average age was 79 with a Mini-Mental State Examination (MMSE) mean score of 22.1, among whom 68% had dementia, 32% had mild cognitive impairment (MCI), and 69.8% were being treated with anti-hypertensive drugs (AHDs). Over-medicating for blood pressure was associated with cognitive impairment:

Patients in the lowest tertile of daytime systolic blood pressure (SBP) (≤128 mm Hg) showed a greater MMSE score change compared with patients in the intermediate tertile (129-144 mm Hg) and patients in the highest tertile (≥145 mm Hg). The association was significant in the dementia and MCI subgroups only among patients treated with AHDs. In a multivariable model that included age, baseline MMSE score, and vascular comorbidity score, the interaction term between low daytime SBP tertile and AHD treatment was independently associated with a greater cognitive decline in both subgroups. The association between office SBP and MMSE score change was weaker. Other ambulatory blood pressure monitoring variables were not associated with MMSE score change.”

Lower is not always better

The authors of a commentary in the same issue of JAMA Internal Medicine write:

“We think it is time to move from the concept of ‘the lower the better’ to the concept of ‘hemodynamic optimization‘ to decelerate the pace of cognitive decline by a proper management of blood pressure.”

Evidence-based guideline from the Eighth Joint National Committee (JNC 8) 2014

Recommendations from these guidelines as listed in Medscape include:

  • In patients aged 60 years or older, start treatment for SBP >150 mm Hg or DBP >90 mm Hg and treat to under those thresholds.
  • In patients aged 18-60 years, treatment initiation and goals should be 140/90 mm Hg.
  • The same goals apply to patients with diabetes or CKD.
  • In nonblack patients, initial treatment can be a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin-converting-enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB).
  • For black patients, initial therapy should be a thiazide-type diuretic or CCB.
  • In patients aged 18 years or older with CKD, initial or add-on therapy should be an ACE inhibitor or ARB, regardless of race or diabetes status.

The authors of the study on blood pressure treatment and cognitive impairment conclude:

Low daytime SBP was independently associated with a greater progression of cognitive decline in older patients with dementia and MCI among those treated with AHDs. Excessive SBP lowering may be harmful for older patients with cognitive impairment. Ambulatory blood pressure monitoring can be useful to help avoid high blood pressure overtreatment in this population.

Nuts reduce inflammation and all-cause mortality

Asia Pacific Journal of Clinical NutritionNuts have been shown to confer multiple health benefits, so it’s disconcerting to see  some apparently popular paleo diet plans that forbid them. In the absence of a nut allergy it’s a shame to forgo the benefit of such a healthful and convenient food. The intent of the paleo diet is to reduce inflammation, so it’s worth considering a paper published in the Asia Pacific Journal of Clinical Nutrition offering evidence that nuts reduce inflammation. The authors note:

“Several large epidemiological studies have associated the frequency of nut consumption with reduced risk of coronary heart disease (CHD), CVD, myocardial infarction, sudden death, and all causes of mortality, Type 2 diabetes (T2D) and other chronic disease.

Nuts are anti-inflammatory

Key inflammatory markers including CRP and IL-6 are reduced by nut consumption:

“Epidemiological and clinical studies suggest that some dietary factors, such as n–3 polyunsaturated fatty acids, antioxidant vitamins, dietary fiber, L-arginine and magnesium may play an important role in modulating inflammation. The relationship observed between frequent nut consumption and the reduced risk of cardiovascular mortality and type 2 diabetes in some prospective studies could be explained by the fact that nuts are rich in all of these modulator nutrients. In fact, frequent nut consumption has been associated with lower concentrations of some peripheral inflammation markers in cross-sectional studies. Nut consumption has also been shown to decrease the plasma concentration of CRP, IL-6 and some endothelial markers in recent clinical trials.”

Nuts also benefit cholesterol and lipids

“In the last two decades, a considerable number of clinical trials have consistently demonstrated beneficial effects on blood lipids and lipoproteins, primarily a decrease in Low-density lipoprotein (LDL) cholesterol, a classical CHD risk factor. This effect has been demonstrated consistently in different population groups, using different types of nuts (walnuts, hazelnuts, almonds, pecan, pistachio and macadamia nuts) and study designs. The favourable effects of tree nuts or tree nut oils on plasma lipid and lipoprotein profiles is a mechanism that appears to account for some of the cardio protective effects observed in the epidemiological studies.”

Nuts and olive oil are a great combination for cardiovascular risk:

“…in a cross-sectional study we evaluated the association between components of the Mediterranean diet and circulating markers of inflammation in a large cohort of asymptomatic subjects with high risk of cardiovascular disease. Subjects with the highest consumption of nuts and virgin olive oil showed the lowest concentrations of VCAM-1, ICAM-1, IL-6 and CRP; although this difference was statistically significant for ICAM-1 only in the case of nuts and for VCAM-1 in the case of olive oil.”

After reviewing several other studies documenting improvements in inflammation and endothelial function the authors conclude:

“In conclusion, nuts are complex food matrices containing diverse nutrients and other chemical constituents that may favourably influence human physiology. These sub- stances may inhibit the activation of the innate immune system, probably by decreasing the production of proinflammatory cytokines such as CRP, IL-6, TNF-α or IL-18, and increase the production of antiinflammatory cytokines such as adiponectin. This may improve the proinflammatory milieu, which in turn ameliorates endothelial dysfunction at the vascular level, and ultimately decreases the risk of insulin resistance, type 2 diabetes and coronary heart disease. The capacity of nuts to modulate inflammation may explain at least in part why frequent nut consumption is associated with reduced risk of diabetes and cardiovascular disease in epidemiological studies.”

Nut consumption reduces total and cause-specific mortality

New England Journal of MedicineA paper published earlier this year in The New England Journal of Medicine add more extensive data presenting evidence that eating nuts reduces death from cancer, heart disease, respiratory disease and ‘all causes’.

“Observational and intervention studies of nut consumption have also shown reductions in various mediators of chronic diseases, including oxidative stress, inflammation, visceral adiposity, hyperglycemia, insulin resistance, and endothelial dysfunction. In prospective cohort studies, increased nut intake has been associated with reduced risks of type 2 diabetes mellitus, the metabolic syndrome, colon cancer, hypertension, gallstone disease, diverticulitis, and death from inflammatory diseases.”

To extend the data to encompass the effects of eating nuts and all causes of death the authors:

“…examined the association of nut consumption with total and cause-specific mortality in two large, independent cohort studies of nurses and other health professionals. These studies provide repeated measures of diet (including separate data on peanuts and tree nuts), extensive data on known or suspected confounding variables, 30 years of follow-up, and data on more than 27,000 deaths for analysis.”

Their data suggest that nuts are among the healthiest foods to eat:

“In two large prospective U.S. cohorts, we found a significant, dose-dependent inverse association between nut consumption and total mortality, after adjusting for potential confounders. As compared with participants who did not eat nuts, those who consumed nuts seven or more times per week had a 20% lower death rate. Inverse associations were observed for most major causes of death, including heart disease, cancer, and respiratory diseases. Results were similar for peanuts and tree nuts, and the inverse association persisted across all subgroups.”

Some nuts every day was the best:

“Our results are consistent with the findings in previous, smaller studies. The Adventist Health Study showed that, as compared with nut consumption less than once per week, consumption five or more times per week was associated with reduced total mortality among whites, blacks, and elderly persons, with hazard ratios ranging from 0.56 to 0.82. Similarly, a study of a U.K. cohort, the Iowa Women’s Health Study, the Netherlands Cohort Study, and an earlier analysis of the NHS all showed significant inverse associations between nut intake and total mortality. Finally, in a recent secondary analysis within the PREDIMED (Prevención con Dieta Mediterránea) trial, a hazard ratio for death of 0.61 (95% CI, 0.45 to 0.83) was found for consumption of more than three servings of nuts per week, as compared with no nut consumption.”

Bottom line: ‘paleo’ and ‘autoimmune’ paleo diets can be fine healing diets for many, but like everything else should not be applied dogmatically or in a ‘rubber stamp’, ‘one-size-fits-all’ manner. In the absence of allergy, the evidence supports the consumption of nuts as wholesome foods with anti-inflammatory and metabolic benefits, exactly what paleo diets intend to accomplish.

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.

Brain atrophy is promoted by both high and low blood pressure

JAMA NeurologyBrain atrophy, with progressive cognitive impairment, can include among causal factors neuronal loss due to diminished oxygen perfusion. Earlier posts have documented the importance of not over-medicating hypertension. A study just published in JAMA Neurology provides evidence that brain atrophy is promoted by low diastolic blood pressure in addition to hypertension. The authors note that…

“Studies have shown that both high and low blood pressure (BP) may play a role in the etiology of brain atrophy. High BP in midlife has been associated with more brain atrophy later in life, whereas studies in older populations have shown a relation between low BP and more brain atrophy. Yet, prospective evidence is limited, and the relation remains unclear in patients with manifest arterial disease.”

So they investigated the associations of baseline blood pressure changes in BP over time with the progression of brain atrophy by examining data for 663 patients over almost four years. In addition to blood pressure their measurements included brain parenchymal fraction, cortical gray matter fraction, and brain ventricular fraction as metrics for the progression of global, cortical, and subcortical brain atrophy. Clinicians who manage blood pressure should take note of their findings:

“Multivariable adjusted regression analysis showed that patients with lower baseline diastolic BP (DBP) or mean arterial pressure had more progression of subcortical atrophy… Furthermore, in patients with higher baseline BP (DBP, mean arterial pressure, or systolic BP), those with declining BP levels over time had less progression of subcortical atrophy compared with those with rising BP levels.”

How should we make practical use of these results? As the authors state in their conclusion, hypertension should be managed appropriately but caution must be taken in lowering blood pressure when the diastolic measurement is already on the low side:

“In patients with manifest arterial disease, low baseline DBP was associated with more progression of subcortical atrophy, irrespective of the BP course during follow-up. Furthermore, in patients with higher baseline BP, declining BP levels over time were associated with less progression of subcortical atrophy. This could imply that BP lowering is beneficial in patients with higher BP levels, but caution should be taken with further BP lowering in patients who already have a low DBP.”

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.