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.”

Moreover…

“…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.”

Moreover…

“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.

Oxidized LDL promotes atherosclerosis

Science SignalingOxidized LDL, low density lipoprotein that has been that has been subject to oxidation as participates in a vascular infllammatory process, is a direct risk factor for heart attacks and ischemic strokes and a more accurate predictor than ‘ordinary’ undamaged LDL. Research recently published in Science Signaling elucidates one of the mechanisms by which oxidized LDL promotes atherosclerosis.

Oxidized LDL promotes foam cell generation

Foam cells are the macrophages (white blood cells) filled with fat that accumulate in the build-up of atherosclerotic plaque.

“One characteristic of atherosclerosis is the accumulation of lipid-laden macrophage foam cells in the arterial wall. We have previously shown that the binding of oxidized low-density lipoprotein (oxLDL) to the scavenger receptor CD36 activates the kinase Lyn, initiating a cascade that inhibits macrophage migration and is necessary for foam cell generation.”

The authors demonstrated that blocking the ion transporter Na+/K+-ATPase, a key link in this signaling chain, protects against diet-induced atherosclerosis:

“We identified the plasma membrane ion transporter Na+/K+-ATPase as a key component in the macrophage oxLDL-CD36 signaling axis. Using peritoneal macrophages isolated from Atp1a1 heterozygous or Cd36-null mice, we demonstrated that CD36 recruited an Na+/K+-ATPase–Lyn complex for Lyn activation in response to oxLDL. Macrophages deficient in the α1 Na+/K+-ATPase catalytic subunit did not respond to activation of CD36, showing attenuated oxLDL uptake and foam cell formation, and oxLDL failed to inhibit migration of these macrophages. Furthermore, Apoe-null mice, which are a model of atherosclerosis, were protected from diet-induced atherosclerosis by global deletion of a single allele encoding the α1 Na+/K+-ATPase subunit or reconstitution with macrophages that lacked an allele encoding the α1 Na+/K+-ATPase subunit. These findings identify Na+/K+-ATPase as a potential target for preventing or treating atherosclerosis.”

Clinical Note

Case management of cardiovascular risk entails the measurement of oxidized LDL as a key predictive biomarker, and interval changes are important to objectively gauge the effectiveness of lifestyle and other interventions.

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.

Metabolic health status and aging determined by inflammation, not weight

JCEM Vol 98 Number 9Metabolic health is not reliably determined by weight or BMI (body mass index). Lean individuals can suffer from cardiovascular and other diseases involving metabolism, and  evidence has been mounting that supports the notion of a subtype of obesity that is metabolically healthy. A study recently published in JCEM (The Journal of Clinical Endocrinology & Metabolism) shows that inflammation can determine metabolic health in both obese and non-obese populations. The authors state:

Inflammation is a potential mechanism linking obesity and cardiometabolic risk… The aim of the study was to investigate the extent to which differences between metabolically healthy and unhealthy obese and nonobese adults, defined using a range of metabolic health definitions, are correlated with a range of inflammatory markers.”

To do so they measured serum acute-phase reactants, adipocytokines, proinflammatory cytokines, and white blood cell counts in 2047 men and women who they classified as obese (BMI more than 30 kg/m2) and nonobese (BMI less than kg/m2). They established metabolic health status with five definitions that included markers such as blood pressure, triglycerides, LDL, HDL, total cholesterol, fasting glucose, and insulin resistance (HOMA). Several of the inflammatory markers were more strongly associated with metabolic health:

“According to most definitions, metabolically healthy obese and nonobese individuals presented with lower concentrations of complement component 3, C-reactive protein, TNF-α, IL-6, and plasminogen activator inhibitor-1; higher adiponectin levels; and reduced white blood cell count compared to their metabolically unhealthy counterparts. Logistic regression analysis identified greater likelihood of metabolically healthy obesity among individuals with lower levels of complement component 3 (odds ratios [ORs], 2–3.5), IL-6 (ORs, 1.7–2.9), plasminogen activator inhibitor-1 (ORs, 1.7–2.9), and white blood cells (ORs, 2.1–2.5) and higher adiponectin concentrations (ORs, 2.6–4.0).”

In other words, lower C3, CRP, TNF-α, IL-6, PAI-1, and white blood cells, along with higher adiponectin were associated with metabolic health in both groups. Lower C3, IL-6, PAI-1 and higher adiponectin were most strongly indicative of metabolic health among the obese. The authors’ conclusion highlights what clinicians should bear in mind:

Favorable inflammatory status is positively associated with metabolic health in obese and nonobese individuals. These findings are of public health and clinical significance in terms of screening and stratification based on metabolic health phenotype to identify those at greatest cardiometabolic risk for whom appropriate therapeutic or intervention strategies should be developed. “

 

CMAJ Vol 185 Num 13Furthermore, inflammation is turning out to be a key determinant of the quality of aging. The authors of a paper recently published in CMAJ (Canadian Medical Association Journal) state:

Chronic inflammation has been implicated in the pathogenesis of age-related conditions, such as type 2 diabetes, cardiovascular disease, cognitive impairment and brain atrophy… For example, obesity increases inflammation, and chronic inflammation, in turn, contributes to the development of type 2 diabetes by inducing insulin resistance, and to coronary artery disease by promoting atherogenesis. Thus, raised levels of inflammation appear to be implicated in various pathological processes leading to diseases in older age… We assessed inflammatory markers twice over a 5-year exposure period to examine the association between chronic inflammation and future aging phenotypes in a large population of men and women.”

They examined interleukin-6 (IL-6) levels for 3044 middle-aged adults at baseline and 5 years earlier and correlated it with cause-specific mortality, chronic disease and functioning from hospital and register data and clinical examinations. The authors focused on IL-6 because:

“Of the various markers of systemic inflammation, interleukin-6 is particularly relevant to aging outcomes. There is increasing evidence that interleukin-6 is the pro-inflammatory cytokine that “drives” downstream inflammatory markers, such as C-reactive protein and fibrinogen. Interleukin-6, in contrast to C-reactive protein and fibrinogen, is also likely to play a causal role in aging owing to its direct effects on the brain and skeletal muscles. In addition, results of Mendelian randomization studies of interleukin-6 and studies of antagonists are consistent with a causal role for interleukin-6 in relation to coronary artery disease, again in contrast to C-reactive protein and fibrinogen.”

They created four aging phenotypes at the 10-year follow-up defined as:

  • Successful aging (free of major chronic disease and with optimal physical, mental and cognitive functioning)
  • Incident fatal or nonfatal cardiovascular disease
  • Death from noncardiovascular causes
  • Normal aging (all other participants)

Chronic inflammation as determined by higher IL-6 levels was clearly associated with the poorer aging phenotypes:

“Of the 3044 participants, 721 (23.7%) met the criteria for successful aging at the 10-year follow-up, 321 (10.6%) had cardiovascular disease events, 147 (4.8%) died from noncardiovascular causes, and the remaining 1855 (60.9%) were included in the normal aging phenotype. After adjustment for potential confounders, having a high interleukin-6 level (> 2.0 ng/L) twice over the 5-year exposure period nearly halved the odds of successful aging at the 10-year follow-up (odds ratio [OR] 0.53) and increased the risk of future cardiovascular events (OR 1.64) and noncardiovascular death (OR 2.43).”

IL-6 is not the only useful metric for chronic inflammation in aging, but the authors interpret their data as offering good evidence for its use:

Chronic inflammation, as ascertained by repeat measurements, was associated with a range of unhealthy aging phenotypes and a decreased likelihood of successful aging. Our results suggest that assessing long-term chronic inflammation by repeat measurement of interleukin-6 has the potential to guide clinical practice.

And, not surprisingly, two measurements of IL-6 were better than one:

“Our results on the associations between inflammation, cardiovascular events and death from noncardiovascular causes are concordant with those reported in the literature. However, our results also show that measuring chronic inflammation twice may be a better predictor of future cardiovascular disease and noncardiovascular death than measuring inflammation only once.”

In conclusion:

“We found that chronic inflammation characterized by a high interleukin-6 level (> 2.0 ng/L) measured twice over the 5-year exposure period nearly halved the odds of successful aging after 10 years of follow-up compared with maintaining a low level of interleukin-6 (< 1.0 ng/L twice over the exposure period). Our study showed that high interleukin-6 levels at baseline were inversely associated with most of the individual components that characterize successful aging…”

 

Experimental GerontologyIn this context it’s important to consider the role of autoimmunity in inflammation that produces poor aging outcomes. A paper just published in Experimental Gerontology shows how an increase in the Th17/Treg ratio, a pro-inflammatory shift that is a hallmark of autoimmune phenomena, is also associated with increased inflammation of aging called ‘inflammaging‘.

Aging is associated with multiple changes in the proliferative and functional abilities of the immune system which are not related to any pathology but consequences in immunosenescence and inflammagingT helper (TH) 17 cells have been implicated in the development of autoimmune and chronic inflammatory diseases in humans. Additionally, a reciprocal relationship between these pro-inflammatory TH17 and the anti-inflammatory regulatory T cells (Tregs) has been described.”

The authors investigated the proportion of pro-inflammatory TH17 cells (CD4 + IL23R +) and anti-inflammatory Tregs (regulatory T cells that modulate the immune response and depend on vitamin D) along with their respective cytokines IL-17 and IL-10 in human healthy donors:

“The data revealed a continual increase of basal CD4 + IL23R + cell amounts in the different age groups. By analyzing the balance of both T-cell subsets it was observed that, on a basal resting level, TH17 cells were significantly increased in older individuals whereas Tregs were reduced.”

Clinical note: This is of great practical significance since almost all the manifold disorders associated with aging, from diminished cognitive function to osteoporosis, have an inflammatory component. The authors conclude:

“…changes of the TH17/Treg ratios in combination with altered cytokine expression during aging may contribute to an imbalance between the pro-inflammatory and the anti-inflammatory immune response. This indicates a higher susceptibility to develop inflammatory diseases with increasing age.”

Dried apples and plums lower cardiovascular disease risk in postmenopausal women

Dried apples? A clinical trial just published in the Journal of the Academy of Nutrition and Dietetics offers evidence that consuming a modest amount of dried apples and plums (prunes) can lower cardiovascular disease risk by improving lipids and reducing inflammation. The authors state…

“Evidence suggests that consumption of apple or its bioactive components modulate lipid metabolism and reduce the production of proinflammatory molecules. However, there is a paucity of such research in human beings…Hence, we conducted a 1-year clinical trial to evaluate the effect of dried apple vs dried plum consumption in reducing cardiovascular disease risk factors in postmenopausal women.”

They randomly assigned 160 qualified postmenopausal women to one of two groups: dried apple (75 g/day) or dried plum (comparative control). While documenting physical activity and diet the collected fasting blood samples at baseline, 3, 6, and 12 months to measure various cardiovascular disease risk markers. The data showed that both dried apples and dried plums were helpful in their own way:

“…women who consumed dried apple lost 1.5 kg body weight by the end of the study, albeit not significantly different from the dried plum group. In terms of cholesterol, serum total cholesterol levels were significantly lower in the dried apple group compared with the dried plum group only at 6 months…women who consumed dried apple had significantly lower serum levels of total cholesterol and low-density lipoprotein cholesterol by 9% and 16%, respectively, at 3 months compared with baseline. These serum values were further decreased to 13% and 24%, respectively, after 6 months but stayed constant thereafter. The within-group analysis also reported that daily apple consumption profoundly improved atherogenic risk ratios, whereas there were no significant changes in lipid profile or atherogenic risk ratios as a result of dried plum consumption. Both dried fruits were able to lower serum levels of lipid hydroperoxide and C-reactive protein. However, serum C-reactive protein levels were significantly lower in the dried plum group compared with the dried apple group at 3 months.”

So both were successful in reducing cardiovascular disease risk factors including ‘bad’ cholesterol and markers of inflammation. The authors conclude.

“There were no significant differences between the dried apple and dried plum groups in altering serum levels of atherogenic cholesterols except total cholesterol at 6 months. However, when within treatment group comparisons are made, consumption of 75 g dried apple (about two medium-sized apples) can significantly lower atherogenic cholesterol levels as early as 3 months. Furthermore, consumption of dried apple and dried plum are beneficial to human health in terms of anti-inflammatory and antioxidative properties.”

Low LDL cholesterol associated with worse cognitive performance

Summary: cholesterol plays critical roles in cell membranes and steroid hormone production. This study associates low LDL cholesterol with worse cognitive performance. As expected, the effect is amplified by inflammation. Care should be taken to apply a balanced approach to cholesterol lowering therapies.

A truly fascinating study was just published in the journal Neurobiology of Aging investigating lipoproteins and loss of cognitive function. The authors state:

“The aim of this study was to examine the associations between high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, and cognition and focus on the modifying effect of inflammation.”

They collected biological and cognitive data on 1003 persons ≥ 65 years of age over 6 years of follow-up, measuring cognition with the Mini-Mental State Examination (general cognition), Auditory Verbal Learning Test (memory), and Coding Task (information processing speed). High HDL was associiated with better memory performance, but their data seem to suggest the importance of sufficient LDL cholesterol in brain neuronal membranes:

“We found an independent association between high HDL cholesterol and better memory performance. In addition, low LDL cholesterol was predictive of worse general cognitive performance and faster decline on information processing speed.”

Not at all surprisingly they found that inflammation compounds the adverse effects of low LDL:

“Furthermore, a significant modifying effect of inflammation (C-reactive protein, α-antichymotrypsin) was found. A negative additive effect of low LDL cholesterol and high inflammation was found on general cognition and memory performance.”

And since high triglycerides are commonly provoked by the high insulin levels due to insulin resistance which also have deleterious effects on the brain…

“Also, high triglycerides were associated with lower memory performance in those with high inflammation.”

The authors conclude by suggesting that HDL, LDL and inflammatory indicators can be used as predictors of poor cognitive function:

“Thus, a combination of these factors may be used as markers of prolonged lower cognitive functioning.”

This compels us to use caution and see the ‘big picture’ when designing strategies to manage lipids—care should be taken to not suppress LDL cholesterol to too low a level.

Sugar turns LDL cholesterol “ultra-bad”

That serving of french toast may be doing more to contribute to cardiovascular disease than promoting insulin resistance and dyslipidemia. A paper just published in the journal Diabetes details how excess blood sugar causes LDL cholesterol to stick more readily to arterial plaque. Inflamed vulnerable plaque on arterial walls is the main precipitating factor for heart attacks and strokes. The authors set out to…

“…study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity.”

Glycation is the damaging process by which sugar binds to substances in the body that it shouldn’t do normally. As the practitioners reading this know, hemoglobin A1c (HbgA1c, produced by glycation of hemoglobin) is an important laboratory metric for determining how high a person’s blood sugar has been on average over the previous few months. People with pre-diabetes (metabolic syndrome) and type 2 diabetes have higher levels. By modifying human LDL by methylglyoxal to reproduce what happens in vivo, the authors were able to measure the effect on LDL particle characteristics and its tendency to deposit in the arterial wall. What did they find?

MGmin-LDL [glycated LDL] had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MGmin-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate–containing proteoglycan. Radiotracer studies in rats showed that MGmin-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall…A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan–binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding.”

In other words, glycated LDL is a nasty compound that is less likely to be scavenged from the bloodstream; and it is smaller, denser and stickier than normal LDL so that it has a higher tendency to adhere to the blood vessel well. Glycated LDL has been called the “ultra-bad cholesterol“. It also shows part of the reason why blood sugar lowering therapies reduce cardiovascular disease. The authors conclude:

MG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin.”

Cholesterol levels vary with the menstrual cycle

A study recently published in The Journal of Clinical Endocrinology & Metabolism proves that we must take the menstrual cycle into consideration when testing cholesterol in cycling women.

“The objective of the study was to evaluate the association between endogenous [internally produced] estrogen and serum lipoproteins across the menstrual cycle.”

The authors found that total and LDL cholesterol were lower during the luteal phase (second half, when progesterone is higher) than the follicular phase:

More women were classified above the desirable range (LDL ≥130 mg/dl or total cholesterol ≥200 mg/dl) when measured during the follicular phase [first half].”

HDL was higher when estradiol had peaked, corresponding also to lower LDL and triglycerides.

Because lipoprotein cholesterol levels vary across the menstrual cycle, cyclic variations in lipoprotein levels may need to be considered in the design and interpretation of studies in reproductive-age women and in the clinical management of women’s cholesterol.

Red rice yeast preferable to pharma statins

We use the natural statin red rice yeast only with caution (and coenzyme Q10 restoration) as a palliative when cholesterol is high and may be contributing to vascular disease due to inflammation and oxidation. But why use it instead of pharmaceutical statins? This randomized trial published in the journal Annals of Internal Medicine documents that patients who had to discontinue conventional statin therapy due to muscle pain could tolerate red rice yeast. The authors set out to…

“…evaluate the effectiveness and tolerability of red yeast rice and therapeutic lifestyle change to treat dyslipidemia in patients who cannot tolerate statin therapy.”

They examined 62 patients with dyslipidemia who had to discontinue statin therapy due to muscle pains. Patients were randomly assigned to receive red rice yeast or placebo and were checked for LDL cholesterol, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, liver enzymes, and creatinine phosphokinase (CPK) levels after 24 weeks. What did the data show?

Low-density lipoprotein cholesterol level was significantly lower in the red yeast rice group than in the placebo group at both weeks 12 and 24. Significant treatment effects were also observed for total cholesterol level at weeks 12 and 24. Levels of HDL cholesterol, triglyceride, liver enzyme, or CPK; weight loss; and pain severity scores did not significantly differ between groups at either week 12 or week 24.”

In other words, the red rice yeast was effective and well tolerated by this group of patients who had adverse reactions to other statins, compelling the authors to conclude:

Red yeast rice and therapeutic lifestyle change decrease LDL cholesterol level without increasing CPK or pain levels and may be a treatment option for dyslipidemic patients who cannot tolerate statin therapy.”