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.

Subclinical hypothyroidism worsens cardiometabolic profile

Subclinical hypothyroidism and cardiometabolic biomarkersSubclinical hypothyroidism (SCH), poor thyroid effect throughout the body in the presence of ‘normal’ thyroid serum tests, is a widespread yet under-appreciated clinical challenge. A recent study published in the Journal of the Endocrine Society documents adverse cardiometabolic biomarkers in the presence of subclinical hypothyroidism. Additionally, practitioners must bear in mind that more than adequate iodine intake can worsen the condition.

Clarifying the definition of normal thyroid function

The authors note that uncertainty around the definition of normal thyroid function can go beyond contention involving different opinions on laboratory reference ranges by examining the effect of suboptimal thyroid function on the entire organism.

“As thyroid function has multisystemic effects, its derangement could affect a broad range of cardiometabolic pathways potentially related to clinical manifestations. However, the definition of normal thyroid function has been intensely debated, with some experts advocating for lowering the upper limit of normal for thyroid stimulating hormone (TSH) and others for maintaining the current standard. In this regard, thyroid-related risk for incident type 2 diabetes (T2D) and cardiovascular disease (CVD) may impact the definition of TSH normality.”

They note some of the mechanisms by which SCH can adversely affect cardiovascular and metabolic function:

“The potential relationship of thyroid hypofunction with T2D and CVD may be mediated by abnormalities in lipids, lipoprotein subclasses, endothelial function, coagulation, inflammatory pathways, and insulin resistance.”

This hardly exhausts the list of adverse physiological effects since every part of the body, including the brain, requires the stimulus of thyroid hormone to produce energy and function. The public health implications are enormous.

“Detailed assessment of thyroid function effects on these mediators/markers may have high population health implications, especially along the milder hypofunction spectrum within euthyroidism and SCH. Understanding the role of thyroid function in cardiometabolic pathways may guide the clinically relevant definition of thyroid function and unveil potential targets for controlling related morbidity.”

Subclinical hypothyroidism increases cardiometabolic risk

Thus the authors set out to…

“…examine thyroid function across the spectrum of euthyroid to HT in relationship to cardiometabolic pathways represented by lipids, lipoproteins, inflammation, coagulation, glycemic, and insulin resistance biomarkers.”

They examined data for 28,024 apparently healthy middle-aged and older women, and indeed found that cardiometabolic health worsens on a gradient from normal thyroid (euthyroid) function, through subclinical hypothyroidism, to full-blown hypothyroid:

Going from euthyroid to HT, the lipoprotein subclass profiles were indicative of insulin resistance: larger very-low-density lipoprotein size (nm); higher low-density lipoprotein (LDL) particle concentration (nmol/L), and smaller LDL size. There was worsening lipoprotein insulin resistance score from euthyroid to SCH and HT. Of the other biomarkers, SCH and HT were associated with higher high-sensitivity C-reactive protein and hemoglobin A1c. For increasing TSH quintiles, results were overall similar.”

TSH, total and LDL cholesterol not so useful

They note that it was other biomarkers that revealed the actual progressive risk:

“In this population of apparently healthy middle-aged and older women, individuals with SCH and HT had differences in the lipid and lipoprotein subclass profile that indicated worsening insulin resistance and higher cardiometabolic risk compared with euthyroid individuals, despite having similar LDL cholesterol and total cholesterol. Of the other biomarkers, only hs-CRP and HbA1c were associated with SCH and HT. For TSH quintiles mostly within the normal range, lipid and lipoprotein results for TSH quintiles were generally similar but null for other biomarkers. Hence, progressive thyroid hypofunction was associated with insulin-resistant and proatherogenic lipids and lipoproteins profile in a graded manner, with potential clinical consequences.”

Mechanisms

Besides thyroid as a driver of metabolic activity, insulin resistance appears to play a key role. They point out that insulin resistance appears to affect lipoprotein metabolism before glucose metabolism, an observation important for clinicians to bear in mind.

Thyroid hormones act as modulators of cholesterol synthesis and degradation through key enzymes. One of the main mechanisms is the stimulus of thyroid hormones over sterol regulatory element–binding protein 2, which in turn induces LDL receptor gene expression. However, it was shown that the association of HT and higher LDL cholesterol levels is present only in insulin-resistant subjects. Indeed, the lack of LDL cholesterol differences could be explained by our insulin-sensitive study population (low HbA1c levels). HT has also been associated with lower catabolism of lipid-rich lipoproteins by lipoprotein lipase, hepatic lipase, and decreased activity of cholesterol ester transfer proteinthat mediates exchanges of cholesteryl esters of HDL particles with triglyceride-rich LDL and VLDL particles. These mechanisms might explain the relationship of thyroid hypofunction with atherogenic and insulin-resistant lipid and lipoprotein abnormalities. Finally, the milder differences noted in HbA1c compared with LPIR across thyroid categories may be explained by the earlier effects of insulin resistance on lipoprotein metabolism than on glucose metabolism.”

Practitioners should be attentive to the authors’ conclusion:

“In this large population of apparently healthy women, individuals with SCH had differences in their biomarker profile that indicated worsening lipoprotein insulin resistance and higher cardiometabolic risk compared with euthyroid individuals, despite having similar LDL cholesterol and total cholesterol levels. These findings suggest that cardiometabolic risk may increase early in the progression toward SCH and overt HT.

Iodine supplementation reminder

More than adequate iodine increases autoimmune thyroiditisClinicians who may be tempted to reflexively offer iodine supplementation for thyroid disorders including subclinical hypothyroidism should remember the body of evidence showing this can fire up autoimmune thyroiditis. One example by way of a reminder is a study published in the European Journal of Endocrinology showing that more thanequate iodine intake may increase subclinical hypothyroidism and autoimmune thyroiditis. The authors describe their intent:

“With the introduction of iodized salt worldwide, more and more people are exposed to more than adequate iodine intake levels with median urinary iodine excretion (MUI 200–300 μg/l) or excessive iodine intake levels (MUI >300 μg/l). The objective of this study was to explore the associations between more than adequate iodine intake levels and the development of thyroid diseases (e.g. thyroid dysfunction, thyroid autoimmunity, and thyroid structure) in two Chinese populations.”

They examined thyroid hormones, thyroid autoantibodies in serum, iodine levels in urine were measured. and B-mode ultrasonography of the thyroid for 3813 individuals, in two areas with differing levels of iodine exposure. The levels of iodine intake were: Rongxing, MUI 261 μg/l; and Chengshan, MUI 145 μg/l. (MUI =median urinary iodine excretion.) They found a blatant difference in thyroid biomarkers:

“The prevalence of subclinical hypothyroidism was significantly higher for subjects who live in Rongxing than those who live in Chengshan. The prevalence of positive anti-thyroid peroxidase antibody (TPOAb) and positive anti-thyroglobulin antibody (TgAb) was significantly higher for subjects in Rongxing than those in Chengshan. The increase in thyroid antibodies was most pronounced in the high concentrations of TPOAb (TPOAb: ≥500 IU/ml) and low concentrations of TgAb (TgAb: 40–99 IU/ml) in Rongxing.”

Their results suggest there is a discrete window for thyroid intake:

“Compared with the adequate iodine intake level recommended by WHO/UNICEF/ICCIDD MUI (100–200 μg/l), our data indicated that MUI 200–300 μg/l might be related to potentially increased risk of developing subclinical hypothyroidism or autoimmune thyroiditis. This result differs from the WHO’s suggestion that MUI >300 μg/l may increase the risk of developing autoimmune thyroid diseases.”

Practitioners should be cautious with dosing of supplemental iodine in keeping with the authors’ conclusion:

“In conclusion, compared with the population with MUI 145 μg/l in Chengshan, the population with MUI 261 μg/l in Rongxing had a higher risk to develop autoimmune thyroiditis and subclinical hypothyroidism. Thus, more than adequate iodine intake might not be recommended for the general population in terms of keeping a normal function of thyroid.”

Readers may wish to also see the earlier post Hypothyroidism can be provoked by small amounts of supplemental iodine.

Prediabetes, chronic inflammation and hemoglobin A1c

PrediabetesPrediabetes, blood glucose is slightly higher than normal but not enough to qualify for diabetes, is associated with an increased systemic burden of inflammation and elevated risk for cardiovascular, cancer, dementia and other diseases. The first study described in this post, published in the European Journal of Nutrition, highlights the link between prediabetes, chronic inflammation and mortality from a range of diseases tied to HgbA1c (hemoglobin A1c, glycosylated hemoglobin), the key biomarker for glucose regulation. The authors state:

Chronic inflammation is associated with increased risk of cancer, cardiovascular disease (CVD), and diabetes. The role of pro-inflammatory diet in the risk of cancer mortality and CVD mortality in prediabetics is unclear. We examined the relationship between diet-associated inflammation, as measured by dietary inflammatory index (DII) score, and mortality, with special focus on prediabetics.”

Pro-inflammatory diet plus prediabetes (increased HgbA1c)

Of great significance is the effect they reveal when a pro-inflammatory diet, measured by the dietary inflammatory index (DII) score, is consumed when there is elevated HgbA1c. They categorized 13,280 subjects between the ages 20 of and 90 years according to whether or not they were prediabetic, which they defined as a HgbA1c percentage of 5.7–6.4. Their data highlighted this connection between all-cause mortality, a pro-inflammatory diet and prediabetes:

“The prevalence of prediabetes was 20.19 %. After controlling for age, sex, race, HgbA1c, current smoking, physical activity, BMI, and systolic blood pressure, DII scores in tertile III (vs tertile I) was significantly associated with mortality from all causes (HR 1.39, 95 % CI 1.13, 1.72), CVD (HR 1.44, 95 % CI 1.02, 2.04), all cancers (HR 2.02, 95 % CI 1.27, 3.21), and digestive-tract cancer (HR 2.89, 95 % CI 1.08, 7.71). Findings for lung cancer (HR 2.01, 95 % CI 0.93, 4.34) suggested a likely effect.”

The authors conclude:

“A pro-inflammatory diet, as indicated by higher DII scores, is associated with an increased risk of all-cause, CVD, all-cancer, and digestive-tract cancer mortality among prediabetic subjects.”

 Prediabetes and cardiovascular risk

Research published in The BMJ (British Medical Journal) focusses on the substantial impact of prediabetes on the risk of heart attack and ischemic stroke. The authors set out to…

“…evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality…”

…by analyzing 53 prospective cohort studies with 1,611,339 individuals that passed the screening tests for validity. In this study they applied several definitions of prediabetes:

“Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L = 101-124 mg/dL), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L = 110-124 mg/dL), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L = 141-198 mg/dL during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47 mmol/mol [5.7-6.4%] according to ADA criteria or 42-47 mmol/mol [6.0-6.4%] according to the National Institute for Health and Care Excellence (NICE) guideline.”

Their data show that prediabetes with a ‘mildly’ elevated HgbA1c was clearly associated with increased cardiovascular risk:

“Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39-47 mmol/mol [5.7-6.4%] or 42-47 mmol/mol [6.0-6.4%] were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.”

Interestingly, risk of stroke does not emerge from these data, suggesting other factors promoting vascular inflammation. The authors conclude:

“…we found that prediabetes defined as impaired fasting glucose or impaired glucose tolerance is associated with an increased risk of composite cardiovascular events, coronary heart disease, stroke, and all cause mortality. There was an increased risk in people with fasting plasma glucose as low as 5.6 mmol/L [100 mg/dL]. Additionally, the risk of composite cardiovascular events and coronary heart disease increased in people with raised HbA1c. These results support the lower cut-off point for impaired fasting glucose according to ADA criteria as well as the incorporation of HbA1c in defining prediabetes.”

HgbA1c and risk of all-cause and cause-specific mortality without diabetes

Similar results were obtained in a study published in Scientific Reports. Here the authors concluded:

“We found evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer in this meta-analysis. The dose-response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. This fact reveals a clear threshold effect for the association of HbA1clevels with mortality. In addition, from the perspective of mortality benefit and health care burden, it suggests that the most appropriate HbA1c level of initiating intervention is approximately 5.7%…higher HbA1c level is associated with increased mortality from all causes, CVD, and cancer among subjects without known diabetes. However, this association is influenced by those with undiagnosed diabetes or prediabetes .Because of limited studies, the results in relation to cancer mortality should be treated with caution, and more studies are therefore warranted to investigate whether higher HbA1c level is associated with increased cancer mortality.”

 

DHEA predicts coronary heart disease risk

Journal of the American College of CardiologyDHEA (dehydroepiandosterone) an adrenal steroid hormone also produced in the brain, is associated with many inflammatory and other disorders. A study recently published in the Journal of the American College of Cardiology shows that low DHEA can predict coronary heart disease in older men. This is especially important because there is still a high incidence of sudden cardiac death in individuals who do not have the traditional risk factors. The authors state:

“The adrenal sex hormone dehydroepiandrosterone (DHEA), which is present in serum mainly as the sulfate DHEA-S, is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. Despite the great amount of literature on vascular and metabolic actions of DHEA/-S, evidence for an association between DHEA/-S levels and cardiovascular events is contradictory.”

To test predictive value for major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events, they measured  baseline levels in a large cohort of men aged 69-81 and correlated this with a 5-year follow-up for complete cardiovascular clinical outcomes.

DHEA predicts coronary heart disease but not stroke

The predictive accuracy persisted even when traditional cardiovascular risk factors were adjusted for :

“During the 5-year follow-up, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the hazard ratios and 95% confidence intervals per SD increase were 0.82 (0.73 to 0.93) and 0.86 (0.77 to 0.97), respectively. In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function, and remained unchanged after exclusion of the first 2.6 years of follow-up to reduce reverse causality.”

Changing the assessment of cardiovascular risk

The authors of an editorial in the same issue of JACC assert:

Everything we once thought we knew about the therapeutic use of estrogen for the prevention of cardiovascular disease (CVD) in women is wrong. Everything we once knew about the role of sex in CVD is still right; men are affected a decade earlier than women. We are still enamored with the idea that sex steroids, particularly androgens, have, if not a causal role in CVD development, at least an association. We simply cannot get the notion out of our heads that androgens (or relative lack of estrogen) drive endothelial dysfunction and atherogenesis, and potentially, even plaque fracture. In this light, new studies that assess the risk associated with low levels of a particularly abundant sex steroid (dehydroepiandrosterone [DHEA] and its sulfated congener [DHEA-S], which can serve as the precursor substrate for either testosterone or estradiol) are of particular interest.”

They note an important difference between the two forms:

“Furthermore, this study measured both DHEA and DHEA-S, and showed a more pronounced negative relationship between mortality and DHEA than that with DHEA-S. This suggests that DHEA could be a more important predictor of outcomes, despite low plasma DHEA concentrations relative to DHEA-S. This has significant implications, because most previous negative studies examined only DHEA-S levels.”

A new arrow in the quiver

Cardiovascular disease is complex and multi-causal…

“Despite advances in primary and secondary prevention of CHD events, there is still a high incidence of death due to CHD, including sudden cardiac death in individuals who do not have traditional coronary disease risk factors…An ideal solution might be the use of weighted patterns of biomarkers, which would take into consideration typical biochemical interactions and provide a personalized biochemical fingerprint to more exactly define an individual’s risk of future events. DHEA may represent a new arrow in the quiver of biomarkers…The findings reported here should, at the least, spur further interest in understanding DHEA as a biomarker of CVD risk.”

Clinical Note

It is, of course, never desirable to recommend or take any hormone, OTC or not, without measuring free-fraction hormone levels comprehensively at baseline and after appropriate intervals. Clinicians, however, can add DHEA levels to CHD risk assessment in older men.

The authors conclude:

Low serum levels of DHEA and its sulfate predict an increased risk of CHD, but not CBD, events in elderly men.

Circadian rhythms of inflammation

Arthritis Research & TherapyCircadian variation of symptoms caused by inflammation is common to conditions including rheumatoid arthritis, polymyalgia rheumatica, ankylosing spondylitis, asthma, depression and many more. The adrenal circadian rhythm is an important factor when serum cortisol is inadequate relative to inflammation. An excellent paper published in Arthritis Research & Therapy examines the dynamics and clinical significance of circadian variation in inflammation associated with glucocorticoid regulation, an important consideration for anti-inflammatory treatment.

Brain’s central circadian oscillator connects with immune system

The suprachiasmatic nucleus of the hypothalamus that generates the circadian rhythm connects profusely to other brain centers and to the immune system through the HPA axis.

“The circadian activity of this particular nucleus is transferred to the immune system via the hypothalamic hypothalamic-pituitary-adrenal (HPA) axis, leading to the typical undulation of clinical symptoms in chronic inflammatory diseases with a maximum in the early morning hours. In this review we will describe circadian rhythms in rheumatoid arthritis (RA) and other rheumatic and chronic inflammatory diseases, dysfunction of the HPA axis in RA and other rheumatic and chronic inflammatory diseases, the problem of adrenal suppression by glucocorticoid (GC) therapy, and whether or not chronotherapy with prednisone is more effective and aggravates adrenal suppression.”

This pertains to the classic aggravation of stiffness and pain in the morning as well as the oscillation of other symptoms caused by inflammation, including neuropsychiatric disorders.

Nocturnal inflammation, melatonin and cortisol

As melatonin goes up at night cortisol, which ‘keeps a lid on’ inflammation, goes down and inflammatory biomarkers are seen to increase.

“Classical symptoms of RA, such as morning stiffness and swelling, show a clear temporal relationship with nocturnally elevated levels of proinflammatory cytokines, as a consequence of a cascade of increased nocturnal inflammation. Several of these cytokines, such as tumor necrosis factor (TNF) alpha and interleukin (IL)-6, are highly increased in patients with active RA in the early hours of the day, but are found at very low levels after noon.”

This is characteristic of a healthy cortisol rhythm…

“Also, the cortisol rhythm – which is also present in healthy individuals, and therefore is primary, with low levels at night – may explain nocturnal inflammation. Since cortisol is the strongest endogenous anti-inflammatory substance, its downregulation during the evening and night is linked to an increase of inflammation during the early morning, and its upregulation in the early morning is most probably related to inhibition of inflammation during the day. The early morning inflammatory signs, typical for many inflammatory rheumatic conditions, can thus be explained.”

Polymyalgia rheumatica, ankylosing spondylitis and asthma

These conditions too have cyclic undulations that correspond to the circadian rhythm of immune activity, with implications for treatment.

“Furthermore, in polymyalgia rheumatica (PMR), symptoms of pain and stiffness typically are most prominent during the early morning, similar to RA…Of note, in ankylosing spondylitis – another inflammatory arthritic condition – pain and stiffness also seem to be most prominent during the early morning hours. Finally, it is now also evident that symptoms of diseases such as RA, which is T helper 1 dependent, but also asthma, which is T helper 2 dependent, are influenced by diurnal rhythms and natural regulatory T cells. In particular, secretion of IL-2, interferon gamma and IL-10 by naïve CD4+ T cells follows a diurnal rhythm.”

This ties together the nervous, immune and hormonal systems that interact in a rhythmic fashion:

“All of these processes are closely linked to regulatory interactions between the endocrine, nervous and immune systems, with distinct 24-hour daily rhythms (neuroendocrine immunology).”

HPA axis dysfunction in chronic inflammatory disorders

HPA axis function in inflammationNormally the adrenocortical response should track the circadian oscillator or inflammation. The authors describe a fascinating study in which the cortisol response to infusions of the pro-inflammatory cytokine IL-6 were delineated:

“In a fairly heroic study in 18 healthy young men, either saline or low or high doses of recombinant human IL-6 were infused into one femoral artery for 3 hours. Subjects experienced clinical symptoms such as shivering and discomfort during high-dose IL-6 administration, but were asymptomatic during low-dose IL-6 administration. Plasma cortisol concentrations did not change during infusion of saline but markedly increased during both high and low doses of IL-6. While concentrations of plasma cortisol declined after 2 hours of infusion in low doses of IL-6, they remained elevated in high doses of IL-6 at 3 hours of infusion…The increase of cortisol levels in reaction to IL-6 infusion is provoked by activation of the HPA axis. Remarkably, the relation between IL-6 levels and the adrenocorticotropic hormone (ACTH)/cortisol levels is linear. In a study of 15 healthy young men in which recombinant IL-6 was applied subcutaneously, plasma ACTH concentrations and plasma cortisol levels increased dose dependently, and the ratio of hormone to IL-6 serum levels was constant.”

By contrast however, in chronic inflammation levels of cortisol are insufficient to ‘put out the fire.’

In chronic inflammation, cortisol secretion appears to be inadequate in relation to inflammation. In a retrospective study with 34 patients with RA, 46 patients with reactive arthritis and 112 healthy subjects, the authors measured serum levels of IL-6, TNF and cortisol. The absolute levels of IL-6 were lower in healthy controls than in reactive arthritis and RA patients. However, the ratio of serum cortisol to serum cytokines was much higher in healthy controls than in reactive arthritis and RA patients, due to similar cortisol levels in all groups.”

And in another RA study…

“…comparing the circadian course of ACTH and cortisol levels in patients with RA and in healthy subjects, despite 10 times higher serum levels of cytokines in patients with RA, serum level curves of ACTH and cortisol were identical. The ACTH/cortisol hormone secretion in patients with RA is thus inadequate in relation to inflammation.”

And giant cell arteritis…

“In a study comparing serum values of ACTH, cortisol and CRP in patients with PMR/giant cell arteritis and controls, ACTH and cortisol levels were not different in patients with PMR/giant cell arteritis and controls, whereas the ratios of serum ACTH/serum CRP and serum cortisol/serum CRP were significantly lower in PMR/giant cell arteritis patients than in healthy controls. Thus, in PMR/giant cell arteritis there also appears to be an inadequate cortisol secretion in relation to inflammation in terms of relative adrenal insufficiency.”

The liver-HPA-kidney axis in chronic inflammation

In important observations that call to mind principles of traditional Chinese medicine (TCM), the authors delineate the function of hepato-hypothalamic-pituitary-adrenal-renal axis:

“Recently, evidence has accumulated, been reviewed and presented as a concept that dysfunction of the HPA axis in chronic inflammation is not simply an adaptation to chronic stress, but may be due to increased negative feedback of active cortisol on the HPA axis. The HPA axis has been recognized to be extendable to a hepato-hypothalamic-pituitary-adrenal-renal axis by GC [glucocorticoid] metabolism.”

The liver in chronic inflammation

HPA axis dysfunction in inflammationThe kidney inactivates cortisol to protect its receptor from over-stimulation and subsequent suppression, and the liver turns it back on:

“Active cortisol is converted to inactive cortisone mainly by the kidney, via 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2, in order to protect the nonspecific mineralocorticoid receptor from activation by cortisol. On the other hand, the major organ for converting inactive cortisone to active cortisol is the liver, via 11β-HSD1.”

Pro-inflammatory cytokines over-activate the liver 11β-HSD1 enzyme:

Expression of 11β-HSD1 is markedly enhanced by TNF and proinflammatory cytokines. The liver therefore becomes an important player in systemic inflammation, even if the conversion also occurs in multiple other tissues including the brain, adipocytes, vascular cells, osteoblasts and fibroblasts. Given the role of the 11β-HSD1 in GC metabolism, its effect on the HPA axis and its interaction with inflammatory cytokines, it is hypothesized that in chronic inflammatory diseases, cytokine-induced increased expression of 11β-HSD1 induces a change in the HPA axis. Increased negative feedback of active cortisol on the HPA axis induced during inflammation may thus be the mechanism of dysfunction of the HPA axis in chronic inflammation.”

Tertiary adrenal insufficiency

Synthetic glucocorticoids such as prednisone suppress adrenal function through the same negative feedback mechanism:

“During the physiological regulation of the HPA axis, cortisol release is terminated by negative feedback regulation of cortisol on the hypothalamus and anterior pituitary. Also, synthetic GCs – as applied in GC therapy – can cause negative feedback regulation, leading to adrenal suppression in terms of tertiary adrenal insufficiency.”

Besides the clinical presentation, this can be confirmed by low cortisol and ACTH levels and lack of increase in plasma cortisol with the corticotropin-releasing hormone (CRH) or ACTH stimulation test. The magnitude of the dose matters:

“The frequency of adrenal suppression increases with increasing GC dosages. In arthritis and asthma patients treated with prednisone equivalent doses ranging from 5 to 20 mg, cortisol response in the ACTH test was normal (that is, cortisol rise ≥7 μg/dl) in all of the patients taking a single morning dose of 5 to 7.5 mg prednisone, was blunted (that is, cortisol rise <7 μg/dl) in 33% and 47% of the patients taking 10 to 12.5 mg and 15 mg prednisone, respectively, and was suppressed (no rise) in 44% of the patients taking 20 mg prednisone.”

Duration also takes its toll:

After 12 weeks of 7.5 mg prednisolone, the mean values for the 60-minute response to ACTH were reduced by 35%. Following treatment, 46% of patients taking 7.5 mg prednisolone failed to reach the normal maximum cortisol response to ACTH, even if the HPA axis response generally remained within the normal range.”

Chronotherapy with prednisone

Primary concerns are maximizing effectiveness while minimizing adrenal suppression through negative feedback regulation. Several daily divided doses worsen the tendency to suppression:

“In the 1960s several studies confirmed that splitting the daily dose into several divided doses strongly increases the risk of adrenal suppression. For example, whereas endogenous cortisol secretion was not altered with a single dose of 8 mg triamcinolone given at 8:00 a.m., application of four divided 2 mg doses resulted in marked suppression of cortisol levels.”

Timing of the single dose also matters:

“The time point of application of the single daily dose also plays a role for adrenal suppression. This can be explained easily: circadian GC secretion exhibits two peaks, one large peak in the morning around 8:00 a.m. and a smaller peak in the afternoon around 2:00 p.m. Of note, cortisol levels are high during the first peak in the morning, causing downregulation of ACTH levels via negative feedback regulation. In consequence, cortisol secretion is also downregulated. At a certain point, reduced cortisol levels cause upregulation of ACTH again, leading in turn also to upregulation of cortisol secretion during the second peak in the afternoon. If exogenous GCs were applied in the evening, the so-called quiet period for the adrenal gland, this would cause a negative signal on ACTH and therefore also cortisol secretion in the morning.”

Note: With a healthy cortisol rhythm the afternoon “bump” in cortisol may be barely discernible. A single daily dose is easier to manage but many patients require two to control inflammation.

Several studies evaluating nocturnal doses at 2:00 a.m. yielded better results for morning stiffness than conventional morning doses. But the impracticality of dosing at 2:00 am plus questions about HPA suppression led to the development of a modified-release (MR) prednisone tablet that releases the dose four hours after ingestion (2 a.m. if taken at 10 p.m.).

MR prednisone produced a clinically relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone…These results lead to the question of whether chronotherapy with MR prednisone affects adrenal suppression. The influence of long-term, low-dose chronotherapy with MR prednisone on the HPA axis was investigated by CRH tests in a subgroup of 28 patients in the CAPRA-1 study…There were no measurable differences in mean cortisol changes after CRH injection between baseline and the end of the study. Furthermore, there was no indication that changing treatments from immediate-release prednisone to MR prednisone increased the risk of HPA axis insufficiency, or resulted in deterioration of preexisting suppression.There was thus no difference between immediate-release prednisone and MR prednisone in numbers of normal/suppressed/no response reactions. In addition, no adverse events that could be attributed to HPA axis insufficiency were observed during treatment with low-dose MR prednisone for the entire treatment period of 12 months.”

Dosing at 2:00 a.m. (by modified release) may even benefit HPA axis activity:

“A recent study showed an increase of endogenous cortisol after 2 weeks of MR prednisone therapy in patients with active RA who had received no GCs by any route in the preceding 3 months. MR prednisone released at 2:00 a.m. suppressed the pathological early morning rise in plasma IL-6 in RA. The nocturnal rise in plasma cortisol was not suppressed but was enhanced with a peak value increase from 14.1 to 19.3 μg/dl, consistent with a changing relationship between HPA axis and immune system activation. This observation may be an indication that the HPA axis is preserved and is activated even more during MR prednisone treatment compared with pre-MR prednisone treatment.”

Clinical Note

Nutrition JournalMinimizing adrenal suppression while enhancing anti-inflammatory effectiveness by circadian dosing of prednisone also implies that effect of other anti-inflammatory agents can be enhanced by chronotherapeutic timing. Curcumin is one of the most extensively researched natural anti-inflammatory agents. A study published in the Nutrition Journal on the comparative absorption of curcumin formulations demonstrates that a newer preparation markedly extends the plasma concentrations of bioactive components including the key metabolite tetrahydrocurcumin.

“The potential health benefits of curcumin are limited by its poor solubility, low absorption from the gut, rapid metabolism and rapid systemic elimination. The purpose of this study was the comparative measurement of the increases in levels of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) and the metabolite tetrahydrocurcumin after oral administration of three different curcumin formulations in comparison to unformulated standard.”

A curcumin phytosome formulation (CP), a formulation with volatile oils of turmeric rhizome (CTR) and a formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants (CHC) were compared to a standardized curcumin mixture (CS). There was a dramatic result in favor of the CHC preparation.

“Total curcuminoids appearance in the blood was 1.3-fold higher for CTR and 7.9-fold higher for CP in comparison to unformulated CS. CHC showed a 45.9-fold higher absorption over CS and significantly improved absorption over CP (5.8-fold) and CTR (34.9-fold, all p < 0.001).”

Plasma concentrations time-curves for curcumin productsTetrahydrocurcumin is particularly valuable…

“Tetrahydrocurcumin plays an important role in the antioxidant mechanism of curcumin and has been shown to be the most potent antioxidant of the curcuminoids measured in this study. In addition, tetrahydrocurcumin has been reported to have health promoting benefits. It has been shown to have greater anti-inflammatory potency than curcumin in carrageenan-induced paw edema.”

The data shows that the CHC preparation yields high levels of curcuminoids that would sustain through the night into the morning if taken at bedtime to cover the critical inflammatory period when cortisol levels are naturally low. Adrenal suppression is, of course, not a concern with curcumin. This is advantageous not just for rheumatological disorders but all conditions involving chronic inflammation.

The authors of the first study conclude:

“From a GC perspective, circadian rhythms of the HPA axis and connected subsystems, including the immune system, appear to be essential for understanding of pathophysiology and treatment in rheumatology. The circadian rhythm of the HPA axis in chronic inflammatory diseases may be defective in terms of not bringing the body into a position to overcome the signs and symptoms of the disease. GC therapy serves as a necessary aid to overcome the disease and perhaps restore the deranged circadian rhythm. In a number of patients (around 50%), GC therapy causes adrenal suppression, probably mainly due to as yet undefined individual factors (apart from dose, substance and duration of therapy). In order not to aggravate adrenal suppression, GC therapy should be applied in accordance with the circadian rhythm, to achieve greatest efficacy along with highest safety. It has been suggested that when the single morning dose is not effective enough to achieve sufficient disease control, especially in patients with strong night symptoms and morning stiffness, split doses in the morning and afternoon, or chronotherapy with MR prednisone, can to some extent avoid aggravation of adrenal suppression.”

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.

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.”

Low normal sodium a cardiovascular risk

Nutrition, Metabolism & Cardiovascular DiseasesSerum sodium levels are influenced by a number of factors linked to cardiovascular health including dysglycemia (blood glucose disorders), hypothyroid, adrenal dysregulation and others. Research just published in Nutrition, Metabolism & Cardiovascular Diseases identifies low serum sodium within the normal range as a risk predictor for cardiovascular disease and stroke. The authors state:

Hyponatremia, usually defined as serum sodium concentration <136 mEq/L, is one of the most common electrolyte abnormalities observed in hospitalised patients and in patients with chronic kidney disease (CKD), coronary heart disease (CHD) and heart failure (HF). Several clinical and epidemiological studies have shown hyponatremia to be associated with increased total mortality in these patients. More recently, attention has turned to the possibility that mild hyponatremia, may be associated with adverse outcomes in the general population…in the three population studies that have examined the relationship between hyponatremia and mortality in community based subjects, there is evidence that hyponatremia is associated with increased mortality and even a level of sodium concentration in the lower normal range (serum sodium 135-137 mEq/L), a level usually considered benign, is associated with increased mortality.”

Less is known about the association between serum sodium and potassium and the risk of cardiovascular disease and stroke in older men withoutmthese disorders. So the authors examined data for 3099 men aged 60-79 years without a history of cardiovascular disease for an average 11 years. During that time there were 528 major CVD events (fatal coronary heart disease [CHD] and non-fatal MI, stroke and CVD death) and 873 total deaths.

Mildly low sodium is not benign

 Although no association was seen between serum potassium and cardiovascular disease, low serum sodium within the normal range as well as high serum sodium is associated with increased risk of stroke and cardiovascular disease mortality:
“A U shaped relationship was seen between serum sodium concentration and major CVD events and mortality. Hyponatremia (<136 mEq/L) and low sodium within the normal range (136-138 mEq/L) showed significantly increased risk of major CVD events and total mortality compared to men within the upper normal range (139-143 mEq/L) after adjustment for a wide range of confounders and traditional risk factors [adjusted HRs 1.55 and 1.40 for major CVD events respectively and 1.30 and 1.30 respectively for total mortality]. Hyponatremia was associated with inflammation, NT-proBNP, low muscle mass and alkaline phosphatase; these factors contributed to the increased total mortality associated with hyponatremia but did not explain the increased risk of CVD events associated with hyponatremia or low normal sodium concentration. Hypernatremia (>145 mEq/L) was associated with significantly increased risk of CVD events and mortality due to CVD causes.”
In other words, both low normal and high sodium are a significant risk factor for cardiovascular disease and mortality.

Clinical Implications

Practitioner’s should bear in mind the authors’ conclusions and not dismiss low normal serum sodium:
“Hyponatremia and hypernatremia are both associated with increased risk of CVD incidence and mortality. Low sodium within the normal range is associated with significantly increased CVD events and total mortality in older men without major CVD or HF even in the absence of diuretic use and renal dysfunction. The data lends further evidence to the suggestion that the presence of mild hyponatremia is not benign. The findings may have important implications for the monitoring of sodium levels in clinical practice in older adults. The presence of mild hyponatremia in the absence of known causes such as renal dysfunction and diuretics may warrant further investigation in these men to assess CVD risk factors or possible underlying ill-health such as chronic inflammation. Further large studies are required to confirm and elucidate the nature of the association between low normal sodium and risk of incident CVD.”

Insulin resistance indicated by neutrophil-lymphocyte ratio

BMC Endocrine DisordersInsulin resistance (IR) is central to type 2 diabetes and a contributing cause to cardiovascular and neurodegenerative disorders, chronic kidney disease (CKD), a number of cancers and more. A study recently published in BMC Endocrine Disorders the ratio between neutrophils and lymphocytes (neutrophil-lymphocyte ratio, NLR) is a valuable and inexpensive predictive marker for insulin resistance. The authors note:

“Insulin resistance (IR) is a reduction in reaction or sensitivity to insulin and is considered to be the common cause of impaired glucose tolerance, diabetes, obesity, dyslipidemia, and hypertensive diseases….several studies have confirmed the relationship between systemic inflammation and insulin resistance, in which an altered immune system plays a decisive role in the pathogenesis of DM. The immune response to various physiological challenges is characterized by increased neutrophil and decreased lymphocyte counts, and NLR is often recognized as an inflammatory marker to assess the severity of the disease.”

Furthermore…

“Scholars have rarely investigated the relationship between IR and NLR. This study aims to evaluate the relationship between IR and NLR, and determine whether or not NLR is a reliable marker for IR.”

Mean neutrophil-lymphocyte ratio (NLR) values of the groups. Group 1 is diabetic w/o IR, Group 2 is diabetic with IR.

Mean neutrophil-lymphocyte ratio (NLR) values of the groups. Group 1 is diabetic w/o IR, Group 2 is diabetic with IR.

So they investigated the neutrophil-lymphocyte ratio in 413 patients with T2DM, 310 of whom had a HOMA-IR value (fasting plasma glucose (mmol/L) multiplied by fasting serum insulin (mIU/L) divided by 22.5) of > 2.0, indicating insulin resistance. They were compared to a control group of 130 healthy subjects and found a strong association:

“The NLR values of the diabetic patients were significantly higher than those of the healthy control, and the NLR values of the patients with a HOMA-IR value of > 2.0 are notably greater than those of the patients with a HOMA-IR value of ≤ 2.0. Pearson correlation analysis showed a significant positive correlation of NLR with HOMA-IR. Logistic regression analysis showed that the risk predictors of IR include NLR, TG and HbA1c. NLR levels correlated positively with IR. The IR odds ratio increased by a factor of 7.231 (95%) for every one unit increase in NLR.”

 Diabetes, cancer and cardiovascular diseases

In relation to their confirmation of NLR as a predictor for insulin resistance the authors observe…

“Many epidemiological studies have determined that DM is associated with chronic inflammation, which may contribute to the acceleration of diabetic microangiopathy and the development of macroangiopathy; IR is a characterized of T2DM, whereas the exact molecular action leading to IR is not yet understood, several studies have associated IR with inflammation, experimental studies have demonstrated a link between chronic inflammation and insulin resistance through mechanisms involving obesity and atherosclerosis. NLR has been recently defined as a novel potential inflammation marker in cancer and cardiovascular diseases. NLR can easily be calculated using the neutrophil-lymphocyte ratio in peripheral blood count. Calculating NLR is simpler and cheaper than measuring other inflammatory cytokines, such as IL-6, IL-1β, and TNF-α.”

Diabetes and chronic inflammation

These findings highlight the relationship between chronic inflammation, insulin resistance and type 2 diabetes.

“he pathological activation of innate immunity leads to inflammation of the islet cells, resulting in a decrease in pancreatic beta-cell mass and impaired insulin secretion. Patients with T2DM are in a state of low-degree chronic inflammation that induces hypersecretion of inflammatory factors, such as CRP, IL-6, TNF-α, and MCP-1, which results in a constantly elevated neutrophilic granulocyte count. One mechanism by which increased levels of neutrophils could mediate IR may be through augmented inflammation. The increase in NLR appears to underlie the elevated levels of pro-inflammation, as evident from the persistent neutrophil activation and enhanced release of neutrophil proteases with T2DM.”

 NLR tracks HgbA1c and triglycerides

Glycation of hemoglobin (HgbA1c) and triglycerides (TG) both go up as insulin resistance progresses along with the neutrophil-lymphocyte ratio.

“A logistic regression analysis of the following risk factors was conducted: NLR, TG and HbA1c. In our study, in conjunction with the rising of the level of HbAlc, the degree of IR increased significantly. HbA1c showed an association with early-phase insulin secretion assessed by insulinogenic index. Heianza et al. reported that elevated HbA1c levels of above 41 mmol/mol (>5.9%) were associated with a substantial reduction in insulin secretion and insulin sensitivity as well as an association with β-cell dysfunction in Japanese individuals without a history of treatment of diabetes. Increased accumulation of TG has been observed in human muscle tissue of obese and type 2 diabetic subjects, and associated with IR, which is in agreement with the present study. IR reduces the inhibition effect of lipolysis in adipose tissue, resulting in the increase of the free fatty acid (FFA) level in plasma.”

NLR is a superior biomarker

Although susceptible to modification by dehydration, elevated PSA or catecholamine release induced by exercise, the NLR is more sensitive than the neutrophil count alone or CRP levels.

“NLR represents a combination of two markers where neutrophils represent the active nonspecific inflammatory mediator initiating the first line of defense, whereas lymphocytes represent the regulatory or protective component of inflammation. NLR is superior to other leukocyte parameters (e.g., neutrophil, lymphocyte, and total leukocyte counts) because of its better stability compared with the other parameters that can be altered by various physiological, pathological, and physical factors. Thus, as a simple clinical indicator of IR, NLR is more sensitive compared with the neutrophilic granulocyte count and CRP levels, which are widely used as markers of IR.”

Clinical bottom line

Practitioners should not fail to make use of this significant, inexpensive biomarker that is under our noses every day. The authors sum it up:

“…in the present study, NLR serves an important function in predicting the risk of IR. IR in diabetic patients is related to chronic inflammation, and NLR may be helpful in assessing the prognoses of these patients…We recommend that the NLR values of diabetic patients be calculated as NLR is a cheap, predictive, and prognostic marker for IR. High NLR values were independently related to IR.”

Women’s heart risk lower with exercise 2-3x/week than daily

CirculationExercise is a measured stress applied to the body to exploit a desirable genetic, cardiometabolic, endocrine and immune response. Like almost every other physiological intervention there is a dose-response curve: too little doesn’t elicit a sufficient reaction while the benefits degrade and harm can accrue with too much (over-training). A large study using data from 1.1 million women recently published in the journal Circulation offers evidence that strenuous physical activity 2-3 times per week significantly lowered their coronary heart disease risk while more frequent strenuous exercise actually increased it. The authors state:

“Although physical activity has generally been associated with reduced risk of vascular disease, there is limited evidence about the effects of the frequency and duration of various activities on the incidence of particular types of vascular disease…We describe here the relationships of the frequency, duration, and type of physical activity with incident CHD, cerebrovascular disease (overall and separately for hemorrhagic and ischemic stroke), and VTE (venous thromboembolism, overall and separately for those with and without pulmonary embolism), excluding the first 4 years of follow-up from recruitment into the study to limit the possible effects of reverse causation attributable to preclinical disease.”

They note the findings of a previous study on cardiovascular mortality in both sexes and running frequency:

“A recent prospective study of men and women aged 44 years on average at baseline, suggested a U-shaped association between running frequency and cardiovascular mortality. Although the lowest risk appeared to be among those reporting running 3 times per week, the confidence intervals were large.”

The low central portion of the ‘U’ corresponds to decreased mortality with exercise of moderate frequency.

Less cardiovascular disease with strenuous exercise 2-3 times per week

Absolute risks and 95% group-specific confidence intervals (gsCI) for incident vascular diseases, by strenuous and any physical activity, excluding the first 4 years of follow-up.

Absolute risks and 95% group-specific confidence intervals (gsCI) for incident vascular diseases, by strenuous and any physical activity, excluding the first 4 years of follow-up.

The authors analyzed data on physical activity an exercise for 1.1 million women without prior vascular disease along with and many other personal characteristics in including time spent walking, cycling, gardening, and housework each week. This was linked to National Health Service (UK) cause-specific hospital admissions and death records. The adjusted relative risks were calculated for first vascular events in relation to physical activity:

“During an average of 9 years follow-up, 49 113 women had a first coronary heart disease event, 17 822 had a first cerebrovascular event, and 14 550 had a first venous thromboembolic event. In comparison with inactive women, those reporting moderate activity had significantly lower risks of all 3 conditions. However, women reporting strenuous physical activity daily had higher risks of coronary heart disease, cerebrovascular disease, and venous thromboembolic eventsthan those reporting doing such activity 2 to 3 times per week.”

They comment on these results:

“Results from this prospective study of 1.1 million UK women showed that women who engaged in physical activity had a lower incidence of CHD, cerebrovascular disease, and VTE than women who were inactive. Overall, the main difference in risk was between those doing some activity versus none, with the lowest risks being observed among women doing moderate amounts of activity. These associations were evident for different pathological types of stroke and of VTE, and across analyses using different measures of physical activity, including the frequency of any or strenuous activity, excess MET-hours expended, and durations of specific types of activity. Among active women, there was little evidence of progressive reductions in risk with more frequent activity, and some evidence of an increase in risk for CHD, cerebrovascular disease, and VTE in the most active group, compared to those who were moderately active.”

Keep up the moderate exercise, no need to push harder

The data suggests that pushing past moderation goes over the hump of the dose-response curve into over-training with degraded outcomes. The authors conclude:

“Moderate physical activity is associated with a lower risk of coronary heart disease, venous thromboembolic event, and cerebrovascular disease than inactivity. However, among active women, there is little to suggest progressive reductions in risk of vascular diseases with increasing frequency of activity.”

Strenuous endurance exercise promotes inflammation

PLOS ONEChronic inflammation, the common denominator of aging and most chronic diseases, is promoted by an imbalance between proinflammatory Th17 cells that drive autoimmunity and the anti-inflammatory Treg cells (regulatory T cells). An important study published in PLOS One reveals one of the mechanisms by which more than moderate strenuous exercise can increase cardiovascular risk. The authors state:

“Endurance, marathon-type exertion is known to induce adverse changes in the immune system. Increased airway hyper-responsiveness and airway inflammation are well documented in endurance athletes and endurance exercise is considered a major risk factor for asthma in elite athletes. Yet, the mechanisms underlying this phenomenon are still to be deduced. We studied the effect of strenuous endurance exercise (marathon and half-ironman triathlon) on CD4+ lymphocyte sub-populations and on the balance between effector and regulatory CD4+ lymphocytes in the peripheral blood of trained athletes.”

Crucial Th17/Treg balance

There is a wealth of scientific evidence for the importance of the Th17 and Treg interplay in autoimmunity and chronic inflammation. The authors of this study note:

T helper (h)17 cells are CD4+ lymphocytes that produce Interleukin (IL)-17, a cytokine that play a crucial role in allergic inflammation and are known as powerful pro-inflammatory cells that promote autoimmunity. On the other end of the spectrum CD4+CD25+ regulatory T cells (Tregs) are differentiated T lymphocytes actively involved in control of peripheral immunity. The identification of these cells has led to new insights into mechanisms of tolerance breakdown in human diseases, including those resulting from allergic, autoimmune, or infectious causes.”

Endurance exercise induced a significant increase in Th17 cells and a sustained decline in peripheral blood Tregs population. These alterations in CD4+ T cell sub-populations may be attributed to changes in TGFβ, IL-6 and IL-2 serum levels.

Endurance exercise induced a significant increase in Th17 cells and a sustained decline in peripheral blood Tregs population. These alterations in CD4+ T cell sub-populations may be attributed to changes in TGFβ, IL-6 and IL-2 serum levels.

They examined the effect of strenuous exercise on the balance between pro-inflammatory effector and anti-inflammatory regulatory CD4+ lymphocytes in the blood of trained athletes who performed in the Emek-Hayarden Half Ironman triathlon or the 2009 Tiberia marathon and documented a marked pro-inflammatory shift:

Endurance exercise induced a significant increase in Th17 cells and a sustained decrease in peripheral blood regulatory T cells (Tregs). While interleukin (IL)-2 levels remained undetectable, post-race serum IL-6 and transforming growth factor (TGF) β levels were significantly elevated. Treg levels in sedentary controls’ decreased in vitro after incubation with athletes’ post-exercise serum, an effect that was attenuated by supplements of IL-2 or anti IL-6 neutralizing antibodies.”

Bottom line

Patients at risk for ‘sedentary death syndrome’ should be enthusiastically encouraged to have a dose of HIIT exercise 2-3 times per week, a fundamental life-style factor that reduces risk across the whole spectrum of chronic disease. HIIT (high intensity interval training) in particular efficiently yields desired cardiometabolic and other benefits with reduced risk for injury. The authors conclude:

“Our data suggest that exercise-induced changes in serum cytokine levels promote alterations in Tregs and Th17 cell populations, which may divert the subtle balance in the immune system towards inflammation. This may explain allergic and autoimmune phenomena previously reported in endurance athletes and contribute to our understanding of exercise-related asthma.”