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.

Elevated platelets may signal increased cancer risk

Platelets as cancer predictorPlatelets (thrombocytes) are active for more than just adhesion and cohesion in the formation of a ‘hemostatic plug’ (blood clot), along with activation of coagulation mechanisms. Platelets also have important secretory functions that release growth factors and communicate with white blood cells and cells that line blood vessels (endothelial cells). Through this they promote inflammation and tissue proliferation (as in wound healing). Now an important study published in the British Journal of General Practice that an increase in platelet count is clinical risk marker for cancer. The authors note:

“The commonest route to cancer diagnosis follows the development of symptoms, and definitive diagnosis by biopsy and access to specialist care often rely on a primary care physician to recognise the possibility of cancer. It is generally accepted that delay in symptomatic diagnosis is harmful. One feature of possible cancer has only recently been recognised to have diagnostic potential: a raised platelet count, or thrombocytosis.”

Platelets as predictors

Earlier studies have shown the predictive value of thrombocytosis for certain cancers, but none have looked at cancer in general.

“Revised UK national guidance for suspected cancer incorporates thrombocytosis in some of its recommendations for lung, oesophagogastric, and uterine cancers. However, no study has examined thrombocytosis in primary care for all cancers. This study aimed to address that gap.”

The authors examined 1-year data for two groups of subjects: 40,000 patients aged ≥40 years with a platelet count of more than 400 × 109/L (109/L = 10³/uL) and 10,000 matched patients with a normal platelet count. Clinicians, note the reference range: >400 x 10³/uL = thrombocytosisTheir data did show that elevated platelets should be regarded as a cancer risk factor, especially for lung and colorectal cancer.

“A total of 1098 out of 9435 males with thrombocytosis were diagnosed with cancer (11.6%), compared with 106 of 2599 males without thrombocytosis (4.1%). A total of 1355 out of 21 826 females with thrombocytosis developed cancer (6.2%). The risk of cancer increased to 18.1% for males and 10.1% for females, when a second raised platelet count was recorded within 6 months. Lung and colorectal cancer were more commonly diagnosed with thrombocytosis.”

Very importantly:

One-third of patients with thrombocytosis and lung or colorectal cancer had no other symptoms indicative of malignancy.”

The authors summarize their findings:

“This large-scale cohort study is the first from primary care to report the overall risk of cancer in patients with thrombocytosis, compared with those with normal platelet counts. Males with thrombocytosis had an 11.6% incidence of cancer in the following year, and females had an incidence of 6.2%: this compares with 4.1% of males with normal platelet counts. The incidence of cancer rose with age and with a higher platelet count, and at least one-third of patients with lung and colorectal cancer with pre-diagnosis thrombocytosis had no other symptoms indicative of malignancy.”

Commenting in Medscape Family Medicine

“Lead author, Sarah Bailey, MPH, PhD, research fellow at the University of Exeter Medical School, United Kingdom, said in a statement:  “We know that early diagnosis is absolutely key in whether people survive cancer. Our research suggests that substantial numbers of people could have their cancer diagnosed up to three months earlier if thrombocytosis prompted investigation for cancer. This time could make a vital difference in achieving earlier diagnosis.”

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.

Suicide and biomarkers of gastrointestinal inflammation

Suicide and gastrointestinal inflammation

Suicide mostly occurs in association with neuropsychiatric disorders characterized by neuroinflammation (brain inflammation). Neuroinflammation often results from perturbations of the brain-gut axis, with pro-inflammatory immune signaling from the gut to the brain. An important study just published in Psychiatry Research offers data showing the connection between biomarkers of gastrointestinal inflammation and recent suicide attempt. The authors were motivated by the intent to validate biomarkers to help assess, treat and prevent suicide attempts.

Most attempting suicide have an illness associated with neuroinflammation

“Psychological autopsy and epidemiological studies indicate that more than 90% of people who die by suicide have a diagnosable psychiatric illness, particularly major depression, bipolar disorder, or schizophrenia…The identification of blood-based markers would provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts.”

It is an urgent clinical need to identify causes that promote dysregulated activation of the immune system against the neuronal antigens.

The GI tract is often the source of immune activation against the brain

Biomarkers of gastrointestinal inflammation are frequently increased in neuropsychiatric disorders.

“Many individuals with schizophrenia and mood disorders have evidence of immune activation suggesting that immune dysregulation may be part of the etiopathology of these disorders. Studies by our group and others indicate that the gastrointestinal tract is often the primary source of this immune activation as evidenced by increased levels of markers of gastrointestinal inflammation in individuals with serious mental illness.”

IBD (inflammatory bowel disease) and celiac disease appear to increase risk for suicide.

“Furthermore, increased rates of suicide and suicide attempts have been found in some populations of individuals with celiac disease or inflammatory bowel diseases.”

But previous studies have focused on a lifetime history rather than attempts, so the authors set out to:

“…examine the association between levels of markers of gastrointestinal inflammation and a recent suicide attempt in individuals with schizophrenia, bipolar disorder or major depressive disorder in comparison with non-psychiatric controls.”

Elevated IL-6

Interleukin-6 (IL-6), a key pro-inflammatory cytokine which can arise from the GI tract, is associated.

“Results from other investigators indicate that inflammation may be associated not only with a proclivity for a psychiatric disorder, but specifically with suicidal behavior. Studies have found an association between a suicide attempt history and the level of cytokines such as IL-6 which are cell signaling molecules involved in the immune response and which can arise from inflammation from many sources, including the gastrointestinal tract”

Gluten and brain inflammation

Neuroinflammation triggered by non-celiac gluten sensitivity is also implicated:

“Gliadin is a component of gluten, found in wheat and related cereals. Antibody response to dietary gliadin is associated with celiac disease, an immune-mediated enteropathy, and with non-celiac wheat sensitivity and is thought to indicate intestinal inflammation and/or intestinal barrier dysfunction. We have found increased levels of antibodies to gliadin in individuals with schizophrenia and with bipolar disorder and in individuals with acute mania during a hospital stay…”

Additionally, loss of tolerance to a commensal yeast may promote neuroinflammation.

“We also have studied the antibody response to yeast mannans represented by antibodies to Saccharomyces cerevisiae (ASCA), a commensal organism present in some foods and in the intestinal tract of many individuals. Elevated ASCA levels are associated with increased intestinal inflammation. We have previously found increased levels of ASCA in individuals with mood disorders.”

Pathogens and loss of immune tolerance

Various pathogens present at low levels can elicit a persistent cross-reaction to self-antigens, including brain antigens, in individuals disposed to loss of immune tolerance.

“An association between elevated antibodies to Toxoplasma gondii, an apicomplexan parasite, and suicide attempts have also been reported. In a recent study, we found that individuals with serious mental illness who had a lifetime history of a suicide attempt had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV); we also found an association between the levels of these antibodies and the number of suicide attempts.”

Significant link found

Association between suicide and markers of GI inflammation

The authors examined data for 282 participants: 90 with schizophrenia, 72 with bipolar disorder, 48 with major depressive disorder, and 72 non-psychiatric controls; who were enrolled in ongoing studies of the role the immune response to infections in individuals with serious psychiatric disorders. Biomarkers measured included IgA antibody to yeast mannan from Saccharomyces cerevisiae (ASCA), IgG antibody to gliadin, IgA antibody to bacterial lipopolysaccharide (LPS) from E. coli O111:B4, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and levels of C-Reactive protein.

“We found a statistically significant difference between the recent attempters and the control group in levels of IgA ASCA; the level in the recent attempt group was significantly higher…We also found that the level of IgG antibodies to gliadin was significantly higher in the recent attempters vs. the control group…We also found that the level of IgA antibodies to bacterial lipopolysaccharide (LPS) was significantly higher in the recent attempters vs. the control group…In terms of CRP, we found that there was a significantly higher level in the past attempter group.”

Predicting risk and protecting patients

These findings offer a valuable opportunity for clinicians to gauge and ameliorate risk of suicide in patients with serious neuropsychiatric disorders.

“The markers of gastrointestinal inflammation are of interest because they can be readily measured in blood samples. In addition, some of the markers studied here may be an attractive target for therapeutic intervention since intestinal inflammation can be modulated by dietary interventions as well as the administration of available prebiotic, probiotic, and antibiotic medications.”

The authors conclude:

“Suicide, for which a previous suicide attempt is the greatest risk factor, is a major cause of death worldwide and is highly prevalent in patients with serious mental illness. Unfortunately, the ability to predict suicide remains limited and no reliable biological markers are available. The identification of blood-based markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.”

For additional categories of importance in evaluating neuropsychiatric risk see The Parents’ Guide to Brain Health.

Corticosteroids even short term increase adverse events

Corticosteroids, prescribed for as many as one in five Americans in commercial insurance plans, can significantly increase the risk for adverse effects even when given short term, as found in a study recently published in BMJ (British Medical Journal). The authors note that though the severe adverse effects of longer term use or oral corticosteroids is well known, little has been understood about short term risks.

“…long term use of corticosteroids is generally avoided, given the risks of serious acute complications such as infection, venous thromboembolism, avascular necrosis, and fracture, as well as chronic diseases such as diabetes mellitus, hypertension, osteoporosis, and other features of iatrogenic Cushing’s syndrome…Indeed, corticosteroids are one of the most common reasons for admission to hospital for drug related adverse events…In contrast with long term use, however, the risk of complications from short term use is much less understood, and evidence is generally insufficient to guide clinicians.”

Corticosteroids often used where evidence is lacking

Until now little is know about the potential harms of short term use for the range of outpatient conditions for which they are often prescribed.

“…anecdotally corticosteroids are also used often in the short term to treat many other prevalent conditions where evidence is lacking, such as non-specific musculoskeletal pain and rashes. Despite such pervasive indications for use of oral corticosteroids, little is known about the prescribing patterns of short term use of these drugs in the general adult population, or their potential harm.”

Thus they set out to correlate short term use in an outpatient population and the risk of acute adverse events by analyzing data for 1,548,945 subjects who were prescribed oral corticosteroids for less than 30 days (non-oral forms were excluded from this study).

“We chose three acute events listed as adverse events on the Food and Drug Administration mandated drug label for oral corticosteroids (sepsis, venous thromboembolism, fracture). Given the inherent challenges related to confounding, we employed a self controlled case series (SCCS) design. This design has been used to examine drug and vaccine safety.”

The most common prescription was a six day methylprednisolone “dosepak”, most commonly given for upper respiratory tract infections, spinal conditions, and intervertebral disc disorders, allergies, bronchitis, and (non-bronchitic) lower respiratory tract disorders by family medicine and general internal medicine practitioners, but also by specialists in emergency medicine, otolaryngology, and orthopedics.

Significantly higher rates of sepsis, venous thromboembolism, and fracture

The authors identified a serious risk:

“Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P<0.001).”

It defies common sense to use an agent that suppresses the immune system during an infection in all but the rare cases of severe immune excess, especially when there are numerous, more benign alternatives.

Quoted in Medscape Family Medicine, lead author Akbar K. Waljee, MD, an assistant professor of gastroenterology at the University of Michigan in Ann Arbor, states:

“On the basis of these findings, Dr Waljee recommended prescribing the smallest possible amount of corticosteroids for treating the condition in question. “If there are alternatives to steroids, we should be use those when possible,” he said in the release. “Steroids may work faster, but they aren’t as risk-free as you might think.”

From the study:

  • This study of 1.5 million privately insured adults (18-64 years) in the US found that one in five patients in an outpatient setting used short term oral corticosteroid over a three year period (2012-14)

  • Within 30 days of corticosteroid initiation, the incidence of acute adverse events that result in major morbidity and mortality (sepsis, venous thromboembolism, fracture) increased by twofold, to fivefold above background rates

  • Greater attention to initiating prescriptions of these drugs and monitoring for adverse events may potentially improve patient safety

The authors conclude:

“Oral corticosteroids are frequently prescribed for short term use in the US for a variety of common conditions and by numerous provider specialties. Over a three year period, approximately one in five American adults in a commercially insured plan used oral corticosteroids for less than 30 days. The short term use of these drugs was associated with increased rates of sepsis, venous thromboembolism, and fracture; even at relatively low doses.”

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.”

 

Immunotherapy can take 3 years to desensitize to allergens

Sublingual immunotherapyImmunotherapy can induce tolerance for allergens, but what is a realistic time frame? A study recently published in JAMA demonstrates that 3 years of sublingual desensitizing treatment is effective, but 2 years is no different than placebo. This research helps practitioners working in the larger context of immune plasticity, and patients, to consider pragmatic parameters for case management. The authors note:

“Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment.”

But since reducing the inconvenience and expense of treatment is always desirable, the they set out to…

“…assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up.”

3 years of immunotherapy effective, 2 years comparable to placebo

In a randomized double-blind, placebo-controlled, 3–parallel-group study of adult patients with moderate to allergic rhinitis that was severe enough to interfere with normal daily activities and sleep), thirty-six subjects received 2 years of sublingual immunotherapy (SLIT; daily tablets containing 15 µg of a major allergen and monthly placebo injections), another 36 received subcutaneous immunotherapy (SCIT; monthly injections containing 20 µg of the allergen and daily placebo tablets); and 34 received double placebo. The nasal allergen challenge was performed before and at 1 and 2 years during treatment; and at 3 years, which was1 year after treatment concluded. Their data make clear that, while the effectiveness of 3 years of treatment is well established, 2 years of treatment did essentially nothing.

“Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score [total nasal symptom score] for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90; [P = .75]).”

In other words, there were no significant differences between the placebo group and the treatment groups, or between the two treatment groups, despite the finding that SCIT appeared to be more effective than SLIT at reducing TNSS after 1 year.

Medscape Family Medicine quotes an editorial by Linda S. Cox, MD:

“…the cumulative costs of symptomatic drug treatment for perennial or seasonal allergic rhinitis can be significant over time,” because it is a chronic condition. Therefore, any analysis of allergen-specific immunotherapy must take into account its potential for long-term disease modification. However, she warns, any cost-benefit assessment of allergen-specific immunotherapy must include “the duration of treatment required for optimal long-term efficacy.” The time commitment requirement may be an important factor in patients’ decisions to initiate therapy.” Therefore, it is important to clarify the optimum duration of treatment. The findings of this study suggest that “2 years is not sufficient for SLIT treatment to induce long-term clinical efficacy.”

Clinical note

This study leaves open the question as to whether adjunctive forms of immunomodulation can accelerate sustained benefit or improve outcomes in other ways, but it does offer one reference by which clinicians and patients can appreciate the dynamic and time frame of therapies addressing immune and neuroplasticity.

The authors conclude:

“Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up.”

Magnesium mediates insulin resistance, diabetes risk

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

Magnesium and diabetes

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

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

 Prediabetes and insulin resistance

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

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

Condensing these results they state:

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

In the clinic

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

The authors conclude:

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

HgbA1c (hemoglobin A1c) predicts prediabetes better than glucose

HgbA1c predicts prediabetesHgbA1c (hemoglobin A1c) is hemoglobin that has been ruined by glycation (bonding with sugar). It has long been recognized as a biomarker for average glucose over an approximately three month time span as well as a metric for the degree of damaging glycation occurring throughout the body. Now further evidence for its superior value as a predictor for prediabetes is presented in a study just published in The Lancet Diabetes & Endocrinology.The authors…

“…compared the risk of future outcomes across different prediabetes definitions based on fasting glucose concentration, HbA1c, and 2 h glucose concentration during over two decades of follow-up in the community-based Atherosclerosis Risk in Communities (ARIC) study. We aimed to analyse the associations of definitions with outcomes to provide a comparison of different definitions.”

HgbA1c compared to fasting and 2 hour glucose

They compared several prediabetes definitions in their ability to predict major long-term health problems. They analyzed data from over seven thousand subjects drawn from four communities across the USA who participated in the Atherosclerosis Risk in Communities (ARIC) study. HgbA1c was pitted against fasting and 2 hour postprandial glucose:

“Fasting glucose concentration and HbA1c were measured at visit 2 and fasting glucose concentration and 2 h glucose concentration were measured at visit 4. We compared prediabetes definitions based on fasting glucose concentration (American Diabetes Association [ADA] fasting glucose concentration cutoff 5·6–6·9 mmol/L and WHO fasting glucose concentration cutoff 6·1–6·9 mmol/L), HbA1c (ADA HbA1ccutoff 5·7–6·4% [39–46 mmol/mol] and International Expert Committee [IEC] HbA1c cutoff 6·0–6·4% [42–46 mmol/mol]), and 2 h glucose concentration (ADA and WHO 2 h glucose concentration cutoff 7·8–11·0 mmol/L).”

HgbA1c better identifies those at risk for diabetes and serious complications

Chronic kidney disease, cardiovascular disease and death were more accurately predicted by HgbA1c than by fasting glucose:

“After demographic adjustment, HbA1c-based definitions of prediabetes had higher hazard ratios and better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality than did fasting glucose concentration-based definitions (all p<0·05). The C-statistic for incident chronic kidney disease was 0·636 for ADA fasting glucose concentration clinical categories and 0·640 for ADA HbA1c clinical categories. The C-statistics were 0·662 for ADA fasting glucose clinical concentration categories and 0·672 for ADA HbA1c clinical categories for atherosclerotic cardiovascular disease, 0·701 for ADA fasting glucose concentration clinical categories and 0·722 for ADA HbA1c clinical categories for peripheral arterial disease, and 0·683 for ADA fasting glucose concentration clinical categories and 0·688 for ADA HbA1c clinical categories for all-cause mortality. Prediabetes defined using the ADA HbA1c cutoff showed a significant overall improvement in the net reclassification index for cardiovascular outcomes and death compared with prediabetes defined with glucose-based definitions.”

Clinical Significance

HgbA1c study reviewed in Medscape Family Medicine

Medscape Family Medicine remarks:

“The researchers found that using an HbA1c-based definition, those identified as having prediabetes were 50% more likely to develop kidney disease, twice as likely to develop CVD, and 60% more likely to die from any cause compared with those with normal HbA1c.”

The authors, quoted in Medscape Family Medicine, comment on the practical significance of their findings:

“When someone is told they have prediabetes, we hope it will cause them to make changes to their habits in order to prevent the development of diabetes and its complications,” added the study’s senior author, Elizabeth Selvin, PhD, MPH, a professor in the Bloomberg School’s department of epidemiology.

“Being identified as having prediabetes can also make it easier to receive weight-loss and nutritional counseling as well as reimbursement for these services. Intensive lifestyle changes and weight loss can reduce the risk of diabetes, so it is critically important we identify those persons who are at high risk.

At the same time, we also don’t want to overdiagnose people. Using the hemoglobin A1c test allows us to more accurately identify those persons at highest risk,” she added.

This is important information for physicians and it is also important information for professional organizations. Coming to a global consensus on how to define and diagnose prediabetes would really help move the field forward — and help patients all over the world,” she concluded.”

The authors conclude:

“Our results suggest that prediabetes definitions using HbA1c were more specific and provided modest improvements in risk discrimination for clinical complications. The definition of prediabetes using the ADA fasting glucose concentration cutoff was more sensitive overall.”

Brain health is maintained by immune system activity

the-scientistDramatic advances in understanding how brain health is maintained by the immune system are described in an excellent article published recently in The Scientist that accompanies the brief video presentation by neuroscientist Michal Schwartz shown below. Only recently has it been recognized that brain immune function is integrated with the systemic immune system.

Until recently, the brain and the spinal cord were considered immune-privileged sites, strictly cordoned off from immune cells unless something went terribly wrong. Researchers knew, for example, that multiple sclerosis (MS) was caused by T cells that breach the selective border called the blood-brain barrier (BBB), enter the CNS, and attack the myelin sheath covering neurons. Even microglia, specialized macrophage-like immune cells that scientists had recognized as normal CNS residents since the 1960s, were mainly studied in the context of disease.”

Now the pervasive role of the immune system in brain function and maintenance is being observed:

“But over the past two decades, researchers have recognized that the entire immune system is very much a part of a functional CNS, with vital roles in cognition, injury repair, neurodegenerative disease, and sensory systems. Microglia pervade the CNS, including the white and gray matter that constitute the organ’s parenchyma. Other immune cells, including T cells, monocytes, and mast cells, reside in the brain and spinal cord’s outer membranes, known as the meninges, and circulate in cerebrospinal fluid (CSF).”

Immune cells in the brain help repair damage

It was formerly thought that immune cell activity in the brain was only harmful.

Macrophages, for example, can damage neurons by secreting cytokines, proteases, or reactive oxygen species, but in rat and mouse models of spinal cord injury, they also produce transforming growth factor-beta (TGFβ), which promotes wound healing,5 and interleukin 10 (IL-10) which helps resolve inflammation. By the late 2000s, researchers recognized that different subtypes of macrophages can benefit neuronal growth in rodents, and that some were critical to recovery. Views also began to change on the clinical side after the 2004 Corticosteroid Randomization After Significant Head Injury (CRASH) study showed that corticosteroids didn’t help brain injury patients recover, but increased their risk of disability and death.”

Cells of the adaptive immune system residing in the tissue lining of the ventricles can also assist in repair.

Her team also showed that T cells present in this lining, called thechoroid plexus, secrete cytokines such as interferon gamma (IFNγ), which allows selective passage of CD4+ T cells and monocytes from the blood into CSF within the ventricles.  In a model of spinal cord bruising, mice deficient for the IFNγ receptor had reduced immune cell trafficking across the choroid plexus and poor recovery of limb movement. And last year, Kipnis’s team reported that IL-4 produced by CD4+ T cells in the CNS signals neurons to regrow axons after spinal cord or optic nerve injury.”

Immune cells in the brainAn intact blood-brain barrier (BBB), however, is essential:

“His team also found that microglia reinforce the BBB, which is composed of endothelial cells, pericytes, and astrocytes. Microglia fill in spaces left by astrocytes killed or damaged during injury. Without a robust barrier, McGavern says, unwanted immune cells may flood the parenchyma and do more harm than good.”

Immune cells residing in the CSF and choroid plexus

Immune cells residing in the CSF and choroid plexus

Brain needs both anti-inflammatory and pro-inflammatory activity for cognition

Neuroinflammation is well known to be a core feature of neurodegenerative disorders, but inflammatory immune activity is also required for healthy cognition.

“…Rivest used two-photon microscopy to monitor monocytes in blood vessels of living mouse brains, and he watched as the cells migrated toward and cleared amyloid-β deposits within veins. When the researchers selectively depleted monocytes, the mice developed more amyloid-β plaques in the cortex and hippocampus. And when they knocked out the innate immune signaling protein MyD88, which mediates signals from several monocyte-activating receptors, the mice also experienced more amyloid-β accumulation, accompanied by accelerated cognitive decline.”

Even in the classic disease of neuroinflammation, MS, immune cell activity is necessary:

“Rivest’s team found that microglia-forming monocytes are beneficial in a model of MS, where microglia are found within the inflammatory lesions. Last year, the researchers reported that inhibiting monocytes from entering the CNS reduced the clearance of damaged myelin and impeded proper remyelination.”

Evidence for the immune system’s role in preventing neurodegeneration continues to mount:

“Schwartz has similarly found evidence for the immune system’s ability to protect against neurodegeneration. Last year, she and her colleagues reported that the choroid plexus epithelium was less permissive to immune cell trafficking in a mouse model of Alzheimer’s disease than in wild-type mice, due to anti-inflammatory signals produced by regulatory T cells (Tregs). They found that depleting Tregs in Alzheimer’s mice allowed macrophages and CD4+ T cells into the brain, reduced the number of amyloid-β plaques, and improved cognition. Similarly, blocking the T-cell checkpoint protein PD1, which normally supports Treg survival while suppressing the activity of other T cells, reduced amyloid-β plaques in mouse brains and improved the animals’ scores in a learning and memory water maze test.”

Clinicians should be alert to evaluate and support balance

Too much neuroinflammation is clearly adverse.

“But there’s a reason that scientists have believed that immune activity contributes to Alzheimer’s damage: microglia, perhaps best known for trimming back synapses, have the potential to become overzealous, and excessive synapse pruning can cause neural damage in a variety of CNS diseases. By blocking the cells’ proliferation in mice, Diego Gomez-Nicola of the University of Southampton in the U.K. has successfully alleviated symptoms of Alzheimer’s disease, amyotrophic lateral sclerosis, and prion disease. And earlier this year, Beth Stevens of the Broad Institute and her colleagues reported that inhibiting a protein that tags synapses for microglial pruning halted over-pruning and loss of synapse signaling strength in two mouse models of Alzheimer’s disease.”

Regulation of stress is critical

Stress has a major effect on which way the ‘two-edged sword’ swings.

“Kipnis says regulation of stress may be linked to T cells’ role in learning. Stress can signal macrophages to secrete proinflammatory cytokines, some of which block a protein called brain-derived neurotrophic factor (BDNF), which astrocytes need to support learning and memory. CD4+ T cells in the meninges make more IL-4 cytokine after mice have been trained in a water maze—a stressful exercise for the animals—suggesting the signaling molecule might let macrophages know when the brain is dealing with the stress of learning something new, not the stress of an infection. “They tell macrophages, ‘Don’t overshoot,’” says Kipnis. In mice whose meninges are depleted of CD4+ T cells and thus deficient for IL-4, macrophages secrete proinflammatory factors unchecked in times of stress, disrupting their ability to learn and form memories.”

But excess suppression of inflammatory activity in the brain could have unwanted consequences as in the case of mast cells:

“Best known for their involvement in allergic responses in the upper airway, skin, and gastrointestinal tract, mast cells have been found in the meninges as well as in perivascular spaces of the thalamus, hypothalamus, and amygdala. They are known to quickly recruit large numbers of other immune cell types to sites of inflammation, and to play a role in MS. But mast cells also release serotonin into the hippocampus, where the molecule aids neurogenesis, supports learning and memory, and regulates anxiety.”

A ‘goldilocks zone’ for immune activity in the brain

As in every condition clinical evaluation must embrace the whole context…

“Thus, like microglia, mast cells are a double-edged sword when it comes to neural health. It’s a reflection of the entire immune system’s love-hate relationship with the CNS, Kipnis says. “Saying the immune system is always good for the brain, it’s wrong; saying it’s always bad for the brain, it’s wrong. It depends on the conditions.”

Neuroscientist Michal Schwartz — Breaking The Wall Between Body and Mind