Magnesium, inflammation, insulin resistance and diabetes

Posted on October 26, 2010 by Dr. Jonathan

Magnesium is important for a multitude of functions and functional deficiencies of magnesium are extremely common. A study just published in the journal Diabetes Care illuminates the role of magnesium in the chronic inflammation associated with insulin resistance and diabetes. The authors set out…

“To investigate the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation and insulin resistance among young American adults.”

They examined 4,497 Americans, aged 18-30 years and without diabetes, for magnesium intake and the subsequent onset of diabetes; along with key inflammatory markers (high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and fibrinogen) and the homeostasis model assessment of insulin resistance (HOMA-IR). What did the data show?

“During 20-year follow-up, 330 incident diabetic cases were identified. Magnesium intake was inversely associated with incidence of diabetes [those with the lowest magnesium had 53% more chance of developing diabetes]…Consistently, magnesium intake was significantly inversely associated with hs-CRP, IL-6, fibrinogen, and HOMA-IR; and serum magnesium levels were inversely correlated with hs-CRP and HOMA-IR.”

The association between magnesium and the inflammation markers hs-CRP, IL-6 and fibrinogen is significant for more than diabetes because chronic inflammation is a hallmark of most chronic diseases including cardiovascular disease and cancer. The same goes for insulin resistance as indicated by HOMA-IR. Serum magnesium is not a sensitive indicator of deficiency. Measuring magnesium concentration in the red blood cells is a more accurate representation. Urinary organic acids can also indicate when key metabolic pathways are impaired due to magnesium deficiency. Muscle cramps at rest are very often associated with magnesium deficiency and clear up when magnesium sufficiency has been restored.

Magnesium deficiency and death from cardiovascular disease

Posted on September 16, 2010 by Dr. Jonathan

Magnesium deficiency is so common that it’s hard to find individuals with optimal levels. A study just published in the American Heart Journal adds to the growing body if evidence for the great importance of magnesium in cardiovascular disease. The authors state:

“We hypothesized that serum magnesium (Mg) is associated with increased risk of sudden cardiac death (SCD).”

They assessed risk factors and levels of serum Mg in 14,232 45- to 64-year-old subjects and followed them for an average of 12 years. During that time there were 264 cases of SCD that they used to evaluate the association of serum Mg with risk of SCD. The data made a clear statement:

“Individuals in the highest quartile of serum Mg were at significantly lower risk of SCD in all models. This association persisted after adjustment for potential confounding variables, with an almost 40% reduced risk of SCD in quartile 4 versus 1 of serum Mg observed in the fully adjusted model.”

This is a potent result, summed by the authors’ conclusion:

“This study suggests that low levels of serum Mg may be an important predictor of SCD.”

A whole body of emerging research is illuminating the mechanisms by which suboptimal magnesium levels can have this effect. In a study just published in the journal Diabetes Care the authors set out…

“To investigate the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation and insulin resistance among young American adults.”

The authors followed 4,497 Americans aged 18-30 (who had no diabetes at the beginning) for 20 years. During that time they identified 330 cases of diabetes which they correlated with quintiles of magnesium intake. They also investigated the associations between magnesium intake and inflammatory markers including high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and fibrinogen, and the homeostasis model assessment of insulin resistance (HOMA-IR). What did the data show?

“Magnesium intake was inversely associated with incidence of diabetes after adjustment for potential confounders…Consistently, magnesium intake was significantly inversely associated with hs-CRP, IL-6, fibrinogen, and HOMA-IR; and serum magnesium levels were inversely correlated with hs-CRP and HOMA-IR.”

As you know, these are powerful markers for cardiovascular disease risk. As the authors state in their conclusion:

“This inverse association may be explained, at least in part, by the inverse correlations of magnesium intake with systemic inflammation and insulin resistance.”

An earlier paper published in the journal Magnesium Research documents how low magnesium in conjunction with high fructose consumption promotes inflammation associated with metabolic syndrome. The authors begin by observing:

“The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. This syndrome is occurring at epidemic rates, with dramatic consequences for human health worldwide, and appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in fructose intake, which appears to be an important causative factor in the metabolic syndrome. There is also experimental and clinical evidence that the amount of magnesium in the western diet is insufficient to meet individual needs and that magnesium deficiency may contribute to insulin resistance.”

They present present experimental evidence showing that metabolic syndrome, high fructose intake and low magnesium diet may all be linked to the inflammatory response. The data they gathered showed that:

“…a few days of experimental magnesium deficiency produces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines, appearance of the acute phase proteins and excessive production of free radicals. Because magnesium acts as a natural calcium antagonist, the molecular basis for the inflammatory response is probably the result of a modulation of the intracellular calcium concentration.”

These findings remind of the recent research linking calcium supplementation to increased heart attacks. The authors conclude:

“Since magnesium deficiency has a pro-inflammatory effect, the expected consequence would be an increased risk of developing insulin resistance when magnesium deficiency is combined with a high-fructose diet. Accordingly, magnesium deficiency combined with a high-fructose diet induces insulin resistance, hypertension, dyslipidemia, endothelial activation and prothrombic changes in combination with the upregulation of markers of inflammation and oxidative stress.”

It goes without saying that these are primary inducers of cardiovascular disease. Another paper published last year in the same journal note the association of magnesium deficiency and C-reactive protein:

“Recent findings from epidemiologic studies support that magnesium intake is inversely associated with C-reactive protein concentration, an important marker of inflammation strongly associated with cardiovascular disease risk.”

A fascinating study published in the American Journal of the Medical Sciences investigates magnesium deficiency promotes inflammation and cardiovascular disease through neurogenic pathways:

“This review highlights some key observations that helped formulate the hypothesis that release of substance P (SP) [an inflammatory signalling molecule] during experimental dietary Mg deficiency (MgD) may initiate a cascade of deleterious inflammatory, oxidative, and nitrosative events, which ultimately promote cardiomyopathy, in situ cardiac dysfunction, and myocardial intolerance to secondary stresses.”

The authors further state:

“…SP-mediated events may…facilitate development of in situ cardiac dysfunction, especially with prolonged dietary Mg restriction.”

Additional intriguing research published in the British Journal of Anaesthesia adds even more evidence to the assertion that magnesium helps reduce cardiovascular disease by opposing calcium. The authors begin by stating:

“Magnesium sulphate (MgSO4) has potent anti-inflammatory capacity. It is a natural calcium antagonist and a potent L-type calcium channel inhibitor. We sought to elucidate the possible role of calcium, the L-type calcium channels, or both in mediating the anti-inflammatory effects of MgSO4.”

And magnesium sulphate is not the most bioavailable form of magnesium supplementation. When the authors induced inflammation by exposure to lipopolysaccharide (LPS) as evidenced by macrophage inflammatory protein-2, tumour necrosis factor-α, interleukin (IL)-1β, IL-6, nitric oxide/inducible nitric oxide synthase, prostaglandin E2/cyclo-oxygenase-2, and NF-κB activation.

“MgSO4…significantly inhibited the LPS-induced inflammatory molecules production and NF-κB activation. Moreover, the effects of MgSO4 on inflammatory molecules and NF-κB were reversed by extra-cellular calcium supplement with CaCl2 and L-type calcium channel activator BAY-K8644.”

In other words, in addition to opposing inflammation, magnesium is nature’s calcium channel blocker. The authors conclude:

“MgSO4 significantly inhibited endotoxin-induced up-regulation of inflammatory molecules and NF-κB activation… The effects of MgSO4 on inflammatory molecules and NF-κB may involve antagonizing calcium, inhibiting the L-type calcium channels, or both.”

Pro-inflammatory cytokines of rheumatoid arthritis reduced by Vitamin B6

Posted on July 11, 2010 by Dr. Jonathan

We’re always on the lookout for physiological agents that have the potential to calm the activity of pro-inflammatory cytokines when they are elevated in autoimmune disease. An exciting finding was reported in a paper just published in the European Journal of Clinical Nutrition:

“The purpose of this study was to investigate whether vitamin B6 supplementation had a beneficial effect on inflammatory and immune responses in patients with rheumatoid arthritis (RA).”

The control group of patients was given 5 mg/day of folic acid only while the study group was given 100 mg/day of vitamin B6 in addition for 12 weeks. Indicators of inflammation (C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and lymphocyte subsets were measured on day 1 (week 0) and after 12 weeks (week 12) of the intervention.

At the end of twelves the data painted this picture:

“In the group receiving vitamin B6, plasma IL-6 and TNF-α levels significantly decreased at week 12. Plasma IL-6 level remained significantly inversely related to plasma PLP (pyridoxal 5′-phosphate, B6) after adjusting for confounders.”

The bottom line conclusion is worth bearing in mind when evaluating any autoimmune disorder because underlying causal factors are similar regardless of the specific tissue under attack:

“A large dose of vitamin B6 supplementation (100 mg/day) suppressed pro-inflammatory cytokines (that is, IL-6 and TNF-α) in patients with RA.”

The autoimmune aspect of cardiovascular disease and Th17/Treg imbalance

Posted on July 9, 2010 by Dr. Jonathan

Cardiovascular disease, an inflammatory disorder, is a leading cause of death and the autoimmune component is one of the most important and in general practice, overlooked, aspects. Consider this paper published not long ago in the journal Clinical Immunology. As the authors state,

“Atherosclerosis is a chronic inflammatory disease regulated by T lymphocyte subsets.” ['T lymphocyte subsets' refers to the different categories of lymphocytes that participate in immune reactions.]

Regulatory T cells (Treg) ‘referee’ the immune response and quiet inflammation. Vitamin D is necessary for their production. Th1 refers to the lymphocytes that express the ‘innate’, cell-mediated aspect of the immune response; Th2 is the ‘adaptive’, humoral (antibody) mediated aspect. Th17 cells are a more recently recognized subtype that play a potent role in the immune system’s inflammatory attack.

“Recently, CD4+CD25+Foxp3+ regulatory T (Treg) cells and Th17 cells have been described as two distinct subsets from Th1 and Th2 cells and have the opposite effects on autoimmunity. Th17/Treg balance controls inflammation and may be important in the pathogenesis of plaque destabilization and the onset of acute coronary syndrome [ACS, including unstable angina (UA) and acute myocardial infarction (AMI)].”

The authors investigated this by assessing Th17/Treg functions by cell numbers, related cytokine secretion and their transcription factors in patients suffering from heart attacks, angina and control subjects free of heart disease. Their data made a strong impression:

“The results demonstrated that patients with ACS revealed significant increase in peripheral Th17 number, Th17 related cytokines (IL-17, IL-6 and IL-23) and transcription factor levels and obvious decrease in Treg number, Treg related cytokines (IL-10 and TGF-β1) and transcription factor (Foxp3) levels as compared with patients with SA and controls. Results indicate that Th17/Treg functional imbalance exists in patients with ACS, suggesting a potential role for Th17/Treg imbalance in plaque destabilization and the onset of ACS.”

In other words, the inflammatory process of cardiovascular disease that culminates in the rupture of a vulnerable plaque, which is the precipitating event for a heart attack, expresses this Th17/Treg functional imbalance.

You may have read earlier posts discussing oxidized LDL (ox-LDL) as a fundamental feature of cardiovascular disease and a valuable laboratory marker. This fascinating paper published recently in the journal Biochemical and Biophysical Research Communications that reports on the relationship between ox-LDL and Th17/Treg balance.

“Oxidized low-density lipoprotein (ox-LDL) is an instrumental factor in atherogenesis…CD4+CD25+ regulatory T (Treg) cells and Th17 cells, subsets of T-helper cells, play important roles in peripheral immunity and their imbalance leads to the development of tissue inflammation and autoimmune diseases…To explore the shift of Th17/Treg balance in ACS [acute coronary syndrome] patients and the effect of ox-LDL on the balance, we examined the frequencies of Th17 and Treg cells, key transcription factors and relevant cytokines in patients with AMI [acute myocardial infarction = heart attack], UA [unstable angina], stable angina (SA) and controls.”

What did their data show about the connection between these immune cells and inflammatory cardiovascular disease?

“Our study demonstrated that ACS patients have shown a significant increase of Th17 frequency, RORγt expression and serum Interleukin 17 (IL-17), and a obvious decline of Treg frequency, Foxp3 expression, suppressive function, and serum IL-10. Serum ox-LDL positively correlated with the frequency of Th17 cells and negatively correlated with the frequency of Treg cells…. Treg and Th17 cells from ACS patients were significantly more susceptible to ox-LDL-mediated alterations.“

Take a moment to appreciate the profound significance of this for the evaluation and treatment of cardiovascular disease. Cholesterol levels can be high in the absence of CVD, but when it is damaged by oxidation it somehow participates in the inflamed lesions of the vessel wall that are the basic characteristic of condition…

“Th17/Treg numerical and functional imbalance exists in ACS patients, and ox-LDL has a direct effect on Th17/Treg imbalance which may contribute to the occurrence of ACS.”

How else might Th17/Treg imbalance manifest in cardiovascular disease? A study published this year in the Scandinavian Journal of Immunology reveals its role in idiopathic dilated cardiomyopathy, a fairly common cause of heart failure (the enlarged heart fails to pump properly).

“To assess whether Treg/Th17 balance was broken in patients with idiopathic dilated cardiomyopathy (DCM). We studied 25 patients who were diagnosed as idiopathic DCM (18 men and seven women, mean age 35.6 ± 5.2) and 25 normal persons (18 men and seven women, mean age 33.8 ± 4.9). Then, we detected Treg/Th17 functions on different levels including cell frequencies, related cytokine secretion and key transcription factors in patients with idiopathic DCM and controls.”

What did their data show?

“The results demonstrated that patients with idiopathic DCM revealed significant increase in peripheral Th17 number, Th17-related cytokines (IL-17, IL-6, IL-23) and transcription factor (RORγt) levels and obvious decrease in Treg number, Treg-related cytokines (TGF-β1 and IL-10) and transcription factor (Foxp3) levels when compared to normal persons. Results indicated that Treg/Th17 functional imbalance existed in patients with idiopathic DCM, suggesting a potential role for Treg/Th17 imbalance in the development of idiopathic DCM.”

We can also see that this is a mechanism promoting adverse cardiovascular events when uric acid increases in the bloodstream, such as when people undergo dialysis, from a paper published not long ago in the journal Nephrology.

“Adverse cardiovascular events resulting from accelerated atherosclerosis are the leading cause of mortality in uraemic patients on maintenance haemodialysis (MHD). Chronic inflammation due to antigen-specific responses is an important factor in the acceleration of atherosclerosis...The aim of the present study was to assess the Treg/Th17 pattern in uraemic patients on MHD and to explore the significance of Treg/Th17 imbalance in the development and outcome of acute cardiovascular events.”

Their findings offer fascinating insight into the link between uric acid and cardiovascular inflammation:

“Patients with uraemia exhibited an obvious imbalance of Treg/Th17 function when compared to the normal control group, displaying increased peripheral Th17 frequency, Th17-related cytokines (interleukin [IL]-17, IL-6 and IL-23) and RORγt mRNA levels. These patients also displayed decreased Treg frequency, Treg-related cytokines (IL-10, transforming growth factor-β1) and Foxp3 mRNA levels…It was also observed that the imbalance of Treg/Th17 was not only consistent with the cardiovascular disease but also correlated with a microinflammatory state.”

Clinicians and patients should bear their concluding point in mind:

“This Th17/Treg imbalance might act synergistically with microinflammation on immune-mediated atherosclerosis and contribute to the high incidence of adverse cardiovascular events.”

Clinical & Experimental Immunology I would like to note the evidence that Th17/Treg imbalance also plays a role in autoimmune disease associated with organ transplantation since a case this year involving autoimmune attack on the nerves regulating the heartbeat followed by another autoimmune inflammatory reaction to the pacemaker (Dressler’s syndrome). The authors of a paper published in Clinical and Experimental Immunology state:

“…it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD [autoimmune disease] or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL-6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection…”

They sum up their extensive review by concluding:

“Interleukin 17 is a pleiotropic cytokine with multiple proinflammatory functions that is likely to be involved in either the causation or progression of inflammatory diseases and transplant rejection in humans. Regulatory T cells are an anti-inflammatory lineage of T cells… It is possible that acute flares of autoimmune diseases or acute episodes of transplant rejection may be explained by a change in the relative dominance of these pathways…”

What resources can we turn to for correcting Th17/Treg imbalances? A fascinating paper just published in the European Journal of Immunology explains how the proinflammatory cytokine IL-6 (Interleukin-6) is a regulator of Th17/Treg.

“IL-6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL-6 has a very important role in regulating the balance between IL-17-producing Th17 cells and regulatory T cells (Treg). The two T-cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T-cell responses.”

The authors explain the pivotal role played by IL-6 in determining the relative balance of autoimmune inflammation-promoting Th17 versus the anti-inflammatory Treg cells:

“IL-6 induces the development of Th17 cells from naïve T cells together with TGF-β; in contrast, IL-6 inhibits TGF-β-induced Treg differentiation. Dysregulation or overproduction of IL-6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology.”

Their conclusion offers a welcome insight in that we have evidence-based physiological interventions that act to regulate IL-6:

“Given the critical role of IL-6 in altering the balance between Treg and Th17 cells, controlling IL-6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases.”

Further evidence for the pivotal role of IL-6 in regulating T17 and Treg balance is found in an interesting paper published in the journal Mucosal Immunology that points out the same process in inflammatory bowel disease:

“T helper (Th)17 cells have been shown to play a role in the pathogenesis of inflammatory and autoimmune diseases including inflammatory bowel diseases (IBD). It is now well established that although transforming growth factor (TGF)-beta alone induces FoxP3+ regulatory T (Treg) cells, TGF-beta and interleukin (IL)-6, acting in concert, induce differentiation of mouse naive T cells into Th17.”

Going a step further, they were able to discern that IL-6 can act alone in promoting the development of Th17 cells:

“We found that upon activation, Treg cells induce CD4+CD25- naive T cells or Treg cells themselves to differentiate into Th17 in the presence of IL-6 alone without exogenous addition of TGF-beta.”

Another clue to some of the therapies we can use is suggested by a study published in the Journal of Immunology on the ability of retinoic acid (RA), a metabolite of Vitamin A, to inhibit the expression of IL-6. The authors first observe:

“The de novo generation of Foxp3+ regulatory T (Treg) cells in the peripheral immune compartment and the differentiation of Th17 cells both require TGF-β, and IL-6 and IL-21 are switch factors that drive the development of Th17 cells at the expense of Treg cell generation.”

The authors elucidate the pathways by which Treg can be promoted and IL-6 inhibited by retinoic acid (RA):

“Herein we show that RA enhances TGF-β signaling…and this results in increased Foxp3 [Treg] expression even in the presence of IL-6 or IL-21. RA also inhibits the expression of IL-6R{alpha}…and thus inhibits Th17 development. In…experimental autoimmune encephalomyelitis…RA suppresses the disease very efficiently by inhibiting proinflammatory T cell responses, especially pathogenic Th17 responses.”

Their conclusion is well worth keeping in mind when we are researching a treatment plan for the autoimmune component of cardiovascular disease or any other autoimmune condition:

“These data not only identify the signaling mechanisms by which RA can affect both Treg cell and Th17 differentiation, but they also highlight that in vivo during an autoimmune reaction, RA suppresses autoimmunity mainly by inhibiting the generation of effector Th17 cells.”

Inflammation and insulin resistance genes are activated by surgery

Posted on June 28, 2010 by Dr. Jonathan

This interesting paper recently published in the Journal of Clinical Endocrinology & Metabolism describes one of the reasons why support when undergoing a surgical procedure is so important (and links to the risks for delirium and accelerated dementia after surgery in the elderly). The authors set out to investigate the…

“…mechanisms behind postoperative insulin resistanceand impaired glucose utilization…”

They shrewdly analyzed the expression of 21 target genes in abdominal adipose (fat) tissue from samples taken at the beginning and end of patients undergoing abdominal surgery. What did the data show?

“After surgery, both sc [subcutaneous] and omental adipose tissue mRNA levels of genes involved in the IL6 and nicotinamide phosphoribosyltransferase pathways were increased, whereas mRNA levels of insulin receptor substrate 1 and adiponectin were reduced. TNF pathway genes were differently regulated between sc and omental adipose tissue, and glucose transporter 4 mRNA levels were decreased only in omental adipose tissue.”

In other words, surgery elicits a shift in genetic expression that favors insulin resistance and inflammation. The authors conclude:

“The transcriptional output of pivotal inflammatory and insulin signaling pathway genes is altered after surgery…This could be of importance for the metabolic aberrations associated to postsurgical complications…”

This helps to understand why patients who are lucky enough to receive adjunctive support for the insulin and inflammatory signaling pathways and receptors recover faster and with less complications.

Laser therapy reduces inflammatory cytokines

Posted on June 14, 2010 by Dr. Jonathan

Photomedicine and Laser Surgery The therapeutic use of non-invasive, low level (cold) laser and and infrared has not crossed the gap into clinical practice to the degree that the rich body of scientific research justifies. The laser and infrared therapies we use here appear to help even though you can’t feel them (at the time of application); but what evidence is there that they really do anything? And by what mechanisms? Consider this study published in the journal Photomedicine and Laser Surgery a few years ago that documents the effect of visible and infrared light on inflammatory cytokines (immune system messenger molecules). The authors state:

“The aim of this randomized, placebo-controlled, double-blind trial was to investigate changes in the content of 10 cytokines in the human peripheral blood after transcutaneous [through the skin] and in vitro [to blood removed from the body] irradiation with polychromatic visible and infrared (IR) polarized light…”

The magnitude of the effect that they observed by just applying the light to the sacral area of the study subjects is surprising:

“A dramatic decrease in the level of pro-inflammatory cytokines TNF-α, IL-6, and IFN-γ was revealed: at 0.5 h after exposure of volunteers (with the initial parameters exceeding the norm), the cytokine contents fell, on average, 34, 12, and 1.5 times. The reduced concentrations of TNF-α and IL-6 were preserved after four daily exposures, whereas levels of IFN-γ and IL-12 decreased five and 15 times. At 0.5 h and at later times, the amount of anti-inflammatory cytokines was found to rise: that of IL-10 rose 2.7–3.5 times (in subjects with normal initial parameters) and of TGF-β1 1.4–1.5 times.”

But if you expose just the area over the sacrum, what happens when that blood mixes with the rest of the circulation?

“Similar regularities of the light effects were recorded after in vitro irradiation of blood, as well as on mixing the irradiated and non-irradiated autologous blood at a volume ratio 1:10 (i.e., at modeling the events in a vascular bed of the exposed person when a small amount of the transcutaneously photomodified blood contacts its main circulating volume).”

In other words, a small limited application causes system-wide effects. Considering how much we need therapies that physiologically modulate the inflammatory response without side effects, the authors’ conclusion is extremely compelling:

“Exposure of a small area of the human body to light leads to a fast decrease in the elevated pro-inflammatory cytokine plasma content and to an increase in the the anti-inflammatory factor concentration, which may be an important mechanism of the anti-inflammatory effect of phototherapy. These changes result from transcutaneous photomodification of a small volume of blood and a fast transfer of the light-induced changes to the entire pool of circulating blood [!].”

Here’s a little more from the large body of research published in the same journal:

By the way, this is interesting in connection with the earlier post on the infrared treatment of depression.

Just seeing someone who is sick can increase proinflammatory cytokines

Posted on June 12, 2010 by Dr. Jonathan

Those interested in how image and perception modify gene expression and immune function will appreciate this paper recently published in the journal Psychological Science.

“An experiment…tested the hypothesis that the mere visual perception of disease-connoting cues promotes a more aggressive immune response.”

The experimental subjects were exposed to either photographs depicting symptoms of infectious disease or photographs of guns.

“After incubation with a model bacterial stimulus, participants’ white blood cells produced higher levels of the proinflammatory cytokine interleukin-6 (IL-6) in the infectious-disease condition, compared with the control (guns) condition.”

This may not be the first study to demonstrate this effect, but the authors assert…

“These results provide the first empirical evidence that visual perception of other people’s symptoms may cause the immune system to respond more aggressively to infection.”

It’s well known that though we can cognitively discriminate between a photo depicting infection and the immediate material presence of it, our autonomous physiological response does not. Now consider the significance for autoimmune disease when there is hyperarousal of attention to the possibility of infection. This is one of the reasons why I am convinced that dogmatically insisting on a diagnosis of chronic infection (such as Lyme disease) when the most sensitive and advanced tests provide zero evidence—and at the same time demonstrable autoimmune phenomena are present—is doing patients a disservice.

Nervous system regulation of inflammation, cytokines, and heart rate variability

Posted on May 27, 2010 by Dr. Jonathan

As readers here know, inflammation is a fundamental factor in chronic disease and accelerated aging (neurodegeneration). A functional approach to treatment requires an objective understanding of how this system is working for each patient. Here are several of the many studies that illustrate how nervous system function and inflammation can be evaluated with heart rate variability (HRV) analysis and cytokine (‘messenger molecules’ of inflammation) levels.

Shock The practical focus is on restoring parasympathetic nervous system (PNS) activity which inhibits inflammation. (PNS resources decline with disease, stress and age resulting in a state of ‘sympathetic nervous system dominance’.) This paper just published in the journal Shock shows how autonomic nervous system activity (sympathetic and parasympathetic) as measured by HRV corresponds to inflammatory cytokine activity, in this case when stimulated by endotoxins (poisons produced by bacterial infections):

“Autonomic inputs from the sympathetic and parasympathetic nervous systems, as measured by heart rate variability (HRV), have been reported to correlate to the… responses to infectious challenge… In addition, parasympathetic/vagal activity has been shown experimentally to exert anti-inflammatory effects via attenuation of splanchnic tissue TNF-α [cytokine] production. We sought… to determine if baseline HRV parameters correlated with endotoxin-mediated circulating cytokine responses.”

They documented a strong correspondence regardless of gender, body mass index and resting heart rate:

“…we found a significant correlation of several baseline HRV parameters…on TNF-α release after endotoxin exposure.”

This is not a new observation. An interesting study published a few years ago in the journal Psychosomatic Medicine documents the HRV expression of autonomic activity in response to an inflammatory challenge and its correspondence to cytokine production. They begin by noting that:

“…the autonomic nervous system plays a key role in regulating the magnitude of immune responses to inflammatory stimuli. Signaling by the parasympathetic system inhibits the production of proinflammatory cytokines by activated monocytes/macrophages and thus decreases local and systemic inflammation.”

They examined the relationship of HRV to lipopolysaccharide-induced production of the inflammatory cytokines interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-{alpha}, and IL-10. What did the data show?

“Consistent with animal findings, higher derived estimates of vagal activity measured during paced respiration* were associated with lower production of the proinflammatory cytokines TNF-{alpha} and IL-6…These associations persisted after controlling for demographic and health characteristics, including age, gender, race, years of education, smoking, hypertension, and white blood cell count.”

Their conclusion has profound implications for the biological mechanism by which stress causes inflammation:

“These data provide initial human evidence that vagal activity is inversely related to inflammatory competence, raising the possibility that vagal regulation of immune reactivity may represent a pathway linking psychosocial factors to risk for inflammatory disease.”

How might this show up in heart disease? This paper published not long ago in the journal Brain, Behavior, and Immunity investigates the links between HRV, inflammatory cytokines, coronary heart disease and depression:

“Studies show negative correlations between heart rate variability (HRV) and inflammatory markers [less variability = more inflammation]…We investigated links between short-term HRV and inflammatory markers in relation to depression in acute coronary syndrome (ACS) patients.”

They measured C-reactive protein (CRP), interleukin-6 (IL-6, a cytokine), depression symptoms and heart rate variability determinants of autonomic function. What did their data show?

“…all HRV measures were negatively and significantly associated with both inflammatory markers…HRV independently accounted for at least 4% of the variance in CRP in the depressed, more than any factor except BMI.”

Interestingly, they also noted that:

“Relationships between measures of inflammation and autonomic function are stronger among depressed than non-depressed cardiac patients. Interventions targeting regulation of both autonomic control and inflammation may be of particular importance.”

The research of another group published in the Journal of Critical Care used sepsis as their model.

“The aim of the study was to investigate possible associations between different heart rate variability (HRV) indices and various biomarkers of inflammation in 45 septic patients.”

They examined the correlation between HRV, C-reactive protein, and the cytokines interleukin 6 and interleukin 10:

“Our data suggest that low HRV and sympathovagal balance during septic shock are associated with both an increased hyperinflammatory and antiinflammatory response.”

The antiinflammatory response corresponds to high HRV and interleukin-10, the cytokine that is also increased by vitamin D.

Journal of Internal Medicine How can we reduce inflammation by increasing HRV and reducing inflammatory cytokines? There are numerous methods; one is to increase cholinergic activity in the nervous system (parasympathetic activity mediated by the neurotransmitter acetylcholine). We can increase this with natural precursor support for acetylcholine. This study published recently in the Journal of Internal Medicine shows the connection between vagal parasympathetic function (as shown by HRV), inflammatory cytokines, cholinergic activity and rheumatoid arthritis:

“The central nervous system regulates innate immunity in part via the cholinergic anti-inflammatory pathway, a neural circuit that transmits signals in the vagus nerve that suppress pro-inflammatory cytokine production…Vagus nerve activity is significantly suppressed in patients with autoimmune diseases, including rheumatoid arthritis (RA). It has been suggested that stimulating the cholinergic anti-inflammatory pathway may be beneficial to patients…”

They found that increasing cholinergic signaling in stimulated whole blood cultures suppressed cytokine production in rheumatoid arthritis patients whose vagal activity was deficient:

“These findings suggest that it is possible to pharmacologically target the α7nAChR dependent control of cytokine release in RA patients with suppressed vagus nerve activity.”

In a functional medicine practice, of course, we use natural acetylcholine precursors.

This is a drop in the bucket, but here’s one more fascinating paper published recently in the journal Brain, Behavior, and Immunity that shows how acetylcholine activity in the brain (the upper level of autonomic regulation) controls systemic cytokine levels through vagal function:

“The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “cholinergic anti-inflammatory pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine release…Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks…Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF [cytokine] production during endotoxemia.”

They demonstrated that inhibiting the breakdown of acetylcholine† markedly reduced proinflammatory serum TNF levels through the resulting increasing vagus nerve signaling which prevented inflammatory damage. What do they conclude from their research?

“These findings show that inhibition of brain acetylcholinesterase [that breaks down acetylcholine] suppresses systemic inflammation through a central…mediated and vagal…dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor† can be utilized to suppress abnormal inflammation to therapeutic advantage.”

* There are numerous therapies to reduce inflammation by increasing parasympathetic function. Breathing is a powerful stimulus to the autonomic nervous system. We train breathing with biofeedback while simultaneously monitoring for CO2 (capnography) and coherence in HRV to hit the physiological “sweet spot”.

† Agents that inhibit the breakdown of neurotransmitters including reuptake inhibitors do not restore the body’s ability to make its own. Precursor therapy provides the natural ingredients that have been depleted or are insufficient to meet genetic needs so neurotransmitters can be increased naturally.

Mechanisms that link inflammation, obesity and cancer

Posted on May 5, 2010 by Dr. Jonathan

The latest issue of the Journal of the National Cancer Institute comments on recent research investigating how the inflammatory cytokines (cell signaling molecules), which are increased under various conditions that include obesity, can turn healthy liver cells into malignant ones:

“As obesity’s ties to multiple cancers strengthen, a new study suggests that inflammation may be the primary culprit in at least one malignancy: liver cancer.”

Cell The study itself was recently published in the journal Cell. The report that…

“We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice…Obesity-promoted HCC (hepatocellular carcinoma = liver cancer) development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3.”

Readers here will not be surprised that they also assert…

“The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.”

Three important points: (1) nothing increases the storage of fat in the liver like the high levels of insulin associated with insulin resistance (remember the link between insulin and fatty liver disease). (2) Chronic inflammation, whatever the cause, is a component of most chronic degenerative diseases. (3) Those of us who are health care professionals should be using the available laboratory tests for inflammatory cytokines in the care of our patients when appropriate; readers who are patients should be asking about them.

Depression involves brain inflammation

Posted on April 1, 2010 by Dr. Jonathan

Biological Psychiatry Not to oversimplify since depression can have multiple contributing causes, but there have been many studies published about brain inflammation as an important component of major and minor depression. An illuminating paper published in the latest volume of the journal Biological Psychiatry undertakes an extensive analysis of accumulated scientific evidence. The authors begin by noting:

“Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls.”

Cytokines are, among other things, signalling molecules that regulate immune system function. This has great practical significance because there is an evidence-based approach in functional medicine to analyzing and treating cytokine imbalances. The authors evaluated 24 studies that included eight different cytokines. Here’s what their data showed:

“This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-α and IL-6 in depressed subjects compared with control subjects…this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS.”

You may enjoy the interesting comment on this study just published in Journal Watch.

Although this is a valuable study it’s important to keep a broad perspective. Here’s another paper published not long ago in the journal Pharmacopsychiatry, one among many others on cytokines and depression. It documents cases of brain inflammation with a different cytokine pattern. This paper is also interesting for the therapeutic comparison of Prozac and electroacupuncture:

“An increase in inflammatory response and an imbalance between T-helper (Th) 1 and 2 functions have been implicated in major depression. The aims of the present study were to 1) study the relationship between pro- and anti-inflammatory cytokines and between Th1 and Th2 produced cytokines in depressed patients and 2) evaluate and compare the effect of treatments with electroacupuncture (EA) and fluoxetine on these cytokines.”

Th1 and Th2 are the two primary poles of immune system function, cell-mediated and humoral (antibody). Imbalances result in immune dysregulation. Fluoxetine is Prozac. (The inclusion of electroacupuncture might tip you off that this study was done in Germany.) Their data tells a fascinating story:

“Increased proinflammatory cytokine interleukin (IL)-1β and decreased anti-inflammatory cytokine IL-10 were found in the depressed patients. By contrast, Th1 produced proinflammatory cytokines, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were decreased, and Th2 produced cytokine IL-4 was significantly increased in depressed patients…Both acupuncture and fluoxetine treatments, but not the placebo, reduced IL-1β concentrations in responders. However, only acupuncture attenuated TNF-α concentration and INF-γ/IL-4 ratio towards the control level.”

How interesting that what we call a peripheral sensory nervous system modality (stimulation of the brain through the peripheral sensory nerves, in this case with electroacupuncture) reduced inflammation and TNF-α. This corresponds exactly with my clinical experience employing these modalities for a range of conditions including autoimmune disorders, and explains part of why patients feel so much better after a treatment. Their conclusion is worth noting:

“These results suggest that an imbalance between the pro- and anti-inflammatory cytokines (IL-1 and IL-10), and between Th1 and Th2 cytokines (INF-γ or TNF-α and IL-4) occurred in untreated depressed patients. Both EA and fluoxetine had an anti-inflammatory effect by reducing IL-1β. EA treatment also restored the balance between Th1 and Th2 systems by increasing TNF-α and decreasing IL-4.”

Thus depression involves inflammation, but the cytokine expression can vary.

This topic is multifaceted and a proper synopsis of the functional approach to depression is too long for this forum, but here’s one more paper to keep the horizon open. This study published not long ago in the Journal of Psychiatric Practice investigates the role of low testosterone in depression.

“Studies suggest that testosterone (TT) replacement may have an antidepressant effect in depressed patients…The objective of this study was to explore the effect of TT administration on depression using both a systematic review of the literature and a meta-analysis.”

What did the data show?

“Meta-analysis of the data from these seven studies showed a significant positive effect of TT therapy on…depressed patients when compared with placebo. Subgroup analysis also showed a significant response in the subpopulations with hypogonadism…”

This certainly confirms expectations considering the population of testosterone receptors in the brain and their density in the frontal lobe. Hypogonadism means that the testicles are producing too little testosterone in response to stimulation by luteinizing hormone (LH). This validates my common sense practice of always including biologically active free fraction testosterone and LH in workups for male depression. Note: testosterone replacement, especially by a transdermal route (gel, patch, cream) can give a good initial result but end up back-firing. This is a topic for another post. For now just remember there is a better way.