Inflammation caused by allergy promotes weight gain and obesity

Posted on June 29, 2011 by Dr. Jonathan

As clinicians and most lay readers know, healthy weight loss and weight maintenance require healthy insulin signaling. Insulin receptor resistance due to excessive glycemic stimulation results in higher compensatory insulin levels that force the storage of calories as fat. Inflammation also contributes to insulin resistance, with metabolic syndrome and its associated weight gain and eventual type 2 diabetes. A fascinating study just published in the journal Obesity describes how B cell-activating factor (BAFF) contributes to the development of insulin resistance. BAFF can be induced by food hypersensitivity and allergic reactions. The authors state:

“Visceral adipose tissue (VAT) inflammation has been linked to the pathogenesis of insulin resistance and metabolic syndrome. VAT has recently been established as a new component of the immune system and is involved in the production of various adipokines and cytokines. These molecules contribute to inducing and accelerating systemic insulin resistance. In this report, we investigated the role of B cell-activating factor (BAFF) in the induction of insulin resistance.”

They examined BAFF levels in the blood and visceral fat of obese mice, which they found to be increased compared to normal control mice…

“Next, we treated mice with BAFF to analyze its influence on insulin sensitivity. BAFF impaired insulin sensitivity in normal mice. Finally, we investigated the mechanisms underlying insulin resistance induced by BAFF in adipocytes. BAFF also induced alterations in the expression levels of genes related to insulin resistance in adipocytes. In addition, BAFF directly affected the glucose uptake and phosphorylation of insulin receptor substrate-1 in adipocytes.”

In other words, BAFF not only directly induced insulin resistance, but altered the expression of genes related to insulin receptor function and fat inflammatory cytokine (adipokine) production. The authors concluded:

“We propose that autocrine or paracrine BAFF and BAFF-receptor (BAFF-R) interaction in VAT leads to impaired insulin sensitivity via inhibition of insulin signaling pathways and alterations in adipokine production.”

We can also appreciate an earlier paper published in the journal Experimental & Molecular Medicine that also identifies BAFF as an adipokine that links inflammation with obesity. The authors state:

“In the current study, we verified that BAFF expression is increased during adipocyte differentiation…We sought to identify known BAFF receptors (BAFF-R, BCMA, and TACI) in adipocytes, and determined that all three were present and upregulated during adipocyte differentiation…BAFF-R and BCMA expression levels were upregulated under pro-inflammatory conditions…”

They also demonstrated that the BAFF receptors BAFF-R and BCMA were downregulated by rosigliatazone treatment. (Rosigliatzone, trade name Avandia, is a thiazolidinedione type anti-diabetic drug with anti-inflammatory properties whose use has been complicated by serious side effects.) In other words, inflammation associated with BAFF signaling promoted insulin resistance and obesity. The authors conclude:

“Taken together, our results suggest that BAFF may be a new adipokine, representing a link between obesity and inflammation.”

Incidentally, as the authors of a review just published in the Journal of Clinical Investigation note, obesity-associated inflammation has serious global effects:

“The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity…The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases.”

Moreover…

“The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time…While transient inflammatory states such as sepsis can have multi-organ effects, few other chronic inflammatory diseases are characterized by the features of pancreatic, liver, adipose, heart, brain, and muscle inflammation as is seen in obesity.”

Clinicians should never overlook the role of the gut-associated immune tissue (GALT) in disorders of chronic inflammation. A paper just published in Current Opinion in Clinical Nutrition & Metabolic Care highlights this in the link between intestinal inflammation, obesity and insulin resistance. The authors state:

“Current views suggest that obesity-associated systemic and adipose tissue inflammation promote insulin resistance, which underlies many obesity-linked health risks. Diet-induced changes in gut microbiota also contribute to obesity…”

They go on to summarize…

“…the evidence supporting a role of intestinal inflammation in diet-induced obesity and insulin resistance and discusses mechanisms.”

Of course, food allergy and hypersensitivity are major causes of intestinal inflammation. Regrettably, many practitioners may wrongly assume that the phenomenon of inflammation triggered by food sensitivity is limited to the classically defined IgE-mediated acute hypersensitivity reaction. In fact, there are a number of pathways by which food sensitivity can elicit an inflammatory response. A very important study just published in Alimentary Pharmacology & Therapeutics makes this clear in regard to BAFF, which we now understand to be linked to obesity and insulin resistance. The authors first note that…

“Medically confirmed hypersensitivity reactions to food are usually IgE-mediated. Non-IgE-mediated reactions are not only seldom recognized but also more difficult to diagnose.”

They set out to…

“…examine B cell-activating factor (BAFF) in serum and gut lavage fluid of patients with self-reported food hypersensitivity, and to study its relationship to atopic disease.”

So they examined the gut lavage fluid obtained from 60 patients with self-reported food hypersensitivity and the serum from 17 others. From 20 healthy control subjects they obtained gut lavage fluid, along with serum from 11 of them. They then measured BAFF in both serum and the gut lavage fluid. Their findings are most interesting:

“B cell-activating factor levels in serum and gut lavage fluid were significantly higher in patients than in controls…There was no significant correlation between serum levels of BAFF and IgE.”

In other words, patients with food hypersensitivity produced significantly higher levels of BAFF–and IgE failed as an indicator of BAFF associated inflammation with food hypersensitivity. The authors add in their conclusion:

“The results suggest that BAFF might be a new mediating mechanism in food hypersensitivity reactions. Significantly higher levels in non-atopic compared with atopic patients, and no correlation between BAFF and IgE, suggest that BAFF might be involved particularly in non-IgE-mediated reactions.”

Unfortunately, food hypersensitivity is too often dismissed by many in the medical community as a poorly understood phenomenon that ends up being ignored in clinical practice. A clinical study review recently published in the Scandinavian Journal of Gastroenterology investigates this issue and observes the role of BAFF:

“Perceived food hypersensitivity is a prevalent, but poorly understood condition. In this review article, we summarize narratively recent literature including results of our 10 years’ interdisciplinary research program dealing with such patients.”

The studies included more than 400 adults who were referred to a university hospital because of gastrointestinal complaints that they attributed to food hypersensitivity. Most not only fulfilled criteria for irritable bowel syndrome…

“…In addition, most suffered from several extra-intestinal health complaints and had considerably impaired quality of life.”

Sadly…

“Despite extensive examinations, food allergy was seldom diagnosed…However, psychological factors could explain only approximately 10% of the variance in the patients’ symptom severity and 90% of the variance thus remained unexplained.”

Moreover…

“Intolerance to low-digestible carbohydrates was a common problem and abdominal symptoms were replicated by carbohydrate ingestion. A considerable number of patients showed evidence of immune activation by analyses of B-cell activating factor, dendritic cells and “IgE-armed” mast cells.”

Atopic dermatitis (the most common form or eczema, also linked to food sensitivity) has been shown to be associated with high levels of B cell-activating factor (BAFF) in a paper published not long ago in the journal Clinical and Experimental Dermatology. In order to investigate the role of BAFF in serum of patients with atopic dermatitis (AD)…

“Levels of serum BAFF, a proliferation-inducing ligand (APRIL) and total serum IgE level, and total eosinophil count were measured in 245 children.”

Their data showed a distinct association:

“Patients were characterized as having atopic eczema (AE); the remainder were healthy control subjects. Serum BAFF level in children with AE was significantly higher than in non-AE children or healthy controls.“

Not surprisingly considering immune function in the common mucosal barrier system, there is also evidence that B-cell activating factor is induced by airborne hypersensitivity reactions. A study published in The Journal of Allergy and Clinical Immunology documents the increased production of BAFF in the airway tissues after exposure to antigen. The authors state:

“The objective of this study was to investigate the production of B cell-activating factor of the TNF family (BAFF), an important regulator of B cell survival and immunoglobulin class switch recombination, in bronchoalveolar lavage (BAL) fluid after segmental allergen challenge (SAC) of allergic subjects.”

They measured the amount of B cell-active cytokines including BAFF in bronchoalveolar lavage (BAL) fluid after 16 adult allergic subjects where challenged with allergens or saline. The data showed a clear result:

“BAFF protein was significantly elevated in BAL fluid after allergen challenge compared with those at saline sites…BAFF levels were also significantly correlated with other B cell-activating cytokines, IL-6 and IL-13.”

As in the gut, inflammation due to allergen exposure elevated BAFF levels. The authors conclude:

“These findings imply that exposure to antigen in the airway activates a process that stimulates the release of cytokines, including BAFF and others, that are known to promote CSR [class switch recombination = a change in antibody production by B cells] and immunoglobulin synthesis by B cells.”

Finally, B cell-activating factor expression due to gluten sensitivity deserves special mention because of the insidious and distinctively injurious nature of gluten reactions. An interesting study published in the Scandinavian Journal of Gastroenterology investigates this phenomenon, while referring to the link between celiac disease, BAFF and lymphoma. The authors state:

“The B cell-activating factor of the tumour necrosis factor (TNF) family (BAFF) was recently described as a critical survival factor for B cells, and its expression is increased in several autoimmune diseases. Abnormal production of BAFF disturbs immune tolerance allowing the survival of autoreactive B cells and participates in the progression of B-cell lymphomas. Coeliac disease (CD) is a common autoimmune disorder induced by gluten intake in genetically predisposed individuals, associated with autoantibody production and with an increased risk of lymphoma at follow-up. The purpose of this study was to investigate the possible implications of BAFF in CD.”

They examined serum BAFF levels, anti-transglutaminase (a-tTG) and endomysial antibodies in 73 patients with celiac disease confirmed by biopsy and laboratory tests before starting a gluten free diet (GFD), while using 77 blood donors as controls. Their data painted a most interesting and dramatic picture:

“Serum BAFF levels appeared to be significantly more elevated in CD patients than in controls and, compared with other autoimmune diseases where BAFF is increased, a much larger percentage (80.8%) of CD patients presented BAFF levels above the normal range. In addition, serum BAFF levels were found to correlate with a-tTG antibody levels…”

And happily…

“…there was a significant reduction of BAFF after introduction of a GFD [gluten-free diet].”

To summarize the significance for obesity and weight loss:

B cell-activating factor (BAFF), triggered by food hypersensitivity and other allergic reactions, is associated with inflammation .
BAFF induces insulin resistance; the resultant higher levels of insulin force the storage of calories of fat, promoting weight gain and obesity.
A sucessful and physiologically sound weight loss and maintenance program should have a strategy to control inflammation and BAFF signaling. This includes the diagnosis of food allergy or sensitivity, with special emphasis on proper screening for reactions to gluten.

Metabolic syndrome promotes cognitive decline

Posted on February 27, 2011 by Dr. Jonathan

More evidence that metabolic syndrome, and its root causal factor insulin resistance, are damaging to the brain and promote cognitive decline appears in a study just published in the journal Neurology. The authors set out to…

“…examine associations between metabolic syndrome (MetS) and its individual components with risk of cognitive decline on specific cognitive functions.”

The assessed 4,323 women and 2,764 men aged 65 and over for cognitive decline and metabolic syndrome (possessing at least 3 of 5 cardio-metabolic abnormalities: hypertension, high waist circumference, hypertriglyceridemia, low high-density lipoprotein [HDL] cholesterol, hyperglycemia). The risk evaluation was adjusted for a number of variables including the APOE4 genotype. What did their data show?

“MetS at baseline was associated with an increased risk of cognitive decline on MMSE [Mini-Mental State Examination for global cognitive function]…. Among MetS components, hypertriglyceridemia and low HDL cholesterol were significantly associated with higher decline on MMSE; diabetes, but not elevated fasting glycemia, was significantly associated with higher decline on BVRT [Benton Visual Retention Test for visual working memory]and IST [Isaacs Set Test for verbal fluency].”

The practical message for clinicians and the public is that blood sugar and insulin regulation are critical factors for brain health. Management begins with diet and lifestyle factors including exercise and encompasses specific needs for supplementation as determined by reliable laboratory investigations that disclose individual genetic and epigenetic factors. The authors conclude:

“MetS as a whole and several of its components had a negative impact on global cognitive decline and specific cognitive functions in older persons.“

Trans-palmitoleate, a good fat in dairy products

Posted on February 7, 2011 by Dr. Jonathan

Original research published recently in the Annals of Internal Medicine offers evidence that trans-palmitoleate, a fat present in milk, is responsible for metabolic benefits observed with dairy consumption. The authors set out to…

“…To investigate whether circulating trans-palmitoleate is independently related to lower metabolic risk and incident type 2 diabetes.”

They examined 3736 adults in the Cardiovascular Health Study for plasma phospholipid fatty acids, blood lipids, inflammatory markers, and glucose–insulin and dietary habits, taking into consideration relevant demographic, clinical, and lifestyle factors. They then determined how trans-palmitoleate related to major metabolic risk factors. Their data tell an interesting story of a helpful fat:

“In multivariate analyses, whole-fat dairy consumption was most strongly associated with higher trans-palmitoleate levels. Higher trans-palmitoleate levels were associated with slightly lower adiposity and, independently, with higher high-density lipoprotein cholesterol levels, lower triglyceride levels, a lower total cholesterol–HDL cholesterol ratio, lower C-reactive protein levels, and lower insulin resistance. Trans-palmitoleate was also associated with a substantially lower incidence of diabetes…Protective associations with metabolic risk factors were confirmed in the validation cohort.”

Of course, this study does address the widespread problem of dairy allergy, nor does it discriminate between the widely varying qualities of dairy (organic from grass-fed free-range animals versus industrial dairy). But it does caution against the wholesale discrimination against fats in general and the dairy food group in particular. As always, clinical and lifestyle decisions depend on the needs of the individual which can be verified by objective outcome markers. Practitioners and health conscious individuals can consider the authors’ conclusion:

“Circulating trans-palmitoleate is associated with lower insulin resistance, presence of atherogenic dyslipidemia, and incident diabetes. Our findings may explain previously observed metabolic benefits of dairy consumption and support the need for detailed further experimental and clinical investigation.”

Magnesium improves insulin sensitivity

Posted on January 13, 2011 by Dr. Jonathan

More evidence that magnesium improves insulin function to treat metabolic syndrome and prevent type 2 diabetes is presented in a study just published in the journal Diabetes, Obesity and Metabolism. The authors note:

“The incidence of insulin resistance and metabolic syndrome correlates with the availability of magnesium (Mg). We studied the effect of oral Mg supplementation on insulin sensitivity and other characteristics of the metabolic syndrome in normomagnesemic, overweight, insulin resistant, non-diabetic subjects.”

Note that the study subjects were ‘normal’ (normomagnesemic) according to the standard blood (serum) test for magnesium. Their study subjects were screened for eligibility with an oral glucose tolerance test and randomized to either a magnesium supplement or placebo. After 6 months they were evaluated for several insulin sensitivity indices (ISI), plasma glucose, serum insulin, blood pressure and lipids. After the intervention period…

“Mg supplementation resulted in a significant improvement of fasting plasma glucose and some ISI compared to placebo…Several mechanisms may be responsible for the beneficial effect of magnesium on insulin resistance…These include direct effects of magnesium on the insulin receptor and its downstream signaling processes, enhanced enzyme activities involved in glucose utilization, prevention of an intracellular calcium overload supposed to negatively affect insulin sensitivity, and finally, anti-inflammatory effects known to improve insulin resistance.”

The authors’ conclusion adds to the mountain of documentation for the potential value of magnesium supplementation:

“The results provide significant evidence that oral Mg supplementation improves insulin sensitivity even in normomagnesemic, overweight, non-diabetic subjects emphasizing the need for an early optimisation of Mg status to prevent insulin resistance and subsequently type 2 diabetes.“

The magnesium blood test used commonly reported and used in this study is not a reliable marker. It is sensitive only to the most severe magnesium deficiencies and does not accurately reflect tissue content. I suggest to the clinicians reading this that they consider testing sublingual epithelial cell magnesium [Mg]i. This can be performed on a simple buccal scrape by IntraCellular Diagnostics, Inc.

Most US doctors are still not paying proper attention to blood sugar

Posted on October 30, 2010 by Dr. Jonathan

It’s disturbing and worrisome to see how few doctors seem to be alert to the blood sugar dysregulation that precedes type 2 diabetes and many other chronic diseases in their patients as evidenced by a study just published in the journal Diabetes Care. The authors conducted their investigation to…

“…estimate the rates of prevalence, diagnosis, and treatment of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).”

They examined a representative sample of the U.S. population that included 1,547 nondiabetic adults without a history of heart attack to determine the proportion who met the criteria for IFG/IGT, and the proportion of them who: 1) received a diagnosis from their physicians; 2) were prescribed lifestyle modification or medication for blood sugar; or 3) were currently on therapy. Their data painted a dismal picture:

“Of the 1,547 subjects, 34.6% had pre-diabetes; 19.4% had IFG only; 5.4% had IGT only, and 9.8% had both IFG and IGT. Only 4.8% of those with pre-diabetes reported having received a formal diagnosis from their physicians. No subjects with pre-diabetes received oral antihyperglycemics, and the rates of recommendation for exercise or diet were 31.7% and 33.5%, respectively.”

Yikes. It’s really up to the patient to be informed (one of the purposes of this blog) and seek proper care. Blood sugar dysregulation wrecks almost everything that clinicians practicing according to the functional model try to do to correct brain, hormone and immune dysregulation. It’s importance as a clinical focus is hard to over-emphasize. The authors’ disappointment is almost palpable in their conclusion:

“Three years after a major clinical trial demonstrated that interventions could greatly reduce progression from IFG/IGT to type 2 diabetes, the majority of the U.S. population with IFG/IGT was undiagnosed and untreated with interventions. Whether this is due to physicians being unaware of the evidence, unconvinced by the evidence, or clinical inertia is unclear.”

Perhaps this says something about why the scientists who authored another paper in the same issue of Diabetes Care saw fit to ask whether sugar-sweetened beverages would contribute to the risk of metabolic syndrome and type 2 diabetes (!):

“Consumption of sugar-sweetened beverages (SSBs), which include soft drinks, fruit drinks, iced tea, and energy and vitamin water drinks has risen across the globe. Regular consumption of SSBs has been associated with weight gain and risk of overweight and obesity, but the role of SSBs in the development of related chronic metabolic diseases, such as metabolic syndrome and type 2 diabetes, has not been quantitatively reviewed.”

Their meta-analysis included 310,819 participants from 11 acceptable studies. It’s troubling to allow that there may be physicians who might not anticipate the conclusion that their data defined:

“In addition to weight gain, higher consumption of SSBs is associated with development of metabolic syndrome and type 2 diabetes. These data provide empirical evidence that intake of SSBs should be limited to reduce obesity-related risk of chronic metabolic diseases.”

It seems that even fewer physicians and their patients are aware of the role of glucose in ‘feeding’ cancer and the research being done to block the metabolism of sugar by tumor cells as described in a paper just published in the journal Oncogene. The authors state:

“Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials.”

While research investigates possible interventions to aggressively interrupt the glycolytic metabolism of tumor cells, doctors should assist their patients in controlling blood sugar and insulin (another tumor promoter) with the appropriate tools:

“Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels…Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death…”

Blood sugar dysregulation contributes to most chronic diseases including cardiovascular, autoimmune, neurodegenerative and malignant conditions. Supporting healthy blood sugar and insulin regulation is one of the most important things that practitioners and their patients can do together.

Metabolic syndrome accelerates prostate cancer

Posted on October 10, 2010 by Dr. Jonathan

An important study just published in the Annals of Oncology adds more evidence of the exceptional importance of metabolic syndrome for prostate cancer. The authors state:

“Metabolic syndrome (MS) is a set of risk factors that includes obesity and insulin resistance and has been implicated in the development of prostate cancer.”

They proceeded to examine the impact of metabolic syndrome on prostate cancer patients treated with androgen deprivation therapy (ADT, blocking the production or signaling of male hormones). Comparing the data between patients with and without metabolic syndrome for the average time to PSA progression and overall survival (OS) yielded a stark contrast:

“Median time to PSA progression for patients with MS was 16 versus 36 months without MS. The median OS for patients with MS was 36.5 months after commencing ADT compared with 46.7 months for those patients without MS.”

The authors sum up their evidence in the usual understated fashion:

“This preliminary data suggest that MS is a risk factor for earlier development of castration-resistant prostate cancer and support the need for a prospective evaluation of this finding.”

It’s troubling to see how often clinicians fail to emphasize the great importance of blood sugar and insulin control when managing prostate cancer. Patients need to be aware that the lifestyle factors that address this are among the most important things they can do.

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.”

Type 2 diabetes in children can have an autoimmune component

Posted on September 14, 2010 by Dr. Jonathan

Most practitioners and parents think of type 2 diabetes (T2DM) as a metabolic disorder that emerges when the pancreas can no longer keep up with the increasing need for insulin as receptor resistance grows worse. There is growing evidence that T2DM in children and adults is in many cases complicated by the same autoimmune phenomena as in type 1 diabetes. A study just published in the journal Diabetes Care adds to the evidence. The authors set out to:

“…determine the frequency of islet cell autoimmunity in youth clinically diagnosed with type 2 diabetes and describe associated clinical and laboratory findings.”

They screened 1,206 children ages (10-17) who were known to have type 2 diabetes for GAD-65 and insulinoma-associated protein 2 autoantibodies using the new National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH) standardized assays, performed physical examinations, and measured fasting lipids, C-peptide, and HgbA1C. What did the data show?

“Of the 1,206 subjects screened and considered clinically to have type 2 diabetes, 118 (9.8%) were antibody positive…Diabetes autoantibody (DAA) positivity was significantly associated with race, with positive subjects more likely to be white (40.7 vs. 19% and male (51.7 vs. 35.7%. BMI, BMI z score, C-peptide, A1C, triglycerides, HDL cholesterol, and blood pressure were significantly different by antibody status. The antibody-positive subjects were less likely to display characteristics clinically associated with type 2 diabetes and a metabolic syndrome phenotype…”

A clinical ‘pearl’ embedded here is that if a youth with T2DM does not have the characteristics of metabolic syndrome (overweight, etc.), there is strong suspicion of an autoimmune component to their condition. This must, however, be determined by a blood test for the autoantibodies. The authors conclude:

“Obese youth with a clinical diagnosis of type 2 diabetes may have evidence of islet autoimmunity contributing to insulin deficiency. As a group, patients with DAA have clinical characteristics significantly different from those without DAA. However, without islet autoantibody analysis, these characteristics cannot reliably distinguish between obese young individuals with type 2 diabetes and those with autoimmune diabetes.”

Elevated blood sugar increases risk of cancer

Posted on September 9, 2010 by Dr. Jonathan

A research article just published in PLoS (Public Library of Science) Medicine adds more evidence to the association between elevated blood sugar and cancer. The authors begin by stating:

“Prospective studies have indicated that elevated blood glucose levels may be linked with increased cancer risk…The aim of this study was to investigate the association between blood glucose and risk of incident and fatal cancer overall and at specific sites, as well as all-cause mortality, in a large study of six European cohorts including correction for random error in glucose levels..”

The Metabolic Syndrome and Cancer project (Me-Can) includes 274,126 men and 275,818 women from Norway, Austria and Sweden whose average age at the beginning of observation was 44.8 years. Over an average follow-up time of 10.4 years 18,621 men and 11,664 women were diagnosed with cancer, and 6,973 men and 3,088 women died of cancer. When the authors calculated the relative risk for glucose levels (adjusting for BMI and smoking), the data made a strong statement:

“Significant increases in risk among men were found for incident and fatal cancer of the liver, gallbladder, and respiratory tract, for incident thyroid cancer and multiple myeloma, and for fatal rectal cancer. In women, significant associations were found for incident and fatal cancer of the pancreas, for incident urinary bladder cancer, and for fatal cancer of the uterine corpus, cervix uteri, and stomach.”

The authors discuss the possible mechanisms:

“Insulin and bioavailable insulin-like growth factor-I (IGF-I) are possible links between glucose and cancer; hyperglycaemia induces elevation of these hormones that stimulate tumour growth. Glucose may also have a direct tumour-promoting effect as glucose is used as an energy substrate in tumour cells, particularly in fast-growing, highly proliferative tumour cells.”

They boil down their findings in this closing summary:

“In conclusion, abnormal glucose metabolism, independent of BMI, is associated with increases in risk of cancer and cancer death overall and at many specific sites. Furthermore, our data showed a linear and somewhat stronger association among women than among men, and the association was stronger for fatal compared to incident cancer.”

Higher insulin is a major risk factor for prostate cancer

Posted on September 2, 2010 by Dr. Jonathan

An important paper was just published in the journal Cancer Epidemiology that provides further evidence of insulin as a tumor promoter in prostate cancer. The authors state:

“A higher insulin level has been linked to the risk of prostate cancer promotion…the insulin hypothesis was tested once more prospectively in men with a benign prostatic disorder.”

They proceeded by following 389 patients who had lower urinary tract symptoms without prostate cancer over 8-12 years. There were notable differences between the 44 who developed prostate cancer and the rest who didn’t:

“”Men with prostate cancer diagnosis had a higher systolic and diastolic blood pressure, were more obese as measured by BMI, waist and hip measurements than men who did not have prostate cancer diagnosis at follow-up. These men also had a higher uric acid level, and a higher fasting serum insulin level than men who did not have prostate cancer diagnosis at follow-up.”

All of these accessory factors—blood pressure, BMI, waist and hip circumference, uric acid—are directly related to elevated insulin. Considering the prevalence of both prostate cancer and metabolic syndrome (high insulin), it’s important for clinicians and the public alike to bear in mind the authors’ conclusion:

“Our data support the hypothesis that a higher insulin level is a promoter of prostate cancer. Moreover, our data suggest that the insulin level could be used as a marker of the risk of developing prostate cancer. The present findings also seem to confirm that prostate cancer is a component of the metabolic syndrome. Finally, our data generate the hypothesis that the metabolic syndrome conceals early prostate cancer.“