Summary: the hormonal and menstrual irregularities, metabolic dysfunction and adverse cardiovascular changes of PCOS (polycystic ovary syndrome) can be effectively treated with the right dietary and lifestyle interventions according to two recent studies. This is not surprising considering that excessive levels of insulin promote the development of ovarian cysts.

A study recently published in The Journal of Clinical Endocrinology & Metabolism offers excellent evidence that the metabolic and cardiovascular irregularities of PCOS respond well to the appropriate lifestyle changes. The authors state:

“Polycystic ovarian syndrome (PCOS) is associated with cardiovascular risk factors (CRF). Lifestyle intervention is regarded as therapy of choice even if studies in adolescent girls with PCOS are scarce…Our objective was to analyze the impact of lifestyle intervention on menses irregularities, hyperandrogenemia, CRF, and intima-media thickness (IMT) in adolescent girls with PCOS.”

They examined 59 obese girls with PCOS aged 12–18 years for menstrual irregularities,IMT (thickening of the inner layer of the arteries), waist circumference, blood pressure, fasting lipids, insulin, glucose, testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and SHBG (sex hormone binding globulin) before and after a one year intervention of nutrition education, exercise training, and behavior therapy. The results were instructive:

“In contrast to the 33 girls without weight loss, the 26 girls reducing their body mass index during the lifestyle intervention (by a mean of −3.9 kg/m2) improved most CRF and decreased their IMT (by a mean of −0.01 cm). Testosterone concentrations decreased (by a mean of −0.3 nmol/liter) and SHBG concentrations increased (by a mean of +8 ng/ml) significantly in girls with weight loss in contrast to girls with increasing weight. The prevalence of amenorrhea (−42%) and oligoamenorrhea (−19%) decreased in the girls with weight loss. The changes in insulin in the 1-yr follow-up were significantly correlated to changes in testosterone and SHBG.”

These results illuminate the role of insulin resistance and its association with obesity and PCOS. The authors conclude:

“Weight loss due to lifestyle intervention is effective to treat menses irregularities, normalize androgens, and improve CRF and IMT in obese adolescent girls with PCOS.”

These results add savor to another study published shortly afterward in The American Journal of Clinical Nutrition that offers evidence for the most effective protein/carbohydrate ratio for PCOS. The authors state:

“Some evidence has suggested that a diet with a higher ratio of protein to carbohydrates has metabolic advantages in the treatment of polycystic ovary syndrome (PCOS)…The objective of this study was to compare the effect of a high-protein (HP) diet to a standard-protein (SP) diet in women with PCOS.”

They assigned 57 PCOS women to either a high protein (HP) diet (>40% of energy from protein and 30% of energy from fat) or a standard protein (SP) diet (<15% of energy from protein and 30% of energy from fat). Both diets were without caloric restriction, but dietary counseling was given monthly. At baseline and 3 and 6 mo, They took anthropometric measurements and collected blood samples at the beginning and after 3 and 6 months. The results support the replacement of carbohydrates with protein for women with PCOS:

“The HP diet produced a greater weight loss (mean: 4.4 kg) and body fat loss (mean: 4.3 kg) than the SP diet after 6 mo. Waist circumference was reduced more by the HP diet than by the SP diet. The HP diet produced greater decreases in glucose than did the SP diet, which persisted after adjustment for weight changes. There were no differences in testosterone, sex hormone–binding globulin, and blood lipids between the groups after 6 mo. However, adjustment for weight changes led to significantly lower testosterone concentrations in the SP-diet group than in the HP-diet group.”

Considering that PCOS is driven by elevated insulin levels associated with insulin resistance the authors’ conclusion offers sound guidance:

“Replacement of carbohydrates with protein in ad libitum diets improves weight loss and improves glucose metabolism by an effect that seems to be independent of the weight loss and, thus, seems to offer an improved dietary treatment of PCOS women.”

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Summary:

• The use of PSA as a screening tool for aggressive prostate cancer (PCa) is not supported by scientific studies of its effectiveness.
• Many men are subject to disabling, sometimes even fatal, interventions based on PSA tests when they would never have developed aggressive prostate cancer.
• The U.S. Preventive Services Task Force has prepared a draft recommendation to stop screening in those who have not been diagnosed with prostate cancer.
• There are many who, having benefited from PSA screening for PCa, feel strongly that this recommendation by the USPSTF is irresponsible.
• A broader understanding of the underlying causes of elevated PSA and PCa offers a ‘middle path’ of judicious PSA screening, with a meaningful action plan that doesn’t corner patients and doctors into risky invasive procedures or the anxiety of doing nothing. Factors such as insulin resistance and estrogen-testosterone balance are of vital importance for prostate and general health.

Anyone reading this is surely aware of the controversy swirling around the  draft recommendation statement of the U.S. Preventive Services Task Force (USPSTF) that…

“…recommends against prostate-specific antigen (PSA)-based screening for prostate cancer…This recommendation applies to men in the U.S. population that do not have symptoms that are highly suspicious for prostate cancer, regardless of age, race, or family history.”

The Task Force did not evaluate the use of the PSA test for men with highly suspicious symptoms or those with a diagnosis prostate cancer. This recommendation is based on a number of studies finding that PSA (including PSA velocity, the rate at which PSA goes up) is a poor predictor of prostate cancer in general and aggressive prostate cancer in particular, and the assertion that widespread screening has resulted in many unnecessarily invasive and debilitating procedures that themselves can be disabling and even fatal. Feelings are riding high as a large body of public health statistics is pitted against those who feel that a PSA test may have saved their life or the life of a patient. But practitioners and patients face more than a quandary—the debate as it’s currently framed is flawed by a glaring omission.

The PSA discussion is presently structured to assume that the response to a rising PSA can only be ignored (in favor of ‘watchful waiting’) or acted on with invasive biopsies that can seriously damage quality of life and aggressive therapies for what may in fact be indolent, slow growing tumors. That’s it, the clinical decision-making path would appear to fork into only those two roads. Here’s the problem: there is a surprising blind spot for the extensive body of science done on the underlying causes of prostate cancer that offer important opportunities to benefit.  Bear in mind that inflammation or enlargement of prostate tissue caused by various disrupting factors can elevate PSA. These can often be treated with lifestyle or wholesome, non-invasive measures that also reduce the risk of other conditions like diabetes and cardiovascular disease. You may wish to read earlier posts on this topic by typing ‘prostate’ in the search box above. For now consider a couple of the most glaring omissions:

To ignore the role of insulin resistance and metabolic syndrome in prostate disease is gigantic clinical error. Consider just one paper published recently in Nature Reviews Urology in which the authors state:

“The metabolic syndrome is common in countries with Western lifestyles. It comprises a number of disorders—including insulin resistance, hypertension and obesity—that all act as risk factors for cardiovascular diseases. Urological diseases have also been linked to the metabolic syndrome. Most established aspects of the metabolic syndrome are linked to benign prostatic hyperplasia (BPH) and prostate cancer. Fasting plasma insulin, in particular, has been linked to BPH and incident, aggressive and lethal prostate cancer.”

Moreover…

“Overall, the results of studies on urological aspects of the metabolic syndrome seem to indicate that BPH and prostate cancer could be regarded as two new aspects of the metabolic syndrome, and that an increased insulin level is a common underlying aberration that promotes both BPH and clinical prostate cancer.”

This is so important yet has been so ignored. Here it is again:

“Key points

• The metabolic syndrome is a cluster of disorders, including type 2 diabetes, atherosclerotic disease manifestations, hypertension, obesity and dyslipidemia, and is prevalent in countries with Western lifestyles
• The most important common underlying endocrine aberration of these disorders is an increased insulin level, which is also linked to benign prostatic hyperplasia (BPH) and prostate cancer
• Most aspects of the metabolic syndrome are risk factors for BPH and prostate cancer, which seems to suggest that these tumors are themselves aspects of the metabolic syndrome”

Insulin at high levels due to receptor resistance damages sensitive tissues and can act as a tumor promoter. The authors conclude:

“Urologists need to be aware of the effect that the metabolic syndrome has on urological disorders and should transfer this knowledge to their patients.”

Another of the most egregious omissions in prostate cancer management and prevention is attendance to the role played by estrogens in PCa development and progression. Consider a paper published in 2007 in the Journal of Cellular Biochemistry in which the authors observe:

“Prostate cancer is the commonest non-skin cancer in men. Incidence and mortality rates of this tumor vary strikingly throughout the world. Although several factors have been implicated to explain this remarkable variation, lifestyle and dietary factors may play a dominant role, with sex hormones behaving as intermediaries between exogenous factors and molecular targets in development and progression of prostate cancer.”

Furthermore…

“Human prostate cancer is generally considered a paradigm of androgen-dependent tumor; however, estrogen role in both normal and malignant prostate appears to be equally important. Aberrant aromatase expression and activity has been reported in prostate tumor tissues and cells, implying that androgen aromatization to estrogens may play a role in prostate carcinogenesis or tumor progression…In animal model systems estrogens, combined with androgens, appear to be required for the malignant transformation of prostate epithelial cells.”

After reviewing other aspects estrogen stimulation of prostate tissue including the opposing role of ERα and ERβ receptors, the authors conclude:

“In summary, although multiple consistent evidence suggests that estrogens are critical players in human prostate cancer, their role has been only recently reconsidered, being eclipsed for years by an androgen-dominated interest.”

The authors of a review published subsequently in European Urology recognized the dual role of estrogen receptors in prostate cancer when they set out to…

“…examine mechanisms of how oestrogens may affect prostate carcinogenesis and tumour progression.”

They report evidence for the effects of estrogenic stimulation of prostate tissue:

“The human prostate is equipped with a dual system of oestrogen receptors (oestrogen receptor alpha [ERα], oestrogen receptor beta [ERβ]) that undergoes profound remodelling during PCa development and tumour progression. In high-grade prostatic intraepithelial neoplasia (HGPIN), the ERα is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models…The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumour suppressor…The progressive emergence of the ERα and the oestrogen-regulated progesterone receptor (PR) during PCa progression and hormone-refractory disease suggests that these tumours can use oestrogens and progestins for their growth.”

Moreover…

“The TMPRSS2-ERG gene fusion recently reported as a potentially aggressive molecular subtype of PCa is regulated by ER-dependent signalling.”

The authors also conclude:

“Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ERα antagonists and ERβ agonists to prevent PCa and delay disease progression.”

A paper just published in the journal Endocrinology and Metabolism Clinics of North America echoes the theme:

“The mainstay targets for hormonal prostate cancer (PCa) therapies are based on negating androgen action. Recent epidemiologic and experimental data have pinpointed the key roles of estrogens in PCa development and progression. Racial and geographic differences, as well as age-associated changes, in estrogen synthesis and metabolism contribute significantly to the etiology.”

The authors go on to report on how estrogens and estrogen mimics contribute to development of PCa, and the roles of the different estrogen mediators in the process.

As is often the case, the principle of balance comes into play as examined in a fine paper published in The Journal of Steroid Biochemistry & Molecular Biology on the estrogen:androgen ratio in the prostate gland. The authors state:

“Although androgens and estrogens both play significant roles in the prostate, it is their combined action – and specifically their balance – that is critically important in maintaining prostate health and tissue homeostasis in adulthood. In men, serum testosterone levels drop by about 35% between the ages of 21 and 85 while estradiol levels remain constant or increase. This changing androgen:estrogen (T:E) ratio has been implicated in the development of benign and malignant prostate disease.”

They review the role of the aromatase enzyme in the production of estrogens from androgens, and the fact that its aberrant expression plays a critical role in the development of malignancy in a number of tissues. In the case of PCa, it leads to an altered T:E ratio that is associated with the development of disease. And since we do have for treatment purposes wholesome modulators of estrogen receptor function as well as aromatase enzyme inhibitors…

“The role of estrogen and the T:E balance in the prostate is further complicated by the differential actions of both estrogen receptors, α and β. Stimulation of ERα leads to aberrant proliferation, inflammation and pre-malignant pathology; whereas activation of ERβ appears to have beneficial effects regarding cellular proliferation and a putative protective role against carcinogenesis.”

Clinicians who manage, support patients with, or endeavor to prevent prostate cancer must bear their conclusion in mind:

“Overall, these data reveal that homeostasis in the normal prostate involves a finely tuned balance between androgens and estrogens. This has identified estrogen, in addition to androgens, as integral to maintaining normal prostate health, but also as an important mediator of prostate disease.”

A more comprehensive perspective on the use of PSA

There far more evidence for the application of these and other factors in prostate cancer development and expression that are equally important for conditions ranging from cardiovascular disease and diabetes to dementia than can be presented in this post. It is clear, however, that we must go beyond the fascination with the false promise of ‘silver bullet’ medications and lure of lucrative procedures to properly examine and treat the more complex web of underlying factors that support prostate cancer. In the judicious hands of a skilled clinician who has the knowledge and experience to evaluate the risk of prostate cancer in the context of the total health of their patient, observing an elevation of PSA offers more than a specter of indecision over the stark choices of invasive procedures or doing nothing. It is an opportunity to intervene in positive and wholesome ways that advance the overall, not just prostate, health of the patient in their care.

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A sound personalized strategy for eating, exercise and evidence-based supplementation to support healthy insulin regulation decreases the risk for a host of diseases. A paper just published in the journal Hepatology identifies metabolic syndrome as a major risk factor for liver cancer. The authors state:

“Incidence rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have increased in the United States. Metabolic syndrome is recognized as a risk factor for HCC and a postulated one for ICC. The magnitude of risk, however, has not been investigated on a population level in the United States. We therefore examined the association between metabolic syndrome and the development of these cancers.”

They examined the data for 3649 HCC cases and 743 ICC cases in comparison with 195,953 control subjects for the prevalence of metabolic syndrome (taking into consideration other risk factors for HCC (hepatitis, alcoholic liver disease, etc) and ICC (biliary cirrhosis, cholangitis, hepatitis, alcoholic liver disease, inflammatory bowel disease, etc). What did the data show?

“Metabolic syndrome was significantly more common among persons who developed HCC and ICC than the comparison group. In adjusted multiple logistic regression analyses, metabolic syndrome remained significantly associated with increased risk of HCC (odds ratio = 2.13) and ICC (odds ratio = 1.56).”

In other words, the adjusted odds ratio for hepatocellular carcinoma (HCC) was 213% (more than double) and 56% for intrahepatic cholangiocarcinoma (ICC). And very significantly, 43% of the patients with liver cancer had no other previously established risk factors for it. Considering that both HCC and ICC are on the increase, the authors’ conclusion is notable:

“Metabolic syndrome is a significant risk factor for development of HCC and ICC in the general U.S. population.”

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New research just published in the journal Obesity contributes to the evidence for weighty metabolic consequences of the hypoxia (reduced oxygen saturation) that occurs with sleep disordered breathing. The authors state:

“The main aim of this study is to evaluate the effects of chronic intermittent hypoxia (CIH), a hallmark of sleep apnea, on IR [insulin resistance] and NAFLD [non-alcoholic fatty liver disease] in lean mice and mice with diet-induced obesity (DIO).”

They fed the study subjects either a high fat or regular diet for 12 weeks, after which they were exposed to CIH or normal room air as a control condition for 4 weeks. Then they measured fasting blood glucose, insulin, homeostasis model assessment (HOMA) index, liver enzymes, and performed an intraperitoneal glucose tolerance test. Their data paints an interesting picture:

“In DIO mice, body weight remained stable during CIH and did not differ from control conditions…Compared to lean mice, DIO mice had higher fasting levels of blood glucose, plasma insulin, the HOMA index, and had glucose intolerance and hepatic steatosis at baseline. In lean mice, CIH slightly increased HOMA index, whereas glucose tolerance was not affected. In contrast, in DIO mice, CIH doubled HOMA index, and induced severe glucose intolerance. In DIO mice, CIH induced NAFLD, inflammation, and oxidative stress, which was not observed in lean mice.”

In other words, even though hypoxia did not further increase the body weight of the subjects with diet induced obesity, the metabolic effects including glucose intolerance, inflammation, fatty liver disease and oxidative stress were severe. I often find that the possibility of sleep disordered breathing has been overlooked in the work-up of patients with overweight or metabolic syndrome. This research adds to the compelling evidence that clinicians should bear this in mind.

“In conclusion, CIH exacerbates IR and induces steatohepatitis in DIO mice, suggesting that CIH may account for metabolic dysfunction in obesity.”

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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:

1. B cell-activating factor (BAFF), triggered by food hypersensitivity and other allergic reactions, is associated with inflammation .
2. BAFF induces insulin resistance; the resultant higher levels of insulin force the storage of calories of fat, promoting weight gain and obesity.
3. 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.

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Most readers of these posts, practitioner and layperson alike, have probably long been aware of the role of insulin resistance in cardiovascular disease, chronic inflammation and cancer as described in last week’s New York Times article. A fascinating study that adds to the mountain of scientific evidence was just published in the Public Library of Science (PLoS One) in which the authors show that higher insulin levels are associated with the unstable form of carotid artery plaque:

“The stability of atherosclerotic plaques determines the risk for rupture, which may lead to thrombus formation and potentially severe clinical complications such as myocardial infarction and stroke. Although the rate of plaque formation may be important for plaque stability, this process is not well understood. We took advantage of the atmospheric 14C-declination curve (a result of the atomic bomb tests in the 1950s and 1960s) to determine the average biological age of carotid plaques.”

The authors dissected the cores of carotid plaques from 29 patients with carotid stenosis and analyzed them for 14C. Their findings are fascinating:

“The average plaque age (i.e. formation time) was 9.6±3.3 years. All but two plaques had formed within 5–15 years before surgery. Plaque age was not associated with the chronological ages of the patients but was inversely related to plasma insulin levels…plaques in the lowest tercile of plaque age (most recently formed) were characterized by further instability with a higher content of lipids and macrophages…Microarray analysis of plaques in the lowest tercile also showed increased activity of genes involved in immune responses and oxidative phosphorylation.”

As readers here know, a heart attack or stroke occurs when a vulnerable plaque ruptures and blocks a smaller vessel downstream. These investigators show that unstable plaque is associated with higher insulin levels. Intervening to reduce insulin resistance is one of the most important things that clinicians and patients can do for a host of conditions. The authors conclude:

“Our results show, for the first time, that plaque age, as judge[d] by relative incorporation of 14C, can improve our understanding of carotid plaque stability and therefore risk for clinical complications. Our results also suggest that levels of plasma insulin might be involved in determining carotid plaque age.”

Regarding laboratory testing to determine the presence of inflamed vulnerable plaque, see the earlier post on Lp-PLA2.

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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.“

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Research just published in the journal Science Translational Medicine is a further reminder of the critical need  for caution and sound physiological thinking when considering the use of growth hormone. The authors note in their introduction:

“Reduced activity of growth hormone (GH) and insulin-like growth factor–1 (IGF-1) signaling proteins or of their orthologs in nonhuman organisms…contribute to extended life span and protection against age-dependent damage or diseases…”

Pursuant to these earlier observations they formulated an important investigative objective:

“Mutations in growth signaling pathways [that diminish the GH effect] extend life span, as well as protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor–1) deficiencies.”

Combining this information with surveys that identified the cause and age of death for their subjects who died before this period, the data paint a compelling picture:

“The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects.“

They describe earlier studies that help explain the very low incidence of cancer. In one, serum from subjects with GHR deficiency had reduced DNA breakage yet increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. In others, serum from GHR-deficient subjects caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells. These changes in signaling promote cellular protection and life-span extension in model organisms.

Importantly, in their present study the authors also observed:

“……reduced insulin concentrations and a very low HOMA-IR (homeostatic model assessment–insulin resistance) index in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects.”

These comments, along with an earlier post on growth hormone research, are a plea for caution along with sound thinking. There seem to be good reasons why we have evolved to reduce growth hormone activity with age. The authors advance the idea that blocking growth hormone receptor function may…

“…prevent or reduce the incidence of cancer, diabetes, and other age-related diseases, including inflammatory disorders, stroke, and neurodegenerative diseases.”

Clinicians and individuals tempted to experiment with growth hormone therapy should consider the authors’ conclusion:

“Our finding that human GHRD [growth hormone receptor deficient] subjects are protected against age-related pathologies is consistent with the elevated cellular protection in both yeast and human cells with reduced expression of specific pro-growth genes and with the effect of serum from GHRD subjects in lowering their expression. The results from the human cohort also show similarities with those from GHRD- and GH-deficient mice, which display lower incidence (49%) or delayed occurrence of fatal neoplasms and increased insulin sensitivity… These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.”

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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.

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A report just published in the Journal of the National Cancer Institute adds more evidence to the importance of insulin regulation in ER (estrogen receptor) negative breast cancer. The authors first note a conundrum in breast cancer epidemiology:

“Body mass index is inversely associated with risk of premenopausal breast cancer, but the underlying mechanisms for this association are poorly understood. Abdominal adiposity is associated with metabolic and hormonal changes, many of which have been associated with the risk of premenopausal breast cancer.”

They investigated the association between body fat distribution, hip circumference, and waist to hip ratio, and the incidence of premenopausal breast cancer in the Nurses’ Health Study II:

“During 426 164 person-years of follow-up from 1993 to 2005, 620 cases of breast cancer were diagnosed among 45 799 women. Hormone receptor status information was available for 84% of the breast cancers.”

When they looked at the group as a whole, no statistically significant associations were found. However…

“…each of the three body fat distribution measures was statistically significantly associated with greater incidence of estrogen receptor (ER)–negative breast cancer.”

The risk for ER-negative breast cancer was increased by 275% for waist circumference, 240% for hip circumference, and 195% for waist to hip ratio (comparing the highest to the lowest quintile). The authors state:

“These findings may suggest that an insulin-related pathway of abdominal adiposity is involved in the etiology of premenopausal breast cancer.“

The implication is that factors associated with increased abdominal adiposity influence the development of breast cancer through estrogen independent pathways, specifically the influence of excess levels of insulin on tumor growth that also promote the accumulation of fat around the waist. As experienced clinicians know, tumors often have mixed cell types. The role of insulin as a tumor promoter should never overlooked in case management, with careful attention to the regulation of blood sugar and insulin.

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