Metabolic syndrome and high blood pressure can be helped by sleep apnea treatment

Summary: the stress of oxygen starvation that occurs with sleep disordered breathing (sleep apnea and hypopnea) contributes to metabolic syndrome and high blood pressure. CPAP (continuous positive airway pressure) can help .

I have been finding that people coming to our practice who have been struggling with the depredations of metabolic syndrome including overweight, hypertension, elevated lipids and HgbA1c, etc. have not been evaluated for sleep disordered breathing. A study recently published in The New England Journal of Medicine offers evidence that treatment for sleep apnea can provide significant benefit. The authors state:

“Obstructive sleep apnea is associated with an increased prevalence of the metabolic syndrome and its components…In our double-blind, placebo-controlled trial, we randomly assigned patients with obstructive sleep apnea syndrome to undergo 3 months of therapeutic CPAP followed by 3 months of sham CPAP, or vice versa, with a washout period of 1 month in between.”

They measured anthropometric variables, blood pressure, fasting blood glucose levels, insulin resistance, fasting blood lipids, glycated hemoglobin, carotid intima–media thickness, and visceral fat before and after the real and sham CPAP interventions. Their data showed a worthwhile effect:

“A total of 86 patients completed the study, 75 (87%) of whom had the metabolic syndrome. CPAP treatment (vs. sham CPAP) was associated with significant mean decreases in systolic blood pressure (3.9 mm Hg), serum total cholesterol (13.3 mg per deciliter), non–high-density lipoprotein cholesterol (13.3 mg per deciliter), low-density lipoprotein cholesterol (9.6 mg per deciliter), triglycerides (18.7 mg per deciliter), and glycated hemoglobin (0.2%). The frequency of the metabolic syndrome was reduced after CPAP therapy (reversal found in 11 of 86 patients [13%] undergoing CPAP therapy vs. 1 of 86 [1%] undergoing sham CPAP).”

Clinicians should not fail to consider the possibility of sleep disordered breathing when managing hypertension, overweight and other components of metabolic syndrome. Do you snore or wake in the morning unrefreshed and fall asleep inappropriately during the day? If so, a screening may be appropriate. The authors conclude:

“In patients with moderate-to-severe obstructive sleep apnea syndrome, 3 months of CPAP therapy lowers blood pressure and partially reverses metabolic abnormalities.”

Dietary macronutrient composition for weight loss and weight maintenance

Summary: When designing a dietary strategy for weight loss and maintenance the individual patient’s functional and genetic constitution must be carefully considered, but there is an accumulation of evidence indicating that a high protein, low carbohydrate regimen is a good starting point.

There is a large body of evidence that can instruct us in how to fashion an eating plan to promote both short and long-term success in weight loss and healthy body composition. As a paper published in the journal Obesity demonstrates, the way many Americans eat—referred to as a ‘cafeteria diet’ (CF)—is worse than a diet high in lard. The authors note:

“Obesity has reached epidemic proportions worldwide and reports estimate that American children consume up to 25% of calories from snacks. Several animal models of obesity exist, but studies are lacking that compare high-fat diets (HFD) traditionally used in rodent models of diet-induced obesity (DIO) to diets consisting of food regularly consumed by humans, including high-salt, high-fat, low-fiber, energy dense foods such as cookies, chips, and processed meats.”

They investigated the effects on weight gain and inflammation of a cafeteria diet (CAF) compared to a lard-based 45% HFD by feeding their rodent models either HFD, CAF or a chow control for 15 weeks. Their data clearly show that even consuming almost half the diet in lard is better than the lethal mix that many now consume:

Body weight increased dramatically and remained significantly elevated in CAF-fed rats compared to all other diets. Glucose- and insulin-tolerance tests revealed that hyperinsulinemia, hyperglycemia, and glucose intolerance were exaggerated in the CAF-fed rats compared to controls and HFD-fed rats.”

Moreover, the cafeteria diet was markedly worse in promoting inflammation:

“It is well-established that macrophages infiltrate metabolic tissues at the onset of weight gain and directly contribute to inflammation, insulin resistance, and obesity. Although both high fat diets resulted in increased adiposity and hepatosteatosis, CAF-fed rats displayed remarkable inflammation in white fat, brown fat and liver compared to HFD and controls. In sum, the CAF provided a robust model of human metabolic syndrome compared to traditional lard-based HFD, creating a phenotype of exaggerated obesity with glucose intolerance and inflammation.”

A study published in The New England Journal of Medicine examined specific dietary factors that stand out in their contribution to obesity noting that they…

“…may affect the success of the straightforward-sounding strategy “eat less and exercise more” for preventing long-term weight gain.”

They performed investigations involving 120,877 U.S. women and men who were free of chronic diseases and not obese at baseline for as long as twenty years. Relationships between changes in lifestyle factors and weight change were evaluated every four years. There were several factors that stood out:

“Within each 4-year period, participants gained an average of 3.35 lb. On the basis of increased daily servings of individual dietary components, 4-year weight change was most strongly associated with the intake of potato chips (1.69 lb), potatoes (1.28 lb), sugar-sweetened beverages (1.00 lb), unprocessed red meats (0.95 lb), and processed meats (0.93 lb) and was inversely associated with the intake of vegetables (−0.22 lb), whole grains (−0.37 lb), fruits (−0.49 lb), nuts (−0.57 lb), and yogurt (−0.82 lb)…Other lifestyle factors were also independently associated with weight change, including physical activity (−1.76 lb across quintiles); alcohol use (0.41 lb per drink per day), smoking (new quitters, 5.17 lb; former smokers, 0.14 lb), sleep (more weight gain with <6 or >8 hours of sleep), and television watching (0.31 lb per hour per day).”

Potatoes are clearly ‘sugar grenades’, but in my opinion further studies are required to examine the difference between red meat from animals treated with hormones and fed a grain diet versus those that are free of growth-stimulating medications and eat mainly grass.

With the most egregious insults to a metabolically healthy diet out of the way, we can proceed to the roles of glycemic index and glycemic load on weight loss as examined in a study published recently in the Journal of Nutrition:

“This study assessed the effect of changes in glycemic index (GI) and load (GL) on weight loss and glycated hemoglobin (HbA1c) among individuals with type 2 diabetes beginning a vegan diet or diet following the 2003 American Diabetes Association (ADA) recommendations.”

99 subjects with type 2 diabetes were randomized to follow 1 of 2 diet treatments for 22 weeks. Glycemic index and glycemic load changes were assessed and their relationships with changes in weight and HbA1C were calculated. (Glycemic index is a metric for rate which a food will cause blood sugar to rise. Glycemic load is determined by multiplying the glycemic index by the amount of carbohydrate in grams provided by a food and dividing the total by 100; this amounts to the sum of the glycemic loads for all foods consumed in the diet.) Interestingly, glycemic index predicted weight gain while glycemic load did not:

“…the vegan group reduced GI to a greater extent than the ADA group, but GL was reduced further in the ADA than the vegan group. GI predicted changes in weight, adjusting for changes in fiber, carbohydrate, fat, alcohol, energy intake, steps per day, group, and demographics, such that for every point decrease in GI, participants lost ~0.2 kg (0.44 lb)…Weight loss was a predictor of changes in HbA1C. GL was not related to weight loss or changes in HbA1C.”

Thus glycemic index takes precedence over glycemic load in choosing foods for weight loss and blood sugar regulation. Also notable was the finding regarding GI and HbA1C:

GI was not a predictor for changes in HbA1C after controlling for weight loss.”

Every wonder why a patient’s HbA1C didn’t go down even though they were eating a low GI diet? This shows that if they don’t lose weight as a result, the the HbA1C will tend to stay the same. The authors conclude:

A low-GI diet appears to be one of the determinants of success of a vegan or ADA diet in reducing body weight among people with type 2 diabetes. The reduction of body weight, in turn, was predictive of decreasing HbA1C.”

The interesting difference between the effects of glycemic index and glycemic load revealed here help to explain the inconsistency noted in a review published earlier in journal IUBMB (International Union of Biochemistry and Molecular Biology) Life:

“Recently, due to its possible link to appetite control and metabolism, several clinical studies have assessed the effect of low glycemic index (GI) and glycemic load (GL) diets on weight loss. To determine the application of GI/GL in the prevention and treatment of obesity, we searched several databases and identified 23 clinical trials that examined low GI/GL diets and weight loss as the primary outcome measure.”

Here the pooling of GI and GL seems to have obfuscated the issue. The authors conclude:

“Over the past decade, the body of research that links low GI/GL diets to weight loss has grown rapidly and significantly. While there is a significant amount of inconsistency in the current findings, the majority of studies found a trend that favored low GI/GL diets in weight loss.”

Moreover…

“…the benefits of low GI and GL diets extend beyond weight loss and have favorable effects on obesity-related risk factors such as heart disease and diabetes by mechanisms that are independent of weight loss.”

What about protein versus carbohydrate for weight loss? A number of investigators have examined this question, but an interesting study published recently in the Nutrition Journal corrects some important limitations in earlier work:

“Studies have suggested that moderately high protein diets may be more appropriate than conventional low-fat high carbohydrate diets for individuals at risk of developing the metabolic syndrome and type 2 diabetes. However in most such studies sources of dietary carbohydrate may not have been appropriate and protein intakes may have been excessively high. Thus, in a proof-of-concept study we compared two relatively low-fat weight loss diets – one high in protein and the other high in fiber-rich, minimally processed cereals and legumes – to determine whether a relatively high protein diet has the potential to confer greater benefits.”

They eighty-three overweight or obese women to either a moderately high protein (30% protein, 40% carbohydrate) diet (HP) or to a high fiber, relatively high carbohydrate (50% carbohydrate, > 35 g total dietary fiber, 20% protein) diet (HFib) for 8 weeks. During that time their energy intakes were reduced by 478 to 955 calories per day to achieve weight loss of between 0.5 and 1 kg per week. Which diet resulted in better weight loss?

“Participants on both diets lost weight (HP: -4.5 kg and HFib: -3.3 kg), and reduced total body fat (HP: -4.0 kg and HFib: -2.5 kg, and waist circumference (HP: -5.4 cm and HFib: -4.7 cm), as well as total and LDL cholesterol, triglycerides, fasting plasma glucose and blood pressure. However participants on HP lost more body weight (-1.3 kg) and total body fat (-1.3 kg). Diastolic blood pressure decreased more on HP (-3.7 mm Hg).”

High protein wins out over high carbohydrate, even when the carbohydrate is high fiber. The authors conclude:

A realistic high protein weight-reducing diet was associated with greater fat loss and lower blood pressure when compared with a high carbohydrate, high fiber diet in high risk overweight and obese women.”

Importantly, the benefits of a high protein to carbohydrate ratio diet include the slowing of tumor growth and prevention of cancer initiation as described in an excellent paper (you may wish to read it in its entirety) published recently in the journal Cancer Research. It includes a significant consideration for reducing carbohydrate by increasing protein rather than fat. The authors state:

“Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction–induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein.”

They were able to formulate diets that demonstrated that the tumor inhibiting effects were due to factors other than weight loss from calorie restriction (CR):

“To exploit the fact that cancer cells rely more heavily on glycolysis than normal cells, we designed low CHO, high protein diets to see if we could limit BG and tumor growth. In designing our diets, we wanted to avoid NCKDs [no calorie ketogenic diets] because of the difficulty in achieving long-term compliance with no CHO diets in potential future human studies and because Masko and colleagues recently reported that a 10% or 20% CHO diet slows tumor growth as effectively as NCKDs. Following early studies with 8% CHO diets, using 10% and 15% CHO, high protein diets in which 70% of the CHO was in the form of amylose, we found that, compared with a Western diet, they were indeed capable of reducing BG, insulin, and lactate levels and, importantly, in slowing the growth of implanted murine and human tumors, with little or no effects on mouse weight.”

There is good reason to apply these finding to human case management:

“Consistent with the notion that reducing BG in humans can be beneficial, there is a wealth of epidemiologic evidence showing a clear association between BG and/or insulin levels (which are determined by BG levels) and the incidence of human cancers. Thus, although our studies were conducted, out of necessity, with mice, the fact that human BG can be significantly reduced with low CHO diets and the association of many cancers with high BG levels suggest that our findings are very likely relevant to human cancers as well, particularly in cancers that have been associated with higher baseline BG and/or insulin levels, such as pancreatic, breast, colorectal, endometrial, and esophageal cancers.”

This also has application to prostate cancers:

“In addition to these cancers, a low CHO diet may also be beneficial in early-stage prostate cancer, even though it is not typically detectable by PET. This is because the metastases of these tumors kill the patients and, given the pivotal role of lactate in promoting metastasis, our low CHO diets could significantly reduce metastasis by reducing tumor-associated lactate levels.”

Regarding concerns about the impact on kidney function…

“In terms of macronutrient composition, even though high protein has been shown to promote satiety—thus reducing obesity, BG, and insulin levels—and enhance both antitumor immunity, through amino acid supplementation, and life span, we were concerned, based on the literature, that high protein levels might cause kidney damage. More recent data, however, suggest that this may only occur in individuals with existing chronic kidney disease and that in normal people, the increase in glomerular filtration rate and kidney cellularity that occur with long-term high protein consumption may be a normal response.”

Incidentally, amylose starch prevents DNA damage in the colon that may otherwise be caused by red meat:

“Interestingly, colonic cancer-inducing damage caused by red meats may be avoided with high amylose, low CHO diets. These studies suggest that macronutrient sources and combinations are very important…”

The authors conclude:

“Our study, herein, shows that a high amylose containing low CHO, high protein diet reduces BG, insulin, and glycolysis, slows tumor growth, reduces tumor incidence, and works additively with existing therapies without weight loss or kidney failure. Such a diet, therefore, has the potential of being both a novel cancer prophylactic and treatment, warranting further investigation of its applicability in the clinic, especially in combination with existing therapies.”

Regarding weight loss, what if exercise is added to the program? Will high protein still beat high carbohydrate. A study published in the journal The Physician and Sports Medicine studies this question as the authors set out to…

“…determine whether sedentary obese women with elevated levels of homeostatic model assessment (HOMA) insulin resistance (ie, > 3.5) experience greater benefits from an exercise + higher-carbohydrate (HC) or carbohydrate-restricted weight loss program than women with lower HOMA levels.”

221 women who participated in a 10-week supervised exercise and weight loss program were assigned low-fat (30%) diets that consisted of 1200 kcals per day for 1 week (phase 1) and 1600 kcals per day for 9 weeks (phase 2) with either high carbohydrate (HC) or higher protein (HP). Fasting blood samples, body composition, anthropometry, resting energy expenditure, and fitness measurements were obtained at the beginning and end. Again we see high protein win out over high carbohydrate:

Subjects in the HP group experienced greater weight loss (−4.4 ± 3.6 kg vs −2.6 ± 2.9 kg), fat loss (−3.4 ± 2.7 kg vs −1.7 ± 2.0 kg), reductions in serum glucose (3% vs 2%), and decreases in serum leptin levels (−30.8% vs −10.8%) than those in the HC group.”

The authors conclude:

A carbohydrate-restricted diet promoted more favorable changes in weight loss, fat loss, and markers of health in obese women who initiated an exercise program compared with a diet higher in carbohydrate. Additionally, obese women who initiated training and dieting with higher HOMA levels experienced greater reductions in blood glucose following an HP diet.”

Regarding the use of vegetable or fruit juices in programs designed for weight loss, a study published in the journal Obesity demonstrates that this is counter-productive:

“Beverage consumption has been implicated in weight gain, but questions remain about the veracity of the association, whether the relationship is causal and what property of beverages is responsible. It was hypothesized that food form is the most salient attribute. Thus, a randomized controlled trial of food form was conducted. Energy-matched beverage or solid forms of fruits and vegetables were provided to 34, lean or overweight/obese adults for two 8-week periods with a 3-week washout interspersed.”

During the solid food arm of the study the lean group had no significant weight change while the overweight/obese group had weight gain, but during the juice phase…

“In contrast, incomplete dietary compensation and weight gain occurred in both the lean (43%) and overweight/obese (61%) groups during the beverage arm…These data demonstrate energy consumed as beverages may be especially problematic for weight gain.”

And for the carbohydrates that are consumed, a curious study also published in Obesity offers evidence that eating them mainly at dinner further aids in weight loss, satiety and more:

“This study was designed to investigate the effect of a low-calorie diet with carbohydrates eaten mostly at dinner on anthropometric, hunger/satiety, biochemical, and inflammatory parameters. Hormonal secretions were also evaluated. Seventy-eight police officers (BMI >30) were randomly assigned to experimental (carbohydrates eaten mostly at dinner) or control weight loss diets for 6 months. On day 0, 7, 90, and 180 blood samples and hunger scores were collected every 4 h from 0800 to 2000 hours. Anthropometric measurements were collected throughout the study.”

Amazingly…

Greater weight loss, abdominal circumference, and body fat mass reductions were observed in the experimental diet in comparison to controls. Hunger scores were lower and greater improvements in fasting glucose, average daily insulin concentrations, and homeostasis model assessment for insulin resistance (HOMAIR), T-cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were observed in comparison to controls. The experimental diet modified daily leptin and adiponectin concentrations compared to those observed at baseline and to a control diet.”

Wow…all that just from shifting carbohydrates to dinner. The authors conclude:

A simple dietary manipulation of carbohydrate distribution appears to have additional benefits when compared to a conventional weight loss diet in individuals suffering from obesity. It might also be beneficial for individuals suffering from insulin resistance and the metabolic syndrome.”

The scientific data addressing various aspects of dietary fat is treated in a separate post, but it’s suitable here to consider a study published in The Journal of Clinical Endocrinology & Metabolism offering evidence that a low carbohydrate diet is equivalent to a low fat diet for weight loss:

“Overweight and obese men and women (24–61 yr of age) were recruited into a randomized trial to compare the effects of a low-fat (LF) vs. a low-carbohydrate (LC) diet on weight loss…Subjects on the LF diet consumed an average of 17.8% of energy from fat, compared with their habitual intake of 36.4%, and had a resulting energy restriction of 2540 kJ/d [585 calories]. Subjects on the LC diet consumed an average of 15.4% carbohydrate, compared with habitual intakes of about 50% carbohydrate, and had a resulting energy restriction of 3195 kJ/d [763 calories].”

At the end of the study period the LC group lost as much weight and had better insulin regulation:

Both groups of subjects had significant weight loss over the 10 wk of diet intervention and nearly identical improvements in body weight and fat mass. LF subjects lost an average of 6.8 kg and had a decrease in body mass index of 2.2 kg/m2, compared with a loss of 7.0 kg and decrease in body mass index of 2.1 kg/m2 in the LC subjects. The LF group better preserved lean body mass when compared with the LC group; however, only the LC group had a significant decrease in circulating insulin concentrations.”

The authors conclude:

“”These data suggest that energy restriction achieved by a very LC diet is equally effective as a LF diet strategy for weight loss and decreasing body fat in overweight and obese adults.”

Bottom line: When designing a dietary strategy for weight loss and maintenance the individual patient’s functional and genetic constitution must be carefully considered (inflammation, immune regulation, insulin sensitivity, allergy, intestinal permeability, sleep disordered breathing and hormonal function are fundamentals); but there is an accumulation of evidence suggesting that a high protein, low carbohydrate regimen is a good starting point.

Intermittent hypoxia (low oxygen) of sleep apnea exacerbates insulin resistance and inflammation

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.”

Inflammation caused by allergy promotes weight gain and obesity

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.

 

Type 2 diabetes in children can have an autoimmune component

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.”

Losing weight can release pollutants into the blood

Adipose tissue (fat) is the body’s primary storage depot for environmental toxins. There they can be sequestered from the circulation and other tissues. A study just published in the International Journal of Obesity reveals that weight loss can release toxic pollutants into the circulation with potential adverse consequences for health. The authors state:

“There is emerging evidence that persistent organic pollutants (POPs) can increase the risk of various chronic diseases. As POPs mainly bioaccumulate in adipose tissue, weight change can affect serum concentrations of POPs.”

The authors set out to examine serum concentrations of seven POPs in association with weight change over 1 year and 10 year periods in 1,099 adults age 40 or older. What did their data show?

Serum concentrations of most POPs were higher in those with long-term weight loss, whereas they were lower in those with long-term weight gain. Weight change for 1 year showed similar but weaker associations, compared with those of long-term weight changes.”

Their conclusion contains a note of irony:

“Although both beneficial health effects after weight loss and harmful health effects after weight gain are generally expected, changes in serum concentrations of POPs in relation to weight change may act on health in directions opposite to what we expect with weight change.

There are ample resources in the functional medicine model to objectively investigate the release of toxins into circulation, the presence or absence of harm from them, and the capacity of the individual to metabolize and eliminate them efficiently. The complete picture is too extensive for this post, but the casual reader may be interested in simple tests for blood contamination by volatile solvents, polychlorinated biphenyls (PCBs), and chlorinated pesticides.

The tape measure: a powerful predictive ‘instrument’ for mortality

More research recently published in the Archives of Internal Medicine further validates the power of waist circumference measurements to predict death from all causes. This study provides evidence that its accuracy is far superior to body mass index (BMI).

Waist circumference (WC), a measure of abdominal obesity, is associated with higher mortality independent of body mass index (BMI). Less is known about the association between WC and mortality within categories of BMI or for the very high levels of WC that are now common.”

The authors examined the association between WC and mortality among 48 500 men and 56 343 women between 1997 and 2006, during which 9315 men and 5332 women died. Considering the adverse metabolic and hormonal activity of visceral (intra-abdominal versus subcutaneous) fat, their data is not surprising:

“After adjustment for BMI and other risk factors, very high levels of WC were associated with an approximately 2-fold higher risk of mortality in men and women…The WC was positively associated with mortality within all categories of BMI.”

Very high levels of WC means 47 inches for men and 43 inches for women. Waist circumference is a more reliable indicator than weight or BMI. If you’re losing weight without your WC getting smaller, you’re probably losing more muscle than fat. As the authors state in their conclusion:

“These results emphasize the importance of WC as a risk factor for mortality in older adults, regardless of BMI.”

Coffee protects against fatty liver disease

Digestive Diseases and SciencesThere seems to be one study after another about the benefits of coffee. This paper just published in the journal Digestive Diseases and Sciences verifies that coffee protects against Non-alcoholic Fatty Liver Disease (NAFLD), the most common cause of non-infectious hepatitis and a growing cause of liver failure. I very often see elevated liver enzymes on laboratory tests; no wonder, since this is commonly fueled by insulin resistance. The authors of this study began by observing…

“The benefits of coffee on abnormal liver biochemistry, cirrhosis and hepatocellular carcinoma have been reported…this study aims to investigate if coffee use has any relationship with bright liver, measured by ultrasound bright liver score (BLS), in patients with non-alcoholic fatty liver disease (NAFLD), and which relationship, if any, is present with BMI and insulin resistance.”

‘Bright liver’ refers to the appearance of a fatty liver on ultrasound imaging, and a higher BLS measurement means more fat deposits in the liver. What did they find?

Less fatty liver involvement is present in coffee vs. non-coffee drinkers. Odds ratios show that obesity, higher insulin resistance, lower HDL cholesterol, older age and arterial hypertension are associated with a greater risk of more severe BLS; to the contrary, coffee drinking is associated with less severe BLS…Coffee use is inversely associated with the degree of bright liver, along with insulin resistance and obesity…”

Their conclusion is similar to numerous other studies:

“A possible opposite, if not antagonistic, role of coffee with regard to overweightness and insulin resistance, similar to that reported in hepatocarcinoma and cirrhosis, is envisaged in the natural history of NAFLD.”

Fructose even worse than glucose for fat and insulin

Journal of Clinical InvestigationThis is why the ubiquitous high-fructose corn syrup is such a disaster for public health. The authors of this study published in The Journal of Clinical Investigation note that “Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance.” When they examined the effect in humans they found that all the following were increased markedly in the subjects on fructose but not glucose: visceral adiposity (fat around the organs), plasma triglycerides, fat in the liver, small dense LDL, oxidized LDL, fasting glucose and fasting insulin. At the same time insulin sensitivity decreased in the subjects consuming fructose but not glucose. The authors conclude: “These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.” [DNL = de novo lipogenesis which means making fat from scratch in the liver.] An accompanying commentary in the same journal states: “In the event that any readers harbor some remaining skepticism, an unprecedented thorough analysis in close to 900,000 participants from almost 60 prospective studies was very recently published, proving beyond any possible doubt that progressive excess mortality is caused by increased body adiposity…Stanhope and colleagues provide major scientific progress by demonstrating marked differences in the metabolic effects of these two major sugars with respect to their ability to promote intraabdominal lipid deposition and hepatic lipid production, while shifting cholesterol metabolism in an unfavorable manner and diminishing insulin sensitivity in humans.” Public health is groaning under a burden of overweight/obesity; how much disease could we prevent just by cutting out most of the sweet drinks (including most fruit juices) for children and adults?

Being overweight shrinks the brain

Not surprisingly, this study showed a strong correlation between increased Body Mass Index and brain atrophy. The effect was similar for both overweight and obese BMI values. Considering the connections between high BMI, insulin resistance, chronic inflammation and neurodegeneration, this confirms what we expected. “Bivariate analyses with corrections for multiple comparisons strongly linked body mass index (BMI), fasting plasma insulin (FPI) levels, and Type II Diabetes Mellitus (DM2) with atrophy in frontal, temporal, and subcortical brain regions.”