Dietary macronutrient composition for weight loss and weight maintenance

Posted on October 22, 2011 by Dr. Jonathan

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.

Dairy reduces inflammation and oxidative stress in metabolic syndrome

Posted on September 3, 2011 by Dr. Jonathan

More evidence that dairy foods contain agents with antiinflammatory and antioxidant properties is presented in a study published recently in The American Journal of Clinical Nutrition showing reductions in damaging inflammatory biomarkers. The authors state:

“Oxidative and inflammatory stress are elevated in obesity and are further augmented in metabolic syndrome. We showed previously that dairy components suppress the adipocyte- and macrophage-mediated generation of reactive oxygen species and inflammatory cytokines and systemic oxidative and inflammatory biomarkers in obesity…The objective of this study was to determine the early (7 d) and sustained (4 and 12 wk) effects of adequate-dairy (AD) compared with low-dairy (LD) diets in subjects with metabolic syndrome.”

Their forty overweight or obese subjects with metabolic syndrome were randomly assigned to receive either an ‘adequate dairy diet’ (defined as 3.5 daily servings) or ‘low dairy diet’ (less than half a daily serving) form of weight-maintenance diet for 12 weeks. They measured oxidative and inflammatory biomarkers at the start and after 1, 4, and 12 weeks as primary outcomes, along with body weight and composition to start and after 4, and 12 weeks as secondary outcomes. Their data showed a dramatic difference for the ‘adequate dairy’ diet:

“AD decreased malondialdehyde and oxidized LDL at 7 d (35% and 11%, respectively), with further decreases by 12 wk. Inflammatory markers were suppressed with intake of AD, with decreases in tumor necrosis factor-α at 7 d and further reductions through 12 wk (35%); decreases in interleukin-6 (21%) and monocyte chemoattractant protein 1 (14% decrease at 4 wk, 24% decrease at 12 wk); and a corresponding 55% increase in adiponectin at 12 wk. LD exerted no effect on oxidative or inflammatory markers. Diet had no effect on body weight; however, AD significantly reduced waist circumference and trunk fat, and LD exerted no effect.”

While these findings don’t obviate the need to attend to the possibility of dairy allergies or the quality of dairy foods consumed, this is strong evidence that there agents in an ‘adequate dairy’ diet that can do more than a low dairy diet even when the same amount of weight is lost.

“Data from this study show that an increase in dairy intake from suboptimal to adequate levels (≈3.5 servings/d) significantly attenuates both oxidative and inflammatory stress in metabolic syndrome. Notably, although these effects may result, in part, from reductions in adiposity on higher dairy diets, the rapid onset (within the first 7 d of dietary change) suggest that there is an adiposity-independent effect as well. This is further supported by our previous evidence that showed direct effects of dairy components on adipocyte cytokine expression and secretion.”

GGT is an important predictor of diabetes and cardiovascular risk

Posted on September 1, 2011 by Dr. Jonathan

I always include GGT (Serum γ-Glutamyltransferase) in our basic screening blood panel, but find often that this is not included in lab work that patients bring from elsewhere. A study recently published in the journal Obesity shows that, besides being associated with fatty liver, GGT is an important metric for predicting metabolic syndrome, diabetes and hypertension. The authors state:

“Serum γ-glutamyltransferase (GGT) is associated with oxidative stress and hepatic steatosis. The extent to which its value in determining incident cardiometabolic risk (coronary heart disease (CHD), metabolic syndrome (MetS), hypertension and type 2 diabetes) is independent of obesity needs to be further explored in ethnicities.”

They examined a cohort of 1,667 adults from a general population age 52 to 63 with 4 year’s follow-up, measuring GGT activity in association with metabolic syndrome (identified by Adult Treatment Panel-III criteria modified for male abdominal obesity) and multiple markers for cardiovascular disease. Their data bolsters the use of GGT for case management:

“Median GGT activity was 24.9 U/l in men, 17.0 U/l in women…while smoking status was not associated, (male) sex, sex-dependent age, alcohol usage, BMI, fasting triglycerides and C-reactive protein (CRP) were significant independent determinants of circulating GGT. Each 1-s.d. increment in (= 0.53 ln GGT) GGT activity significantly predicted in each sex incident hypertension (hazard ratio (HR) 1.20), and similarly MetS, after adjustment for age, alcohol usage, smoking status, BMI and menopause. Strongest independent association existed with diabetes (HR 1.3) whereas GGT activity tended to marginally predict CHD independent of total bilirubin but not of BMI.”

Interestingly…

“Higher serum total bilirubin levels were protective against CHD risk in women.”

While not any stronger a risk predictor for coronary heart disease (CHD) than body mass index (BMI), GTT is a valuable and underutilized marker to use for the case management of cardiometabolic disorders. The authors conclude:

“We conclude that elevated serum GGT confers, additively to BMI, risk of hypertension, MetS, and type 2 diabetes but only mediates adiposity against CHD risk.”

Soluble fiber decreases belly fat

Posted on August 27, 2011 by Dr. Jonathan

It’s well known that visceral fat (visceral adipose tissue, VAT—the fat in the abdomen that surrounds vital organs) is associated with chronic inflammation, metabolic syndrome, diabetes, fatty liver disease, hypertension and other mounting ailments. Research published recently in the journal Obesity offers welcome evidence that consuming soluble fiber significantly decreases VAT. As the authors did, the most accurate way to determine the amount of VAT is with CT scans…

“The objective of this study was to examine whether lifestyle factors were associated with 5-year change in abdominal fat measured by computed tomography (CT) in the Insulin Resistance and Atherosclerosis (IRAS) Family Study.”

They measured visceral (VAT) and subcutaneous (SAT) adipose tissue at the L4/L5 vertebral level at baseline and at 5 years for 339 subjects ages 18-81. Examining physical activity and dietary intake, they assessed the associations between change in fat accumulation and a number of relevant variables including physical activity and soluble and insoluble fiber intake. Their data showed benefits for both physical activity (no surprise there) and soluble fiber:

“Soluble fiber intake and participation in vigorous activity were inversely related to change in VAT, independent of change in BMI. For each 10 g increase in soluble fiber, rate of VAT accumulation decreased by 3.7%. Soluble fiber was not associated with change in SAT. Moderately active participants had a 7.4% decrease in rate of VAT accumulation and a 3.6% decrease in rate of SAT accumulation versus less active participants. Total energy expenditure was also inversely associated with accumulation of VAT.”

Ten grams of soluble fiber is approximately equivalent to a cup of green peas, two small apples and a half cup of pinto beans. (See also an earlier post on prunes.) The authors conclude:

“Soluble fiber intake and increased physical activity were related to decreased VAT accumulation over 5 years.”

Metabolic syndrome doubles the risk of liver cancer

Posted on August 5, 2011 by Dr. Jonathan

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.”

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

Posted on August 2, 2011 by Dr. Jonathan

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

Posted on June 29, 2011 by Dr. Jonathan

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

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

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

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

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

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

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

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

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

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

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

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

Moreover…

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

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

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

They go on to summarize…

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

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

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

They set out to…

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

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

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

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

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

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

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

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

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

Sadly…

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

Moreover…

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

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

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

Their data showed a distinct association:

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

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

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

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

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

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

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

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

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

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

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

And happily…

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

To summarize the significance for obesity and weight loss:

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

Sugar turns LDL cholesterol “ultra-bad”

Posted on June 19, 2011 by Dr. Jonathan

That serving of french toast may be doing more to contribute to cardiovascular disease than promoting insulin resistance and dyslipidemia. A paper just published in the journal Diabetes details how excess blood sugar causes LDL cholesterol to stick more readily to arterial plaque. Inflamed vulnerable plaque on arterial walls is the main precipitating factor for heart attacks and strokes. The authors set out to…

“…study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity.”

Glycation is the damaging process by which sugar binds to substances in the body that it shouldn’t do normally. As the practitioners reading this know, hemoglobin A1c (HbgA1c, produced by glycation of hemoglobin) is an important laboratory metric for determining how high a person’s blood sugar has been on average over the previous few months. People with pre-diabetes (metabolic syndrome) and type 2 diabetes have higher levels. By modifying human LDL by methylglyoxal to reproduce what happens in vivo, the authors were able to measure the effect on LDL particle characteristics and its tendency to deposit in the arterial wall. What did they find?

“MGmin-LDL [glycated LDL] had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MGmin-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate–containing proteoglycan. Radiotracer studies in rats showed that MGmin-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall…A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan–binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding.”

In other words, glycated LDL is a nasty compound that is less likely to be scavenged from the bloodstream; and it is smaller, denser and stickier than normal LDL so that it has a higher tendency to adhere to the blood vessel well. Glycated LDL has been called the “ultra-bad cholesterol“. It also shows part of the reason why blood sugar lowering therapies reduce cardiovascular disease. The authors conclude:

“MG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin.”

As insulin goes up so does the danger of arterial plaques

Posted on April 15, 2011 by Dr. Jonathan

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.

Less mortality and cardiovascular risk with metformin than other diabetes drugs

Posted on April 11, 2011 by Dr. Jonathan

It’s by far best to prevent type 2 diabetes by acting on the earliest signs of metabolic syndrome with appropriate lifestyle changes and evidence-based support for genetic and epigenetic needs based on objective laboratory data. All too often, however, this isn’t accomplished and the case advances to type 2 diabetes as insulin resistance mounts and insulin production can no longer compensate. When we enter the realm of pharmaceuticals for T2DM there are choices. A huge study just published in the European Heart Journal offers valuable evidence that metformin is associated with much less risk of cardiovascular disease and all-cause mortality. The authors state:

“The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study.”

The authors examined the data for all Danish residents over 20 years old who starting taking an a single-agent insulin secretagogue (medication that provokes the secretion of insulin, ISs) or metformin between 1997 and 2006, a total of 107,806 subjects. They were followed for up to 9 years (3.3 years on average) for all-cause mortality, cardiovascular mortality, and the combination of myocardial infarction (MI), stroke, and cardiovascular mortality. This was correlated with the use of individual ISs. What did their data show?

“Compared with metformin, glimepiride: 1.32, glibenclamide: 1.19, glipizide: 1.27, and tolbutamide: 1.28 were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30, glibenclamide: 1.47, glipizide: 1.53 (1.23–1.89), and tolbutamide: 1.47. Results for gliclazide and repaglinide and were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint.”

In other words, for example, patients (who had never had a heart attack) taking glimepiride had a 32% increased chance of dying compared with taking metformin. The authors conclude by stating:

“Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.”

This outcome is not unexpected when we consider that, in addition to suppressing hepatic glucose production, metformin acts to increase insulin receptor sensitivity. The authors of an editorial published in the same journal comment on the gravity of this study:

“While this is not the first study to evaluate outcomes with these drug classes comparatively, the observations are among the most robust published based on the very large sample of patients with drug choices largely free of selection bias, sufficient numbers of events ascertained to yield substantial statistical power to analyse outcomes for each insulin secretagogue individually, with additional stratification by history of previous myocardial infarction.”

Important: metformin is known to interfere with vitamin B12 absorption (see previous posts). Patients should be followed carefully for indications of suboptimal vitamin B12 levels, preferably by urine or serum methylmalonic acid assays.