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ERDExamine.comResearch Digest

Greg Nuckols ◆ 5 Year Anniversary Edition

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From the EditorFirst, we want to thank you for taking the time to check out the Examine.com Research Digest (ERD). We feel a connection to those who love to get their hands dirty, wading through interesting and complex topics in nutrition and supplementation.

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The Examine.com Research Digest is my go-to resource for nutrition information. It helps keep up up to date on the latest studies that are relevant to my clients and I, and its presentation and readability make it beneficial for both the seasoned researcher and the layman.

- Greg Nuckols

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Table of Contents05 Beyond ‘eat less, move more’: treating obesity in 2016

By Spencer Nadolsky, DO

11 High versus low fat diets for insulin sensitivityMore body weight means more risk for metabolic syndrome. But the question of whether more fat (and especially saturated fat) impacts insulin sensitivity hasn’t been adequately addressed until now.

19 Root rage: The impact of ashwagandha on muscleSo called “adaptogens” like ashwagandha are typically studied for stress-easing potential. A randomized trial looked into this popular herb for a different purpose: bolstering adaptations to weight training.

28 Not-so-safe supplementsStudies have shown that supplement buyers generally trust the supplements they buy. That might not be the safest assumption, as dietary supplements that are presumed helpful or neutral may sometimes cause serious side effects, as quantified by this study.

35 Throwdown: plant vs animal protein for metabolic syndromeThe DASH diet is frequently tested in clinical trials, and often performs well. But the diet’s formulation includes strong limitations on red meat, which may be based on outdated evidence. This study compared animal-protein rich diets with a typical DASH diet.

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ContributorsResearchers

Margaret WertheimM.S., RD

Alex LeafM.S(c)

Courtney SilverthornPh.D.

Zach BohannanM.S.

Anders Nedergaard Ph.D.

Jeff Rothschild M.Sc., RD

Greg PalcziewskiPh.D. (c)

Gregory LopezPharm.D.

Pablo Sanchez SoriaPh.D.

Kamal PatelM.B.A., M.P.H., Ph.D(c)

Editors

Arya SharmaPh.D., M.D.

Natalie MuthM.D., M.P.H., RD

Stephan GuyenetPh.D.

Sarah BallantynePh.D.

Katherine RizzoneM.D.

Spencer NadolskyD.O.

Mark KernPh.D., RD

Gillian MandichPh.D(c)

Adel MoussaPh.D(c)

Reviewers

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Beyond ‘eat less, move more’:

treating obesity in 2016

By Spencer Nadolsky, DO

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The mainstay therapy for obesity management among clinicians and researchers that don’t specialize in obe-sity treatment is providing advice along the lines of eating fewer calories and/or burning more calories. Obesity is not thought of as a disease, but as a sequel-ae of laziness and lack of willpower. Many people say

“put the fork down” or “push yourself away from the table,” implying that these are ways to manage obesi-ty. Unfortunately, following this advice has a very low success rate, which is why we need to shift the way we think about obesity management.

To shift our perception of how to manage obesity, we must first change our views of obesity itself. Instead of being a result of sheer laziness, the pathophysiology of obesity is actually quite complex. Sure, there is an energy imbalance, leading to more energy stored as opposed to burned, but the complexities go much deep-er than this. Why does this happen? Does it happen the same way in every person? Why can’t people just lose weight and keep it off? These questions are a good start-

ing point to getting a deeper understanding of obesity.

Obesity as a diseaseThere was an uproar in the fitness community in 2013, when the American Medical Association declared obe-sity a disease. Many people questioned why someone who eats too much and moves too little should be clas-sified as having a disease. I can understand where this sentiment comes from, when it is said by someone that does not understand obesity. However, the term disease describes obesity very well.

A disease is defined as “a condition of the living animal or plant body or of one of its parts that impairs normal functioning and is typically manifested by distinguish-ing signs and symptoms.” In what ways does obesity not fit this? How do other chronic diseases like hyperten-sion and type 2 diabetes differ from obesity? You don’t die from hypertension, you die from the end result of hypertension (e.g. myocardial infarction (MI) or a cerebrovascular accident). Same with type 2 diabetes.

Many people say “put the fork down” or “push yourself away from the table,” implying that these are ways to manage obesity. Unfortunately, following this advice has a very low success rate, which is why we need to shift the way we think about obesity management.

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Obesity doesn’t kill us through excess adipose tissue. We die from the sequelae: obesity leads to hypertension, which ends with an MI. If we aren’t looking at mor-tality, but instead quality of life, then think about type 2 diabetes leading to neuropathy, which causes awful pain. Obesity also results in a lower quality of life due to conditions like obstructive sleep apnea and osteoar-thritis, not to mention the many other affected aspects of health and quality of life.

Obesity is the leading precursor to many of these chronic diseases. If we want to prevent these diseases, shouldn’t we be treating the underlying cause? The answer is yes, of course. If we wouldn’t hold back giving someone with type 2 diabetes a medicine, then why would we not provide someone with obesity effective treatments? We will get into effective treatment options later.

“But fat just sits there as an energy storage depot!” This is where the pathophysiology of obesity gets really interesting. We used to think of adipose tissue as an inert substance, basically serving as a warehouse for energy until when we needed it later. Researchers have found that our fat is the largest endocrine organ in our body! As readers of ERD are aware, there are hormones called adipokines that our fat tissue releases. These adipokines have various effects on our bodies, some good, some bad. Where we store our fat has an effect on the types of adipokines released as well. People with an “apple” shape, with fat stored centrally (visceral) tend to have the more deleterious types of adipokines, whereas people with a “pear” shape (subcutaneous) tend to have the more benign adipokine profile.

People with central obesity and the metabolic derange-ments that result from this condition are said to have adiposopathy, or sick fat. This term was coined by obe-sity researcher and clinician Dr. Harold Bays. Not only is the fat hormonally active, but due to its location (near the liver and portal vein), a higher flux of free fatty acids throughout the body is stored in the muscle, heart,

and other area of the body. The increase in free fatty acids and adipokines are thought to be the cause of the metabolic issues we see with obesity, like insulin resis-tance, dyslipidemia, hypertension, and other conditions. The idea of inert fat is old and needs to be buried.

What about people with the pear shape and subcutane-ously stored adipose? The metabolic issues described above may not be as relevant, but these people still have a condition called fat mass disease. This is the conse-quences of having too much body mass, as mentioned above, and it includes osteoarthritis, obstructive sleep apnea, and even symptoms like reflux.

Either way, obesity be considered a disease. If we think issues caused by lifestyle shouldn’t be called diseases, then we should stop calling type 2 diabetes and hyper-

People with central obesity and the metabolic derangements that result from this condition are said to have adiposopathy, or sick fat.

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tension diseases too. Yes, there are non-lifestyle causes of the aforementioned diseases, but the same can be said for obesity.

The cause(s) of obesityMuch to Gary Taubes’ dismay, the fault of obesity doesn’t rest on the shoulders of a single macronutrient like carbohydrates. While refined carbohydrates play a role in the disease, there are many other strong factors pushing us towards larger waistlines.

Obesity researcher and ERD reviewer, Dr. Stephan Guyenet, often discusses food reward and hyper pal-atability of food. What seems as simple as avoiding certain high caloric foods becomes a much tougher task

when scientists are trying to create foods that cause our brain wiring to short circuit and crave more of them.

Our appetite regulation also doesn’t rely only on the volume of food we eat. The layers of complexities run much deeper. The adipokines mentioned above and the subsequent inflammation can disrupt our appetite and food reward signaling. This partially explains why it might be hard to lose weight once we have gained it.

The microbiome is also involved (another favorite of ERD readers). It’s possible the bacteria in our guts con-trol part of our appetite and cravings. Even viruses have been implicated in weight gain, like adenovirus-36.

As a physician, I often see patients who are taking multiple medicines that are thought to be helpful for certain symptoms or disease, but which cause weight gain as a side effect. Kids are being put on powerful antipsychotics for an off-label use, without regard that they will likely experience weight gain and metabol-ic derangement. Heck, many of my patients use over the counter antihistamines, which could account for a few pounds of weight gain if used chronically. For an exhaustive list of medicines that cause weight gain, refer to my book, The Fat Loss Prescription.

Of course, genetics also play a role in our body weight. Researchers are constantly finding various single nucle-otide polymorphisms (SNPs) related to our weight. We

can’t do anything about our genetics. Even more annoy-ing, we don’t have control over what our parents and grandparents did, which may have had a large effect on our weight, too. Epigenetics, another fun ERD topic, has been studied more recently in the context of obesity. Turns out the effect our parents had on us in utero was stronger than we once thought, and we may be more likely to store fat than if our parents had chosen differ-ent lifestyles.

What can we do though?Inevitably when I discuss this topic with someone who is an “eat less, more more” pusher, they point out that

[...] many of my patients use over the counter antihistamines, which could account for a few pounds of weight gain if used chronically.

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we still do need to “eat less and move more.” They are absolutely correct, but we also need to find out how to get the individual to be able to actually do so.

There is a reason that weight regain after initial weight loss is so common. The envi-ronment, genetic, epigenetic, biological, physiological, and psychological drivers all col-laborate to force us back the wrong way. Think about all of the people you know that have obesity. Think of those with obesity who have lost weight. Have most kept it off successfully? If most of the people you know that have had obesity in the past have now lost the weight and kept it off, then I want you to find out their secret and patent it. Research shows that unfor-tunately lifestyle counseling by itself is not very success-ful. This is due to the factors described above.

Let’s face it, dieting is not fun and often our hunger and cravings get the best of us. The forces that drive us to regain are strong and we need strong treatments to combat them.

As an obesity medicine specialist, my goal is to find the linchpin in a patient’s road map for long-term obesity success. This includes creating a lifestyle they can follow for life, making sure they are not on any medicines that cause weight gain or inhibit weight loss, and deciding on whether they need a medicine and/or surgery that

will help them with their lifestyle.

Many fitness professionals balk at the idea of a medi-cine that helps with weight loss. The truth is that these medicines work in the brain to actually help you “eat less and move more.” Instead of feeling miserable on a diet and feeling driven to eat highly palatable foods, these medicines work in the parts of the brain that con-tain our appetite and food reward centers to take the edge off. As explained above, our brains may not be func-tioning properly due to our weight and other factors. Why not use a deemed safe medicine to push back the other way, toward weight loss?

There are currently four medicines approved for

long-term weight loss in the U.S. Each work in different ways in our brain to help with lifestyle adherence. Since safety is a concern, there are long-term trials currently going on to ensure the adverse effects of these medi-cines are minimal and that our treatment of obesity is saving lives and/or improving quality of life.

While I am a medical bariatrician (nonsurgical weight loss physician), I do understand that weight loss sur-gery is actually the most powerful tool we have when fighting obesity. Just like medicine, the surgery isn’t a magical procedure that automatically makes someone lose weight and keep it off forever. Surgical weight loss

Let’s face it, dieting is not fun and often our hunger and cravings get the best of us. The forces that drive us to regain are strong and we need strong treatments to combat them.

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is another method that allows patients to stick to a life-style over the long term and have a much higher chance of success than without (in many cases). In fact, weight regain (bariatric surgery recidivism) is common when the new lifestyle is not adhered to.

There are multiple bariatric surgeries available today, but the most common are the roux en y gastric bypass and the vertical sleeve gastrectomy. It was thought these worked by shrinking the size of our stomach and there-fore our ability to eat large portions, but we are now finding these procedures also affect the aforementioned

drivers of obesity (adipokines, gut hormones, micro biome, etc). No matter the reason they work, they are the most efficacious treatment we have right now for obesity.

So, do we still believe that obesity is just a matter of “pushing ourselves away from the table?” As heard from ERD reviewer and renowned obesity researcher Dr. Arya Sharma at an obesity conference, we wouldn’t tell someone with depression to just “cheer up.” Why would we tell someone with obesity to just “eat less and move more?” ◆

Dr. Spencer Nadolsky is a board certified Family Medicine Physician and a Diplomate of the American Board of Obesity Medicine. He is the medical editor for Examine.com. Dr. Nadolsky is the author of The Fat Loss Prescription, now available on Amazon.com.

His love for lifestyle as medicine began in athletics, where he worked using exercise and nutrition science to succeed in foot-ball and wrestling. After wrestling at UNC Chapel Hill as a Tar Heel heavyweight and earning a degree in exercise science, he head-ed to Edward Via College of Osteopathic Medicine in Blacksburg. During medical school, Dr. Nadolsky attended multiple obesity

medicine conferences and realized that he wanted to apply the same nutrition and exercise information he learned during his athletics to the general population and health. After medical school, he attended VCU’s Riverside Family Medicine Residency in Newport News to hone his skills. He is currently practicing in Olney, Maryland. He launched the book Skinny on Slim and has a blog called Through Thick and Thin.

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High versus low fat diets for insulin sensitivity

A high-fat, high-saturated fat diet decreases insulin sensitivity without changing intra-

abdominal fat in weight-stable overweight and obese adults

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IntroductionInsulin is a hormone that regulates several physiological functions, such as promoting glucose uptake from the blood, inhibiting glucose release by the liver, and inhib-iting fatty acid release from fat tissue. Insulin’s role is so central to our survival that nearly every cell in the body contains insulin receptors. When these cells become less sensitive to insulin’s signal, more insulin must be secreted by the body to compensate. This combination of insulin resistance and compensatory hyperinsu-linemia may be a fundamental driver of metabolic syndrome and non-alcoholic fatty liver disease.

As depicted in Figure 1, typical insulin resistance is thought to be caused in part by excessive inflammation brought about by an abundance and dysfunction of fat cells. The last few decades has seen an accumulation of evidence showing that fat surrounding organs (visceral or intra-abdominal) is particularly detrimental in this regard. However, the traditional view that fat beneath the skin (subcutaneous) is less detrimental or even

protective when compared to visceral fat has been chal-lenged recently. In either case, the commonality is that there is an excess amount of fat tissue.

Weight loss has been shown to reduce inflammation and increase insulin sensitivity. Moreover, improve-ments in insulin sensitivity have been shown to correlate most strongly with the magnitude of change in visceral fat. Indeed, fat loss appears to be the prima-ry determinant of improvements in insulin sensitivity regardless of whether the individual is consuming a low-fat or low-carbohydrate diet. However, not every-one who is over-fat and insulin resistant is actively seeking to lose weight.

The study under review sought to examine the effects of diets differing in their total and saturated fat con-tent on measures of insulin sensitivity and glucose tolerance during weight-stable conditions. Researchers also investigated whether these changes were mediated through changes in body fat distribution.

Figure 1: How inflammation may contribute to the development of diabetes

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Insulin resistance is considered a hallmark of met-abolic syndrome and fatty liver. It is commonly brought about by fat cell-mediated inflammation. Although fat loss has been shown to improve insulin sensitivity and inflammation regardless of dietary composition, not everyone who is insulin resistant and inflamed is seeking to lose weight. Thus, the current study sought to compare the effects of a high-fat diet to a low-fat diet on insulin sensitivity during weight-stable conditions.

Who and what was studied?This was a randomized, controlled, crossover feeding study with two four-week intervention periods. Each intervention period was preceded by a 10-day con-trol diet and separated by a six-week washout period. During the control and intervention periods, all food was provided to the participants in amounts designed to maintain bodyweight. Each participant picked up their food for off-site consumption and was weighed twice weekly.

Dietary compliance was monitored with a checklist, meaning that there was no guarantee that the par-

ticipants actually ate all their assigned foods and no non-study foods. Still, this design is quite rigorous and far more accurate than just asking people what they ate using a food frequency questionnaire or dietary recall.

The participants consisted of a small group of mid-dle-aged obese men (n=10) and women (n=3). Despite having an average BMI of 33.6, all the participants had normal glucose tolerance based on fasting and two-hour glucose levels after a standard oral glucose tolerance test. However, NAFLD was present in 7 out of 13 participants.

The two intervention diets (broken down in Figure 2) were:

• A high-fat diet (HFD) containing 55% of calories from total fat, 25% from saturated fat, 27% from carbohydrates, and 18% from protein, and ...

• A low-fat diet (LFD) containing 20% calories from total fat, 8% from saturated fat, 62% from carbo-hydrates, and 18% from protein.

The control diet mimicked a standard American diet with 35% calories from total fat, 12% from saturated fat, 47% from carbohydrates, and 18% from protein.

Figure 2: Kinds of fats in the different diets

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The major sources of fat in all three diets were butter and high-oleic (meaning high-monounsaturated fat) safflower oil. Additionally, vegetable content between diets was matched, inulin fiber was added to the HFD to match the LFD fiber content, and fructose was lim-ited to less than 15 grams per 1000 kcal in all diets. However, fructose content was not matched between diets, being roughly 4.5-fold greater in the LFD com-pared to the HFD. Aside from knowing that the diets were based on typical American foods, we don’t know what specific foods were being eaten by the participants.

Study assessments were performed at the end of the control diet and intervention diet phases. Body com-position was assessed with DXA, abdominal fat was assessed with MRI, and liver fat was assessed with magnetic resonance spectroscopy (MRS). These mea-surement methods are all considered gold standards for their respective uses in this study.

Whole-body and liver-specific insulin sensitivity were assessed with the hyperinsulinemic-euglycemic clamp. This method was discussed previously in ERD #8, Blast from the past: a paleo solution for type 2 diabetes, and is widely accepted as the gold-standard for directly deter-mining insulin sensitivity in humans. The clamp data was complemented by an intravenous glucose tolerance test (IVGGT), which provided information about insu-lin sensitivity, glucose tolerance, and β-cell function.

This was a randomized, crossover, controlled feeding study in which 13 middle-aged obese men and wom-en with normal glucose tolerance consumed a low-fat (20% fat, 8% saturated fat) or high-fat (55% fat, 25% saturated fat) diet for four weeks each. Gold stan-dard measurement methods were used to determine body composition, abdominal and liver fat, insulin sensitivity, and β-cell function after each dietary intervention period.

What were the findings?Since this was a crossover study, the participants served as their own controls for analysis. However, only seven par-ticipants completed both the LFD and HFD interventions, whereas the other six completed only one. Therefore, a lack of statistical power to detect differences between the LFD and HFD is a potential limitation of this study.

As intended by the study design, bodyweight remained stable during the LFD and HFD periods relative to the respective control periods that preceded them. Despite a stable bodyweight, the HFD showed a significant 6% increase in subcutaneous fat, and the LFD showed a significant 22% reduction in liver fat (absolute change from 9.4 to 7.2%).

Figure 3 shows some of the main study results. The hyperinsulinemic-euglycemic clamp data suggests that

Figure 3: How the high-fat diet compared to the low-fat diet

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whole-body insulin sensitivity was reduced by 12-19% on the HFD only, and this change was significantly different from the non-significant increases observed in the LFD. Therefore, the HFD impaired the body’s ability to uptake glucose compared to the control diet and LFD.

The reduction in whole-body insulin sensitivity appears to be primarily attributable to reduced insulin sensi-tivity in tissues other than the liver, since liver insulin sensitivity wasn’t different between the two intervention diets (according to measures of endogenous glucose production and hepatic insulin resistance).

The IVGTT data largely support the hyperinsuline-mic-euglycemic clamp data. Glucose tolerance was significantly greater during the LFD compared to the control diet and HFD. However, the HFD was not sig-nificantly different from the control diet and neither the LFD or HFD affected beta-cell function.

The fatty acid composition of VLDL was also assessed after each diet, with no significant changes observed for the HFD. However, the LFD led to significant increases in the relative proportions of stearic and palmitoleic acid, a trend for an increase in palmitic acid, and a sig-nificant decrease in linoleic acid.

Finally, correlational analyses revealed that changes in insulin sensitivity in both diets were positively associ-ated with changes in subcutaneous fat and negatively

associated with changes in VLDL concentrations of the omega-6 fatty acid docosapentaenoic acid (22:5 n6). Additionally, only in the LFD was increased pal-mitic acid predictive of increased insulin resistance in the liver. No associations with insulin sensitivity were observed for visceral fat, the subcutaneous to visceral fat ratio, or liver fat.

Four weeks on an HFD led to significant reductions in the insulin sensitivity of tissues other than the liv-er, whereas the LFD led to significant improvements in glucose tolerance and reductions in liver fat. These changes were not related to changes in visceral or liver fat.

What does the study really tell us?This study suggests that a high-fat, high saturated fat diet reduces whole-body insulin sensitivity within a rel-atively short timeframe of four weeks, but that a low-fat, low saturated fat diet does not improve insulin sensitiv-ity compared to a standard American diet.

One possible explanation for the detrimental effect of the HFD but lack of positive effect in the LFD is that the effects were mediated by the saturated fat content rather than the total fat content of the diets. Insulin

No associations with insulin sensitivity were observed for visceral fat, the subcutaneous to visceral fat ratio, or liver fat.

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resistance is directly correlated to the amount of sat-urated fat stored within the muscle (intramuscular triglycerides), as well as the proportion of saturated fatty acids contained within the muscle cell membranes. Both of these have been shown to reflect the fat compo-sition of the diet. As such, consuming a high saturated fat diet would be expected to increase the amount of saturated fat within the muscle tissue, which in turn increases insulin resistance.

The above is in agreement with the current study find-ings. It is possible that the difference between the 12% saturated fat content of the control diet compared to the to 8% of the LFD was not pronounced enough to have an effect on skeletal muscle fat composition and insulin sensitivity. By contrast, the increase from the control diet to the HFD was quite large (12% to 25%). However, this study was not designed to investigate the specific effects of saturated fat. The research-ers changed two variables at once, total and saturated fat, and this precludes us from determining which mediated the observed outcomes.

Alternatively, it is possible that the lack of benefit from the LFD was owed to an increase in deleterious met-abolic pathways that counterbalanced any beneficial effects. The observed increase in the proportion of pal-mitic acid within the VLDL particles during the LFD may reflect an increase in de novo lipogenesis (DNL, or the synthesis of new lipids in the body), which is also known to occur with high carbohydrate intakes such as

that of the current study (62% of calories). Additionally, the proportion of stearic acid was increased, and there is evidence in mice that this may be involved in insulin resistance of the liver.

It is tempting to add support to the DNL hypothesis by noting the disproportionate intake of fructose among the LFD and HFD. However, this difference amount-ed to 35 grams per day with a total fructose intake in

the LFD being around the average intake of Americans. As discussed in ERD #9, Fructose: the sweet truth, fructose use in experimen-tal trials averaged more than double this amount, often in isolation. Moreover, fructose does not appear to have a detrimental impact on liver fat accumulation when exchanged for other carbohydrates with total caloric intake held constant. It therefore seems unlikely that the difference between the groups in fructose intake played any substantial role in the observed outcomes.

As already mentioned, the small sample size was a notable limitation of this

study. Many of the effects were large but not statistically significant. This is why future work with a larger sample size is needed to corroborate this study.

Another limitation is that the saturated to unsaturat-ed fatty acid ratios of the diets were not matched. It has been argued that the quality of dietary fat is more important than the quantity of fat with regard to insulin resistance and the development of metabolic syndrome.

[...] the small sample size was a notable limitation of this study. Many of the effects were large but not statistically significant.

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There is also evidence to suggest that a threshold for fat intake exists, below which mono- and polyunsaturated fatty acids have a more favorable impact than saturated fatty acids, but above which all fatty acids are similarly detrimental to insulin sensitivity. This threshold was suggested to be 34% of calories. Thus, the different ratios could have had a different impact on the LFD with its 20% total fat, compared to the 55% total fat of the HFD.

Despite these limitations, the control diet preceding each intervention diet was an important strength of this study as it allowed for a standardization of dietary parameters before making changes and eliminat-ed the possibility that the participants’ habitual diet confounded the results. Additionally, the methods of measurement were all considered to be at or near gold standards, thus lending strong support that the observed outcomes were not a result of measurement error.

Several questions that remain include the effects of a very-low carbohydrate or ketogenic diet (with fat less than 10% of daily calories), the effects of consuming more protein, the effects of physical activity, the effects of carbohydrate type and quality, the effects of different types of fatty acids, and the effects over the long-term.

This study suggests that a high-fat, high saturated fat diet reduces whole-body insulin sensitivity when compared to a low-fat, low saturated fat diet and standard American diet (control). However, the study design precludes conclusions about the cause.

The big picture The current study supports the notion that a high-fat, high saturated fat diet impairs insulin-mediated glucose uptake into tissues other than the liver. However, not all experimental evidence does. Two other studies that utilized the hyperinsulinemic-euglycemic clamp had overweight and primarily normal-weight men consume

high-fat (50-55%) and low-fat (20-25%) diets for two to three weeks with no observed changes in insulin sensi-tivity. Unfortunately, these studies do not indicate how much of the fat was saturated. However, an 11-day study in healthy men failed to show a difference in peripher-al insulin sensitivity they ate diets with zero, 41%, and 83% of calories from total fat when the ratio of saturat-ed to unsaturated fatty acids remained constant.

The primary difference between these studies and the current one is the population. The study under review was in obese (BMI of 33.6) individuals, while the above studies were not. It is possible that the reduction in insu-lin sensitivity is owed to an inability to readily switch fuel sources, often referred to as metabolic flexibility.

The current study also showed no improvement in insulin sensitivity with a low-fat, low saturated fat diet. This is in contrast to a study analyzing 548 participants across five different dietary interventions that showed that insulin sensitivity increases when consuming a diet containing 28% total fat and 10% saturated fat. This may be owed in part to the type of carbohydrate being consumed. The current study modeled the standard American diet in food choice, while this other study utilized low-glycemic carbohydrates. Notably, one of the other five dietary interventions was the same low-fat prescription with high-glycemic index carbohy-drates, and this dietary group actually worsened their insulin sensitivity.

In both this and the abovementioned study, the partici-pants were obese. It does also appear that DNL is more pronounced in overweight-obese men compared to lean men, and this may explain why higher glycemic carbo-hydrates override any potential benefit of a low-fat diet. However, we cannot make any definitive conclusions.

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It appears that the effects of high- and low-fat diets on insulin sensitivity are dependent on the carbohy-drate quality of the diet and the metabolic flexibility of the individual. High-fat diets may be more detri-mental in overweight-obese individuals because of an inability to readily switch between using glucose and fat for energy. Low-fat diets may only confer benefits when the increased carbohydrates come from low-glycemic sources.

Frequently asked questionsWhat is DNL and why is it seen as detrimental? A consequence of overconsumption of carbohydrates is increased de novo lipogenesis (DNL), which is a process that involves the synthesis of fatty acids from non-lipid sources. The major end-product of DNL is the saturated fat palmitic acid, which can be desaturat-ed within the body to form the monounsaturated fat palmitoleic acid.

There are numerous studies showing associations between higher proportions of palmitoleic acid in

blood and tissue, and adverse health outcomes such as metabolic syndrome in adults and adolescents, hyper-triglyceridemia, type-2 diabetes, coronary heart disease, and prostate cancer. However, since none of these stud-ies establish causality, it is possible that these conditions lead to higher proportions of palmitoleic acid.

What should I know?Consuming a high-fat, high-saturated fat diet may be detrimental to insulin sensitivity if you are overweight-obese, and consuming a low-fat, low-sat-urated fat diet may be beneficial if you are consuming low-glycemic carbohydrates. However, there are many potential confounding variables that prevent drawing firm conclusions, and this small study does not address many of these. ◆

The most annoying answer to any research question is “it depends”. Yet that is the answer to many questions, including the one of fat impact on glucose regulation. Talk it over at the ERD Facebook forum.

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Root rage: The impact of ashwagandha on

muscleExamining the effect of Withania

somnifera supplementation on muscle strength and recovery: a randomized

controlled trial.

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IntroductionBeing stressed sucks. However, stress has its benefits. It’s been long-known that a moderate amount of psy-chological stress can improve physical performance. And, as many of our readers probably know, exercise is a stressor on the body that actually strengthens it in the long run.

Recently there has been increased interest in a class of herbal supplements known as “adaptogens” (some common ones are shown in Figure 1). Adaptogens are purported to help the body cope with both physical and mental stressors. Well-known examples of adaptogens include ginseng and rhodiola.

Another adaptogen that may help in this context is the root of Withania somnifera, also known as ashwagand-ha, Indian Ginseng, or Winter Cherry. Ashwagandha is a perennial shrub that grows primarily in parts of Asia, and is a member of the nightshade family. Ashwagandha root is classified in traditional Indian Ayurvedic medicine as a rasayana, or a rejuvenator. Initial research on ashwagandha has indicated that it may live up to this classification. Supplementation of

ashwagandha in humans may decrease the stress hor-mone cortisol, increase testosterone, and even improve cardiovascular performance. Yet many of these studies were published in lower-impact journals, which may somewhat call into question the validity of the results.

With that many effects to its name, it is plausible that ashwagandha may also be beneficial for strength train-ing. This is the question the authors of the study under review intended to answer.

Ashwagandha is classified under the loose umbrella of “adaptogen,” meaning an herbal supplement that helps the body cope with stressors. The purpose of this study was to determine if ashwagandha sup-plementation could improve strength gains during resistance training.

Who and what was studied?Healthy men aged 18-50 were recruited for this study. People were excluded if they took performance-en-hancing medications, smoked or drank excessively,

Figure 1: Some common adaptogens

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had an injury in the past six months. Researchers also excluded participants if they had medical conditions deemed problematic for the study. Participants were also excluded if they engaged in resistance training in the past 18 months. Fifty-seven men who met these criteria were recruited for the study. They were asked not to take anti-inflammatory medications for the eight weeks duration of the study.

The participants were then randomized to receive either twice-daily placebo (28 people) or 300 milligrams of KSM-66 twice-daily (29 people). KSM-66 is a com-mercial high-concentration ashwagandha water extract standardized to 5% withanolides, one of the primary active ingredients found in ashwagandha.

Both groups then began the same resistance training program. The program consisted of two weeks of an acclimation phase consisting of multiple free weight and machine exercises done until failure, with a goal of 15 reps. This phase was followed by six weeks of a peri-odization scheme, where the target reps per set rotated between 5-13 on different days, with the weight also being adjusted accordingly.

The main outcome measured for this study was strength gains as measured by the one repetition maximum (1RM) for leg extension and a machine bench press. Similar exercises were part of the training protocol. These were measured on the first day of the acclimation phase and two days after the eight-week training proto-col was complete.

Secondary endpoints were also measured. These included muscle size as measured on the mid-upper arm, chest, and upper thigh, body fat as measured by bioelectrical impedance, serum testosterone, and serum creatine kinase (a measure of muscle damage caused by exertion) 24 and 48 hours after working out at the beginning and end of the study. Participants were also asked to report any side effects.

Healthy men were randomized to take either place-bo or 300 milligrams of ashwagandha twice a day during eight weeks of resistance training. Strength gains before and after were measured as the primary outcome, along with a host of secondary outcomes, including muscle size, body fat, testosterone levels, and serum creatinine kinase.

What were the findings?Three people in the placebo group and four people in the treatment group stopped the resistance training program before completing the study, leaving 25 people in each group who completed the study. There were no major side effects or adverse events in either group.

The study findings are summarized in Figure 2. At the end of the eight weeks, both groups gained strength. However, the ashwagandha group seemed to out-perform the placebo group. The ashwagandha group improved their bench press 1RM by a whopping 20 kilograms (or 44 pounds) more than the placebo group

With that many effects to its name, it is plausible that ashwagandha may also be beneficial for strength training.

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(46 kilogram or 101 pound gain vs. 26 kilogram or a 57 pound gain). The 1RM gains for the leg extension exer-cise of the treatment group was about 4.5 kilograms (10 pounds) more than the placebo group’s gains (14.5 kilograms vs. 9.8 kilograms or 32 vs 22 pounds). Each of the differences between groups were statistically sig-nificant, and will be discussed further later.

Both groups also gained muscle size over the eight-week trial. The ashwagandha group gained more size in the upper arm. They also had an increased chest girth of about two centimeters more than the placebo group, on average. Thigh size was not different between the groups.

Both groups also reduced their body fat percentage. Both groups started at around 22% body fat. The pla-cebo group dropped by 1.5%, while the ashwagandha group lost about 3.5%, which was also a statistically significant difference.

Serum testosterone rose in the ashwagandha group by about 15%, while it remained unchanged in the place-bo group.

Finally, muscle recovery, as measured by serum creatine kinase levels found in the blood 24 and 48 hours after working out, improved in both groups over the eight weeks. The ashwagandha group improved more, to a statistically significant degree. However, the difference between the two groups after the eight weeks was much smaller than the improvement over the eight-week trial in both groups: the serum creatine kinase levels after working out in both groups dropped around 100-fold over the eight weeks. But the difference between the two groups at the end of the study was only about five-fold. In other words, training over time accounted for most of the improved muscle recovery seen in this study, and not supplementation.

Figure 2: Gains over placebo from ashwagandha supplementation combined with resistance training

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The ashwagandha group gained a lot more strength in the bench press and moderately more strength in the leg extension compared to the placebo group. They also lost more body fat, bulked up a little more, had a higher testosterone level, and recovered faster. No side effects were reported.

What does the study really tell us?The results of this study seem to be pretty impressive at first glance, perhaps even unbelievable. Especially the gains seen in the bench press, which were almost dou-ble that of the placebo group. In short, this study found that ashwagandha supplementation, when combined with a sensible resistance training program, improves strength and size in previously untrained men, and with no reports of side effects to boot.

However impressive these results seem, though, there are some important limitations.

Firstly, although the gains seen in the bench press and leg extension 1RM seemed quite large, they also had a pretty large error associated with them. For instance, the 95% confidence interval (essentially the range of values you can be 95% confident the real value lies within) for the 1RM gain for the ashwagandha group in the bench press was 36.56-55.54 kg and for the placebo group 19.52-33.32 kg. Note that the lower estimate of 36.56 for the ashwagandha group is close to the higher estimate of 33.32 for the placebo group. So, there may be a difference between groups, but the data from this study are consistent with the difference being small. For the leg extension, the 95% confidence intervals between ashwagandha and placebo actually overlap, so there could in theory be no difference in that measurement. In short: the large gains in strength seen in this study could be in large part just due to chance.

In addition, this was only an eight-week study. Thus, the safety and efficacy over more extended periods has not been well-tested. In fact, other studies explor-ing ashwagandha’s safety have been of an even shorter duration (and one showed an adverse reaction involv-

How does resistance training affect testosterone levels?

In general, serum testosterone rises immediately following resistance training in men, but returns to baseline, or even below baseline, after about 30 minutes. Several factors may affect the specific testosterone response to working out, however. For instance, high inten-sity or high volume alone isn’t enough to induce a testosterone response. A response is induced by meeting a minimum threshold for both.

In women, some studies have also found short-term increases in serum testosterone, but others haven’t, so the results are more equivocal.

The measurements of serum testosterone taken in this study were done prior to any activi-ty, so the fact that the placebo group’s levels remained unchanged between the initial and final measurements isn’t out of the ordinary, since they were both taken in the morning, before resistance training sessions started.

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ing hallucinogenic effects with vertigo at the lowest dose). So, there’s definitely more work to be done to make sure that ashwagandha supplementation is safe in the long term.

Also, muscle recovery was not measured directly by asking participants about soreness or by testing strength reductions after exercise. Instead, serum cre-atine kinase measures were taken to be a marker of muscle recover. While there’s some evidence that higher levels of this correlates well with soreness and reduc-tions in strength, other studies have found that creatine kinase correlates poorly with functional measures of recovery. So, we can’t necessarily say that the reductions in creatine kinase seen in this study would necessarily translate into better performance.

Another limitation of this study was that it only recruit-ed men with “little experience in resistance training,” according to the authors. Whether or not women or more experienced lifters would experience similar ben-efits is an open question since the results from this study, which only recruited men, may not generalize to women.

The fat loss measurements should also be taken with a grain of salt, since the method used (bioelectrical impedance) is somewhat unreliable.

There were also a couple of weird things going on in the way the study was reported. The paper had an import-ant omission concerning compliance to the resistance training protocol. While the authors mention treatment compliance in terms of pill count, no mention of how well the participants adhered to the strength training protocol itself was mentioned. If, by random chance, participants in the ashwaganda group adhered better to the training protocol than those in the placebo group, it could account for the differences seen between groups. Since these data weren’t reported, this possibility couldn’t be ruled out on the basis of the original paper. However, we contacted the authors, and they indeed tracked the resistance training protocol between groups and found no difference. This increases the plausibility that it was indeed the ashwagandha that lead to the gains.

One other item of note was the exclusion criteria in the study. One of these criteria was that the authors exclud-ed people with “any other conditions which [were] judged problematic for participation in the study.” This is a pretty broad category, and may have skewed the outcome as well as introduced researcher bias into the sample used in this study. Thus, there’s a chance the population studied here may not be representative of the general population.

If, by random chance, participants in the ashwaganda group adhered better to the training protocol than those in the placebo group, it could account for the differences seen between groups.

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The results of this study are only over the short-term and only in relatively untrained men. The results also have pretty large errors associated with them, so the actual effect of ashwagandha may be smaller than seen in this study. Whether ashwagandha is safe and effective in experienced strength trainers, women, or over the long-term is still unknown.

The big pictureThis is the first study to the authors’ (and our) knowl-edge that took a look at ashwagandha’s effects on resistance training in particular. However, ashwagand-ha has been studied in other contexts, many of which also show positive results.

The safety of ashwagandha has been tentatively estab-lished in the short-term in a few different studies, with

one exception. One small study reported no side effects in healthy young people performing cardio exercise over eight weeks. Another small study in healthy vol-unteers reported one adverse event, where a participant experienced “increased appetite, libido, and halluci-nogenic effects with vertigo” at the lowest dose, and was withdrawn from the study. No other participants reported any adverse effects. A third study with partici-pants under chronic stress reported that adverse events were mild and no different from placebo.

Ashwagandha’s effect on increasing testosterone has also been seen in two studies looking at men with stress-related infertility or low sperm count.

Ashwagandha has also been studied in other athlet-ic-related contexts and shown benefit, as seen in Figure 3. The study on healthy volunteers mentioned above showed mild improvements in back and quad strength

Figure 3: Ashwagandha’s effects on physical performance in other studies

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over 30 days, even though the participants were not told to train and did not participate in any exercise program in the month before enrolling in the study. Another study in healthy, untrained young people showed improvements in cardiovascular fitness and jumping power after taking 500 milligrams of ashwa-gandha extract for eight weeks. A third study in trained, elite cyclists found improvements in cardiovascular function after eight weeks of 500 milligram supplemen-tation as well.

While this study fits well with the literature on ashwa-gandha, the literature currently consists of only a few short-term studies of small sample sizes. And in these respects, the current study is no different. While lon-ger-term and larger studies are needed to confirm its effects, the early research on ashwagandha seems quite promising.

This is the the first study to examine ashwagand-ha’s effects on strength training. However, previous studies have noted safety in most people over short time periods, as well as increased testosterone plus improved cardiovascular and muscle performance in untrained or cardiovascularly trained populations. Longer-term and larger studies are needed to con-firm these effects.

Frequently asked questionsBy what mechanisms might ashwagandha improve strength? Nobody is really sure, but the authors of this study offer one suggestion: ashwagandha improves muscle recov-ery while also helping muscle development.

This study saw improved serum creatine kinase levels with ashwagandha supplementation, which is sug-gestive (but not definitive—see above) of improved muscle recovery after training. Ashwagandha has some

anti-inflammatory and analgesic properties as well. The authors suggest that improved muscle healing alongside less pain allowed the ashwagandha group to train hard-er, thereby increasing their gains.

In terms of muscle development, evidence suggests that supplementation could increase testosterone levels, which may be one contributing factor. But ashwagand-ha may also increase the body’s use and/or production of creatine. A previous study found increased levels of the breakdown product of creatine in the blood of healthy people taking ashwagandha, accompanied by mild increases in strength. Thus, the authors of the cur-

While this study fits well with the literature on ashwagandha, the literature currently consists of only a few short-term studies of small sample sizes.

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rent study suggest that ashwagandha may also stimulate creatine utilization through an unknown mechanism.

But, again, these mechanisms are mostly speculation at this point.

Speaking of creatine, how do the gains found in this study compare to those found with creatine supplementation? If the results of this study are to be taken at face val-ue, ashwagandha has a stronger effect. That’s a big “if ” though. A meta-analysis of creatine supplementation found a difference in 1-3RM performance on the bench press of about seven kilograms (15 pounds) versus pla-cebo. In this study, an improvement of 20 kilograms (44 pounds) over placebo on the bench press was seen.

Before you drop your creatine and run for the ashwa-gandha, there are some caveats to keep in mind.

First, keep in mind there was some error associated with the measurements in strength gain, and that the results of this study are also consistent with smaller gains. This was discussed above.

Second, the meta-analysis mentions that almost all of the studies included in the calculation to get the seven kilo-gram number were done on experienced lifters. Recall that the study under review recruited untrained people. So, a large part of the difference between creatine and ashwagandha may be the result of beginner gains.

Also, creatine is a very well-studied supplement at this point, and its effects and safety are quite estab-lished (you can check out the nitty-gritty details on the Examine.com creatine page). While ashwagandha seems promising, its evidence base is much smaller. The great results you see here may diminish or disappear when further research is done, or unpublished research is uncovered. This is actually a common phenomenon in science, known as the decline effect.

Finally, recall that the safety of ashwagandha supple-mentation has only been evaluated on the time scale of a month or two at best. Creatine supplementation, on the other hand, has had much longer term safety stud-ies in various populations and has fared quite well.

So, it may not be wise to drop creatine in favor of ash-wagandha just yet.

What other effects is ashwagandha purported to have? Preliminary evidence suggests that ashwagandha may improve semen quality and anxiety, and may improve glycemic control and cholesterol in diabetics as well. You can check out the details at Examine.com’s ashwa-gandha entry.

What should I know?This is the first study to examine the effects of ashwa-gandha on participants undergoing resistance training. The researchers found that ashwagandha supplementa-tion combined with training over eight weeks improved strength quite significantly, as well as muscle size, in untrained healthy men with no reported side effects. While these results are promising, they would be unprecedented if replicable. The sheer magnitude of the effects (which are more similar to steroid-influenced gains than that of a normal supplement) definitely warrants further research. Longer-term, larger studies are needed to confirm both the safety and the beneficial effects of ashwagandha. ◆

Pumped up to discuss ashwagandha? Head on over to the private ERD Facebook forum!

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Not-so-safe supplements

Emergency Department Visits for Adverse Events Related to

Dietary Supplements

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IntroductionDietary supplements are sometimes erroneously per-ceived as inherently healthy. And because of the way many supplements are advertised, it’s easy to overlook that improper administration can lead to adverse outcomes.

The classification of a supplement is defined in the United States Dietary Supplement Health and Education Act of 1994 (DSHEA) as a vitamin, miner-al, herb or botanical, amino acid, and any concentrate, metabolite, constituent, or extract of these substances. In the U.S., the Food and Drug Administration (FDA) is the governing body that oversees the regulation of dietary supplements. If a supplement has been report-ed to be causing serious adverse events or reactions, the FDA has the authority to pull it from the market. However, no safety testing or FDA approval is required before a company can market their supplement. The lack of oversight authority given to the FDA has even drawn the attention of late night talk shows hosts like John Oliver, who humorously covered the issue in this YouTube video.

Many adults are using one or more supplements to address illnesses or symptoms, and to maintain or improve health. Half of all U.S. adults have report-ed using at least one supplement in the past 30 days. Twelve percent of college students have reported taking five or more supplements a week. Now, more than ever, there are seemingly endless options to choose from. The number of supplement products currently avail-able on the market is thought to be in excess of 55,000. Compare that to the mere 4,000 available in 1994, when DSHEA was passed.

Furthermore, confidence in the safety and efficacy of these supplements is very high despite the lack of rigor-ous oversight by the FDA. A survey conducted by the trade association, Council for Responsible Nutrition, found that “85% of American adults … are confident in the safety, quality and effectiveness of dietary supple-

ments.” An independent survey has echoed these results, finding that 67.2% of respondents felt extremely or somewhat confident in supplement efficacy and 70.8% felt extremely or somewhat confident about their safety.

While the majority of Americans trust in their sup-plements, more than one-third have not told their physician about using them. There are numerous docu-mented drug-supplement interactions ranging from the mild to the severe. The herb St. John’s Wort is thought to be able to reduce symptoms in people with mild to moderate depression. But this ‘natural’ supplement also has 200 documented major drug interactions, including some with common depression medication. However, no good data currently exists to document how com-mon adverse events related to dietary supplements may be. The authors of the present study have used surveil-lance data to try and fill this knowledge gap.

Due to DSHEA, supplements remain largely unreg-ulated by the FDA. But dietary supplements are becoming ever more popular, as about half of U.S. adults report using one or more in the past 30 days. Trust in the safety and efficacy of these supplements also remains high. The authors of this study aimed to investigate how many annual adverse events are caused by improper supplement usage.

Who and what was studied?The researchers looked at 10 years of data (2004-2013) to estimate the adverse events associated with dietary sup-plements in the United States from 63 different hospitals. The selection of these hospitals was meant to be nation-ally representative and included locations that had 24-hour emergency departments. Trained patient record abstractors reviewed the reports from each hospital to identify cases where supplements had been implicated as the likely source of the adverse event. These abstrac-tors have been trained to analyze and compile medical information contained in patient records.

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Cases were scanned for emergency room visits where the treating clinician had explicitly ascribed dietary supplements as the root cause of the medical issue. This included herbal or complementary nutritional products such as botanicals, microbial additives, and amino acids, in addition to micronutrients like vitamins and minerals. Products that may typically be classified as food were excluded, like energy drinks and herbal tea beverages. Topical herbal items and homeopathic products were included in the analysis even though they do not fall under the regulatory definition of dietary supplements.

Adverse events were classified as anything causing adverse or allergic reactions, excess doses, unsu-pervised ingestion by children, or other events like choking. Due to the non-standard death registration practices among different hospitals, cases involving a mortality were not included, as were any cases involv-

ing intentional self-harm, drug abuse, therapeutic failures, nonadherence, and withdrawal.

Researchers examined patient records from 2004 to 2013 from 63 different hospitals. Cases where the treating clinician had identified a supplement as the cause of the medical emergency were extracted from the dataset. However, deaths associated with or caused by supplements were not included, as hospi-tals differ in their practice of registering mortalities.

What were the findings?Some of the major findings are summarized in Figure 1. Over 3,600 cases were identified within the prede-termined 10-year period. The researchers extrapolated from these data that the U.S. experienced an average

Figure 1: Supplement safety by the numbers

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of 23,000 supplement-related emergency department visits per year, with estimates ranging from 18,600 to 27,400. Of these 23,000 emergency room visits, it was calculated that about 2,150 (9.4%) of these result in hospitalization. About 88% of these ER visits were attributed to a single supplement, as opposed to inter-actions or mixtures of multiple supplements. The average age of patients treated for supplement-related adverse events was 32 years, and the majority of these cases were female.

Figure 2 shows age and supplement category related results. About a quarter of ER visits involved people between the ages of 20 to 34, but people older than 65 years old were more likely to have a visit that resulted in hospitalization. Of patients above 65 admitted to the ER, 16% had to be hospitalized. Surprisingly, one-fifth of supplement-related ER visits were due to accidental ingestion by children. When the data covering unsuper-vised ingestion of dietary supplements by children was not included, the researchers found that the majority

of ER visits (65.9%) were due to herbal or complemen-tary nutritional products. The top five products in this category included the following: weight loss (25.5%), energy (10.0%), sexual enhancement (3.4%), cardiovas-cular health (3.1%), and sleep, sedation, or anxiolysis (i.e. anti-anxiety) (2.9%). Multivitamins or unspecified vitamin products were the biggest contributors to ER visits under the micronutrient product category.

ER visits also varied according to gender and age. Weight loss and micronutrient supplements dispro-portionately landed females in the ER, while sexual enhancement and bodybuilding products largely affect-ed males. Among patients younger than four years old and adults over 65, micronutrients were the number one cause of emergency department visits. This is in contrast to the other age groups, where herbal and complementary nutritional products were the biggest contributor. In people ages five to 34, weight loss prod-ucts or energy products were implicated in more than 50% of ER visits. Weight loss products mostly affected

Figure 2: Summary of which types of supplements lead to ER visits by age

Source: Geller AI et al. N Engl J Med. 2015 Oct.

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patients from 20 to 34 years of age, while the micro-nutrients iron, calcium, and potassium mostly affected those older than 65.

About 23,000 people go to the ER for supplement-re-lated visits every year. The biggest contributors to this are herbal or complementary nutritional prod-ucts like weight loss and energy supplements, which largely affect people between the ages of five to 34. Females are more likely than males to end up in the ER due to adverse supplement reactions. Those over the age of 65 are most at risk for an ER visit due to micronutrient supplements such as iron, calcium, and potassium.

What does the study really tell us?While 23,000 annual supplement-related emergency vis-its may sound high, this is less than 5% of pharmaceutical product-related ER visits. However, these ER admittance rates do not line up with the marketing that has promot-

ed dietary supplements as fundamentally healthy. That is, the general public overwhelmingly perceives these prod-ucts to be safe and effective, but the present data does not support this notion (ERD readers excluded. We think you are all ahead of the curve on this one).

However, it should also be noted that overall incidences of supplement-related ER visits have remained con-stant over time. No significant changes were detected between 2004 and 2013 when accounting for popu-lation increases. The only increase that occurred was ER visits associated with micronutrient supplements, which jumped 42.5%, from 3,212 to 4,578 cases in this same time frame.

Unlike their highly regulated pharmaceutical coun-terparts, there are no legal requirements for dietary supplements to identify any potential adverse effects or major drug interactions on their packaging. The lack of adequate warning labels may be a contributing factor to why histories of dietary supplement usage are rarely obtained by clinicians. This can be due to a combina-tion of clinicians not asking proper patient screening questions and to a lack of disclosure by the patient.

Proprietary Blends

The FDA has established labeling standards dictating what must appear on a supplement’s packaging. Manufacturers must list out each ingredient, and are required to display the amount or percentage of daily value of those ingredients.

A proprietary blend falls under a slightly different set of regulations. Blends are a unique mix-ture of ingredients that are typically developed by the manufacturer. The FDA requires that all ingredients of a proprietary blend be listed on the label in descending order according to pre-dominance of weight. While the amount of the blend as a whole must be listed, the amount of each ingredient included in the blend does not.

Blends are used to help prevent the competition from knowing what the specific formulation is. But it can also hide the fact that very little of an active ingredient may be in the bottle. So while a proven performance enhancing ingredient like creatine may be listed in a proprietary blend, it could be well below what is considered to be an effective dose.

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Given that there is a tendency to underreport sup-plement usage, the researchers have noted that their calculations of emergency department visits attributed to supplement-related adverse events are probably an underestimation. A further limitation was the relative-ly small sample of hospitals used. But this method of data collection is likely to yield more accurate results over voluntary reporting despite the fact that volun-tary reporting would have likely allowed for a larger sample population.

While 23,000 annual supplement-related emer-gency visits may not be a large contributor to ER visits in the larger scheme of things, it does provide a counter-narrative to the marketing that often portrays supplements as always health promot-ing. Supplements are not required to come with labels warning of adverse events or potential drug interactions, which can be a contributing factor to supplement-related ER visits.

The big pictureThe supplement industry is the wild west of nutrition. By and large, DSHEA has hampered the ability of the FDA to adequately regulate supplements. If you have ever taken a supplement that makes a health claim, you may have encountered this statement on the label: “These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.” While all ingredients must be declared on the label, there is lit-tle oversight to ensure that these ingredients are present in the supplement, at the doses that are advertised on the packaging. Under DSHEA, there is no requirement for companies to provide any data to the FDA showing that their supplement is safe and effective, unless they are introducing a new or novel ingredient. It falls on the FDA to show that a supplement is unsafe before any action can be taken.

In light of this lack of regulatory oversight, if you are currently taking or thinking about adding a supplement to your diet, be sure to notify your doctor. Supplements can interact with prescription medication or could exacerbate certain medical conditions. Warfarin (Coumadin) is a good example. It is a blood-thinning medication that can be prescribed to people at risk of forming blood clots. To ensure that the medication works properly, these patients are usually placed on a low vitamin K diet, as vitamin K plays an essential role in forming blood clots. If these patients do not disclose that they are taking a multivitamin with vitamin K, multivitamins being one of the most commonly used supplements, they could be putting themselves at risk for developing unwanted clots.

Currently, the supplement industry is partially policed by itself. Companies that market and sell supplement products do not have to show the FDA data of safety or efficacy in the same fashion that pharmaceutical companies do. The FDA can step in when a supplement has been shown to cause harm and pull it from the market. It is important to dis-cuss all supplements you may be taking with your doctor to avoid unpleasant or dangerous interactions. Be sure to tell them even if they do not ask during your screening.

Frequently asked questionsIs there any way to ensure that I’m purchasing a quality supplement?? There are companies out there that do supply third-par-ty certifications to supplement manufacturers. These companies will verify that the supplements listed on the ingredient list are present in the concentrations claimed. There are four major companies that provide these certifications, which are shown in Figure 3: NSF International, Informed Choice, Consumer Lab, and U.S. Pharmacopeia. With the exception of Consumer

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Lab, all of these third-party certifiers print their seal on the products they have screened.

The testing process often involves looking at the puri-ty, strength, and bioavailability of the product. Good manufacturing practices, which help to provide systems that track proper design, monitoring, and control of the manufacturing process and facilities, are also frequently taken into account. Many employ continuous random testing in order for a given supplement to remain cer-tified. It is very important to note that these companies do not test for efficacy. That is to say, these certifications do not ensure that any health claims made about the supplement are truthful.

What should I know?While 23,000 dietary-supplement related ER visits may not seem like a lot when compared to something like the 610,000 deaths caused by heart disease every year in the U.S., it is something that can be easily prevented with education and awareness. Although supplement

related deaths were not included in the ER visit pro-jection, which could lead to an underestimation, it is also possible that emergency department physicians may have incorrectly ascribed certain signs and symp-toms to supplements, which could consequently lead to overestimation. Essentially, the 23,000 annual ER visits should be viewed as a very rough estimation.

If you are currently taking or planning to introduce a supplement to your diet, be sure that you are con-suming the recommended dose for that product and consult your doctor before hand. Supplements are not automatically beneficial for health, no matter what the marketing says. Treat dietary supplements the way you would treat medication, with caution and respect for their ability to both help and harm your health. ◆

An incredibly effective supplement may also be incred-ibly harmful given the right (well … wrong) context. Talk about the under-discussed issue of supplement safety at the ERD Facebook forum.

Figure 3: Third-party supplement certifications

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Throwdown: plant vs animal protein for

metabolic syndromeType and amount of dietary protein in

the treatment of metabolic syndrome: a randomized controlled trial

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IntroductionMetabolic syndrome is a cluster of risk factors that greatly increases the risk of dying from any cause (1.5-fold) and especially cardiovascular disease (CVD) specific causes (2.4-fold). This condition is diagnosed as either having or being on medications to treat at least three of the five following criteria:

• Abdominal obesity (waist circumference greater than 40 inches (men) or 35 inches (women)),

• Elevated fasting blood glucose (more than 110 mg/dL),

• Elevated fasting triglycerides (more than 150 mg/dL),

• Low HDL-c (less than 40 (men) or 50 (women) mg/dL), and

• Hypertension (systolic blood pressure higher than 130 mmHg and/or diastolic blood pressure higher than 85 mmHg).

Reducing these risk factors for CVD is the primary goal of managing metabolic syndrome, which is often done through lifestyle modification. Notably, changes to diet and exercise that facilitate a 5-10% weight loss can address and significantly improve each risk fac-tor. While a variety of dietary approaches can result in weight loss in overweight and obese adults, as explored in ERD Issue #6 (April, 2015), some dietary approach-es may benefit people with metabolic syndrome more than other approaches.

One currently accepted dietary pattern to reduce CVD risk factors is the Dietary Approaches to Stop Hypertension (DASH) diet, which is high in vegetables, fruit, low-fat dairy products, whole grains, poultry, fish, and nuts. The diet is low in sweets, sugar-sweetened beverages, and red meats. The DASH diet is designed to be low in saturated fat, total fat, and cholesterol, and rich in fiber, potassium, magnesium, and calcium.

In the OmniHeart (Optimal Macronutrient Intake Trial for Heart Health) trial, two variations of the DASH dietary pattern were compared with DASH. One variation replaced 10% of total daily energy from carbo-hydrate with protein, and the other replaced the same amount of carbohydrate with unsaturated fat. Both variations led to greater reductions of estimated CVD risk than the standard DASH diet. Notably, all three tested diets had a roughly even split between animal- and plant-based protein.

This study sought to expand upon the findings of the OmniHeart trial by comparing the effects of three vari-ations of the DASH diet, which differed in protein type (plant vs. animal) and amount (18% vs. 27%), on meta-bolic syndrome criteria.

Metabolic syndrome is a cluster of risk factors that greatly increases the risk of cardiovascular diseases, the treatment of which includes diet and exercise to facilitate weight loss. The DASH diet is considered a prudent dietary pattern to address these risk fac-tors, but other research has shown variations of the diet to be more efficient. The study under review was designed to determine how protein type (plant vs. animal) and amount (18% vs. 27%) affected metabol-ic syndrome criteria.

Who and what was studied?This six-month, randomized, parallel-arm, con-trolled-feeding study recruited 62 sedentary overweight and obese adults with metabolic syndrome. The partic-ipants were free of established cardiovascular diseases, diabetes, or liver, kidney, and autoimmune diseases. Two participants on glucose-lowering drugs and seven participants on lipid-lowering medications were asked to discontinue their use for the duration of the study, but the eight participants taking medication for high blood pressure were allowed to continue.

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The entire study consisted of four phases:

1. A two-week healthy American diet (HAD) run-in period to establish a baseline for comparison during the subsequent phases and establish weight-maintenance caloric intake for each participant.

2. A five-week weight maintenance (WM) phase fol-lowing one of three experimental diets.

3. A six-week weight loss (WL) phase consuming the same experimental diet as in WM but with a minimum 500 kcal per day deficit through dietary restriction and increased physical activity; and

4. A 12-week free living (FL) phase where partic-ipants were asked to continue their assigned hypocaloric diets and physical activity, but with-out the provision of food and drinks. To prepare for this phase, each participant met with a dieti-tian three times during the WL phase. They were educated on the unique features of their assigned diet and given practical advice, including suggest-ed menus and recipes.

All food and drink were prepared by a metabolic kitch-en and provided to the participants during the HAD,

WM, and WL phases, but only one meal per day was consumed under the supervision of research personnel. The remainder of the food was packed for taking home. This means that even though all experimental diets were tightly controlled, there was no guarantee that the par-ticipants would eat all of the food provided to them, and only the food provided (i.e. no outside food or drink).

The experimental diets were a modified-DASH (M-DASH) diet rich in plant protein (18% of the calo-ries from protein, two-thirds from plants), an M-DASH diet rich in animal protein (BOLD, which stands for Beef in an Optimal Lean Diet; 18% protein, two-thirds from animals), and a higher-protein BOLD diet (BOLD+; 27% protein, two-thirds from animals).

These diets were matched for total fat (as seen in Figure 1), saturated fat, monounsaturated fat, polyunsaturat-ed fat, cholesterol, sodium, potassium, calcium, and magnesium so as to help isolate the effects of differ-ent amounts and sources of protein. However, the M-DASH diet was significantly higher in fiber (55 vs. 38 grams) than the other two diets because of the reli-ance on plant-based protein sources. Examples of each study diets are shown in Table 1.

Figure 1: Macronutrient breakdown of the four diets

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Overweight and obese adults with metabolic syndrome were randomized to follow a modified DASH diet rich in either plant protein (M-DASH) or animal protein (BOLD), or a higher protein BOLD diet (BOLD+) for a five-week weight maintenance phase and a six-week weight loss phase, with all food and drink prepared and provided by the research staff. Afterward, the par-ticipants were asked to continue their respective diets for 12 weeks under free-living conditions.

What were the findings?Over the entire six-month intervention, there were no

differences in any outcome between the three dietary groups. Most of the significant health improvements occurred only after the WL phase. Accordingly, there was no change in the prevalence of metabolic syndrome among the participants from baseline through WM, but prevalence dropped substantially to 50-60% after the WL phase and was maintained through the FL phase. In other words, roughly half of the participants were no longer classified as suffering from metabolic syndrome after the WL phase. A summary of the study findings is shown in Figure 2.

The resolution of metabolic syndrome was the result of significant improvements in every criterion except for blood glucose levels. On average, after the WL phase

Table 1: Examples of the four study diets: Menus for the test dietsHAD M-DASH BOLD BOLD+

Breakfast

• Pancakes with butter and light syrup

• Peaches, canned in juice

• Cottage cheese (1%)• Apple Juice

• Pancakes with butter and light syrup

• Blueberries• Skim Milk

• Orange Juice

• Bran flakes with raisins and skim milk• Whole-wheat mini-bagel and margarine

• Orange Juice• Banana

• Bran Flakes with raisins and skim milk• Cottage cheese (1%)

• Orange Juice

Lunch

• Turkey, provolone cheese, and lettuce sandwich on white

bread with mayonnaise• Granola bar

• Spinach/baby greens salad with cherry

tomatoes, mandarin, oranges, grilled chicken

breast, and dressing• Edamame beans

• Whole-wheat dinner roll with butter

• Pistachios

• Barbeque beef sandwich on whole-

wheat bun• Spinach salad with

cherry tomatoes and dressing

• Thin pretzels• Pear

• Beef chili with shredded cheddar

cheese (low fat) and while-wheat crackers

• Peaches, canned in juice

Dinner

• Szechuan stir-fry entré with pork and white rice

• White dinner roll with butter

• Romaine lettuce salad with carrots

and italian dressing

• Ratatouille (eggplant/peppers) with pasta

• Spinach salad with carrots, cherry tomatoes, red bell pepper, chickpeas,

and dressing

• Spinach and beef skillet with ribeye steak

• Brown rice• Mixed baby greens salad with carrots, cherry tomatoes,

and dressing

• Pot roast with mashed potatoes and gracy• White dinner roll

with margarine• Broccoli and

edamame beans• Romaine salad with

cherry tomatoes and dressing

Snack• Plain bagel with

cream cheese

• Light yogurt• High-fiber cereal

• Almonds

• Light yogurt• Orange

• Almonds

• Hummus with whole wheat pita and baby carrots

• Trail mix

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and compared to the WM phase, there was a three to four centimeter (about 3%) reduction in waist cir-cumference, a 13-30% reduction in triglycerides, a one to four mmHg reduction in systolic blood pressure, a one to three mmHg reduction in diastolic blood pressure, and a 4-9% increase in HDL-c. Additionally, total and LDL-cholesterol were reduced from baseline during both the WM and WL phases, possibly due to the reduced saturated fat intake among all diets, but returned to baseline values during the FL phase. The WL phase also led to significant improvements in CRP (a marker for inflammation), endothelial function, and vascular stiffness.

The only difference between the WM and WL phases was a 500 kcal reduction in the food provided to the participants and a significant increase in the number of daily pedometer-measured steps taken, from 6,300 to 10,500. Together, this resulted in a significant 5% weight loss across all groups, with roughly 80% coming from fat mass. Since metabolic syndrome resolved only after the WL phase, these findings suggest that weight loss was the primary driver of health improvement.

Compliance during the WM and WL phases was determined through daily questionnaires. Participants were classified as noncompliant on any day that they consumed a non-study food or beverage or did not consume a study food or beverage. Accordingly, dietary compliance ranged from 70-90% throughout the WM and WL phases, but appeared to be higher in the M-DASH (82-90%) group than the BOLD (70-75%) or BOLD+ (77-80%) groups.

Regardless of diet, weight loss appeared to be the primary driver of improved health among the partic-ipants. In all diet groups, the number of individuals with metabolic syndrome was reduced by 40-50% after they lost about 5% of their bodyweight during the weight-loss phase.

Figure 2: Effects of all the diets on metabolic syndrome factors

Note: ranges are based on average changes across all the diets. None of the diets’ effects were statistically different from one another.

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What does the study really tell us?The researchers conducting this study sought to explore how protein type and amount affects the health of people with metabolic syndrome through three dif-ferent phases of energy balance: weight maintenance, weight loss, and free living. The results indicate that nei-ther protein type or amount have a significant impact on health at any stage, and that clinically significant weight loss (5% in this study) is the primary driver for reductions in abdominal obesity, triglycerides, blood pressure, and inflammation (CRP).

Current DASH diet recommendations include limit-ing the consumption of red meat. Many other dietary patterns that are considered healthy, such as the Mediterranean diet, tend to have relatively less animal protein, with relatively more protein from whole grains and legumes. The current study used unprocessed lean beef (select grade top round, ribeye, chuck shoul-der, and 95% ground beef) and found that consuming nearly seven ounces (200 grams) per day had no det-rimental (or beneficial) impact on CVD risk factors

compared to a diet supplying mainly plant-based pro-teins. This finding is consistent with numerous other intervention trials (1, 2, 3, 4, 5, 6) showing no differ-ence between lean red and white meats and suggests that red meat can be safely included in an otherwise healthy diet.

The current study had a strong design, with ample time in each phase to allow for changes in CVD risk markers to occur. However, the trial was designed to be statisti-cally powered only to detect changes over time in each diet group, meaning that any between-group differenc-es may not have manifested due to a lack of statistical power. This may be most apparent when acknowledg-ing the lack of difference between the normal protein and higher protein diet in terms of changes in body composition.

After all, it is recognized that higher protein diets, such as those used in this study (27%), lead to greater fat loss and retention of muscle mass than normal protein diets. Additionally, higher protein diets facilitate weight loss through increased satiety. Unfortunately, the controlled-feeding design of this study required partic-

The current study used unprocessed lean beef and found that consuming nearly seven ounces (200 grams) per day had no detrimental (or beneficial) impact on CVD risk factors compared to a diet supplying mainly plant-based proteins.

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ipants to eat all food provided to them, eliminating the satiety advantage. While not statistically significant, it is noteworthy that only the BOLD+ diet continued to demonstrate weight and fat loss alongside increases in lean body mass during the free-living phase, when the benefits of a higher protein diet could be realized.

Alternatively, the high and low protein diet groups were consuming 2.5 and 1.7 grams of protein per kilogram of lean-body mass, respectively, and it has been sug-gested that optimal intake for resistance-trained obese adults is around 1.9 grams per kilogram. The current study did not utilize resistance training, so an optimal amount of protein would likely be lower and possibly around that of the lower protein diets. Accordingly, the lower protein diet may have been sufficient in protein to account for the insignificant difference in weight loss or lean mass kept from a higher protein intake.

Lastly, the recruitment goals of the study were not met, which may have limited the statistical power to detect significant changes over time within each dietary group. However, there were no trends that presumably may have reached significance with additional participants.

Clinically meaningful weight loss (about 5%) appears to benefit health regardless of protein type or amount. Although this study showed no benefit to higher protein intake, a potential lack of statistical power to detect between-group changes, as has been observed in previous studies evaluating the effect of protein on body composition, suggests the find-ing should be accepted with caution. In agreement with other intervention trials, unprocessed lean red meat may be safely included as part of an otherwise healthy diet.

The big pictureThe DASH diet was developed in the mid-1990s to

address an increasing rate of hypertension among the general public. One of the unique features of the DASH diet is that it focuses on dietary patterns rath-er than single nutrients, based on past observational evidence combined with knowledge of select vitamins and minerals. Accordingly, the DASH diet was built on a foundation of natural foods such including fruit, vegetables, whole grains, nuts, legumes, and seeds that are good sources of potassium, magnesium, and dietary fiber. Additionally, it incorporates low-fat dairy prod-ucts, fish, chicken, and lean meats to reduce total and saturated fat consumption and increase protein and calcium intake.

Because nutrition is not static, this successful dietary pattern has undergone small changes in the last two decades, such as limited red meat in favor of fish and poultry. This change was based on observational evi-dence suggesting a link between red meat and CVD. As follow-up research has shown, this recommenda-tion may have been premature. Associations are not cause-and-effect relationships and there are countless potential explanations for why an association exists. Against that background, it is all the more important to highlight that the study under review — just like sever-al previous studies — found no evidence that lean red meat poses a CVD risk, at least not one that is detect-able by the measurement of common CVD risk markers.

This is certainly not the first time policy makers have based recommendations on associations, only to be unsupported by subsequent intervention trials. In ERD Issue #7 (May, 2015), we discussed the DIABEGG study that sought to clarify whether eggs could be safely included in the diet of people with type 2 diabe-tes. This research was needed because observational evidence showed that people with type 2 diabetes who ate eggs more than once per day were 69% more likely to develop CVD comorbidity than those who ate eggs less than once per week. Other research showed that for each four-per-week increase in egg intake, the risk

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of CVD increased by 40%. Not only did the DIABEGG study show that eggs had no impact on blood lipids or glycemic control, it showed that eggs increased post-breakfast satiety and resulted in a more enjoyable dietary experience by the participants.

Observational evidence is important for notic-ing potential links between diet and health, but it serves only as a starting point that requires further and more rigorous testing. It is not uncommon for dietary recommendations to incorporate observa-tional evidence that is later shown to be incorrect by experimental trials. The study at hand is a great example, showing that the observational link between red meat and CVD may be a bit misleading, based previous trial evidence plus this study showing a lack of difference in CVD risk markers between the plant- and animal-based protein groups.

Frequently asked questionsAre there other dietary patterns with evidence for improving metabolic syndrome? Ultimately, any diet that results in fat loss will help with metabolic syndrome. However, some dietary patterns may better facilitate the necessary caloric deficit. For instance, a paleolithic diet excluding cereal grains, dairy, and legumes in favor of lean meats, fruit, fibrous and starchy vegetables, and nuts has been shown to result in more favorable health outcomes than a healthy refer-ence diet, as discussed in ERD Issue #6 (April, 2015).

The paleo diet referenced above is unique in that it pro-motes the consumption of lean unprocessed meats. This is in contrast to observational evidence that suggests protective dietary patterns are low in red and processed meats, providing yet more evidence that the exclusion of lean red meat is not what makes these other dietary patterns beneficial.

What is the difference between red meat and white meat, other than color? Red meat is a general term referring to meat from land mammals, including cattle, lamb, goat, and sheep, whereas white meat is a general term referring to meat from poultry, lean game like rabbit, and non-fatty fish, such as cod and pollock. The primary difference between these types of meat is their primary muscle fiber type: red meat is “slow-twitch” and white meat is “fast-twitch.” It should be noted that both types of fibers exist in the meat, and these terms refer to the dominant fiber type.

Ultimately, any diet that results in fat loss will help with metabolic syndrome. However, some dietary patterns may better facilitate the necessary caloric deficit.

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Slow-twitch fibers are designed to contract continu-ously for long periods of time and thus rely heavily on oxygen for energy production via the aerobic path-way. The protein myoglobin stores oxygen in muscle cells and is richly pigmented, so the more myoglobin there is in the cells, the redder, or darker, the meat. By contrast, fast-twitch muscles are designed to contract forcefully and rapidly for very short periods of time and rely more on glucose than oxygen to function properly. Therefore, they don’t store a lot of myoglobin, instead favoring glycogen, and thus appear more glossy white.

From a nutritional perspective, the two types of meat are very similar. White meat is much leaner on average, but there are also many types of lean red meat such as bison and beef steak cut from the round of the cow. Red meat also tends to be higher in vitamin B12, zinc, and iron, while white meat contains more niacin and panto-thenic acid.

What should I know?Metabolic syndrome is a cluster of cardiovascular dis-ease risk factors, the treatment of which includes diet and exercise to facilitate weight loss. The DASH diet is

considered a prudent dietary pattern to address these risk factors, but some components of it are based largely on observational evidence, such as the suggestion to limit red meat.

The current study tested the validity of this recommen-dation and showed that consuming up to seven ounces (200 grams) of unprocessed lean red meat per day as a primary protein source has no differential impact on CVD risk factors and metabolic syndrome than a diet where the majority of protein is obtained from plants. Overall, the results suggest that clinically meaningful weight loss (about 5%) will benefit health regardless of protein type or amount. However, protein-specific benefits on other health outcomes like body composi-tion require further research, as the current study may not have been adequately powered to detect significant differences. ◆

The DASH diet has been studied in countless trials, but this is the first to show that its low-red-meat stipula-tion may be misguided. Head over the ERD Facebook forum to talk more about this study.

Overall, the results suggest that clinically meaningful weight loss (about 5%) will benefit health regardless of protein type or amount.

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