Beyond Celiac: Study Sheds New Light on Obesogenic Effects of Gluten - Are PPARs & Bacteria Both Involved?

Cornflakes peanut butter cookies - guaranteed not gluten free ;-)

With Christmas Eve being over, and grandma's cookies, Christmas stollen, and all sorts of other stuff from the bakery in front of you (literally), Christmas Day may actually prove to be a way more "dangerous" than Christmas Eve - not just because of the total amount of calories, but also because of the low satiety effect of these sweet treats.

A recent paper by scientists from the Universidade Federal de Minas Gerais in Belo Horizonte in Brazil does now point to another reason you better give those bakery products a wide berth - not just, but especially with the energy overshoot on Christmas day: Gluten!

Study confirms for the first time what scientists and laymen alike have been speculating about

In what the scientists claim is the first well-controlled study of the effects of gluten intake on metabolic health in a non-celiac, but Western-style diet scenario, Fabíola Lacerda Pires Soares and her colleagues put two groups of C57BL/6 mice on identical, iso-caloric high fat (hypercaloric) diets that differed only in terms of the amount of gluten that was added to the chow (0% gluten vs. 4.5% gluten).

Interestingly, the gluten diet did not influence any of the usual suspects, like food intake, total fat-free mass, fecal lipids excretion, blood lipid profile, blood total protein and ectopic (liver and muscle) lipid concentration (if you look closely you will realize that the gluten-free group actually had higher TRIGs, although the difference did not reach statistical significance).

Figure 1: Usual suspects and closer look at the effects 8 weeks gluten supplemented vs. gluten-free diets had on serum markers of metabolic syndrome and visceral fat parameters (Soares. 2012)

The data in figure 1 (right) does yet also show that the gluten content of the diet did nevertheless have a significant impact on the total body mass, visceral fat mass, lipid content and most importantly the adipocyte size.

Figure 2: Absolute adipokine levels (left) and fasting glucose and insulin levels, as well as Homa-IR (Soares. 2012)

Add to that the blunted expression of the anti-inflammatory and anti-diabetic fat hormone adiponectin and the increased the >5x higher expression of leptin (figure 2). And mix that with the reduced expression of PPAR-alpha and gamma of which Soares et al. argue that they may well be the key factor in the detrimental modulatory effect the addition of gluten had on the visceral fat structure and the lowered expression of the fat liberating enzymes LPL and and HSL, as well as reduced levels of the fat burning proteins ACC and CPT-1 (figure 3).

Figure 3: PPAR-alpha, -gamma, LPL, HSL, ACC and CPT-1 expression compared to rodents on regular chow (left); crown like structures in stained slices from visceral fat, inflammatory markers TNF-alpha and IL-6 (Soares. 2012)

So, even if the initially mentioned blood markers (aka the usual suspects) would suggest that both the gluten-consuming and gluten-free rodents were similarly bad off, the profound difference in inflammatory markers within the adipose tissue and the presence of comparatively many necrotic and inflammatory adipocytes in the crown like structures stand in line with increases in HOMA-IR, fasting glucose and insulin and an already compromised glucose clearance which are well-known harbingers of the metabolic syndrome.

These observations do not simply shed a whole new light on a hitherto largely ignored contributer to the etiology of the metabolic syndrome, they do also show that one of the reasons it has not been identified before is an over-reliance on BMI, total fat mass and serum lipids in the early stages of diabesity.

Reardless of whether the gut microbiome is part of the mechanism by which gluten predisposes the development of metabolic syndrome. Eating more inulin- and beta-glucan rich foods like Jerusalem artichokes, agave, bananas, onion, steel cut oats, wild yams, yacon, etc. certainly won't hurt your efforts to get lean, stay lean and leave the role of the obese diabetic to the other (read more)

Bottom line: The study at hand provides a good reason to limit your intake of "healthy whole grains" and other gluten containing foods, regardless of whether you suffer from celiac or not. Whether the established detrimental effects of gluten on the integrity of the intestinal wall and the increased leakage of bacterially produced endotoxins from the highly unfavorably changes in the gut microbiome in response to the high fat diets (Hildebrandt. 2009) are part of, or even the primary cause of these observations still has to be elucidated. The same goes for strategies to counter the translocation of the endotoxins across the gut lining (cf. "Shedding some light on the leaky gut") and the dose response relationship between the total amount of gluten in your diet and its effects on your metabolism. With 7% of pure gluten, it goes without saying that you would basically have to live of wheat in order to get to anywhere similar amounts of gluten in the diet... that said: Is it possible that the effects occur only in the presence of the high fat diet? After all, this alone has been shown to favor a pro-inflammatory gut microbiome.

You see there are enough questions to be answered in 2013 and the SuppVersity is going to be the place you will read the respective answers first ;-)

References:

• Hildebrandt MA, Hoffmann C, Sherrill-Mix SA, Keilbaugh SA, Hamady M, Chen YY, Knight R, Ahima RS, Bushman F, Wu GD. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology. 2009 Nov;137(5):1716-24.e1-2.
• Soares FL, de Oliveira Matoso R, Teixeira LG, Menezes Z, Pereira SS, Alves AC, Batista NV, de Faria AM, Cara DC, Ferreira AV, Alvarez-Leite JI. Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression. J Nutr Biochem. 2012 Dec 17.

The Fat Truth Behind the Dairy Weight Loss Miracle: MUFA and PUFA Impair, Saturated Fat and Plenty of Micronutrients Drive Full-Fat Dairy-Powered Fat Loss.

Image 1: Kids who drink more milk, tend to be leaner... and that despite (?) the fact that this stuff comes out of an animal and is full of bad cholesterol and fat - outrageous ;-)

Plenty of interesting news, lately, so this one - just like the recently released hypertrophy / hormone correlation study by Stuart Phillips, about which I have been talking in yesterday's installments of the Intermittent Thoughts got somewhat delayed. With the Christmas holidays and the approaching and all those New Year's weight loss resolutions (I would prefer the term "fat loss resolution", though ;-) already on your mind, I do yet think that it is about time to break the news on the "fat" reason for the purported beneficial effects an increased consumption of dairy products during periods of caloric restriction appears to have on weight and more specifically body fat loss (Linn. 2000; Peirara. 2002; Shahar. 2010).

Dairy, calcium or simply the right macronutrient composition?

The scientific results I am going to present are taken from a study that was published in the Journal of Nutrition and Metabolism a few weeks ago (Smilowitz. 2011). In a randomized, placebo-controlled study Jennifer T Smilowitz and her colleagues from the USDA-funded (keep that in mind, when interpreting the results, or rather the scientists interpretation of the latter ;-) Western Human Nutrition Research Center assigned their 62, against the background of the rampant obesity epidemic, only slightly overweight young subjects (mean age: 25y; BMI ~28) to a calorically restricted diet (-500kcal) that was specifically designed to "provide comparable levels of macronutrient and fiber, to approximate the average consumption in the US" (35% fat, 49% carbohydrate, 16% protein and 2-3g fiber), which contained either

• 0-1 servings of dairy, with 500mg dietary calcium (from the whole diet) + placebo,
• no dairy (still 500mg calcium from diet), 900mg of supplemental calcium carbonate, or
• 3 servings of dairy, with 1400mg of dietary calcium (from the whole diet) + placebo

Thusly, the study basically mimicked, what would happen if you told the average American to just keep their usual sedentary life-style (the subjects were instructed not to start to exercise or anything like that) and either just reduce his caloric intake by 500kcal, to do the former and to make sure to have three servings of dairy per day, or to just take an additional "healthy" calcium carbonate supplement.

Eat dairy + whatever you want and lose weight?

Now, interestingly, the subjects were not only free to chose whether they wanted to consume the dairy from low or normal fat cheese, milk and/or yoghurt, they were also relatively free as far as the rest of their dietary choices were concerned so that the detailed analysis of their food-logs allowed for conclusions to be drawn that went beyond the initial scope of the study... but let's take one thing after the other.

Figure 1: Dietary intake (macronutrients in kcal/day) of the subjects before and at the end of the 12-week study period and relative changes in carbohydrate, protein and fat intake (data calculated based on Smilowitz. 2011)

If you take closer look at the analysis of the dietary records the subjects had to keep, you will notice that the minor differences in the dietary prescriptions induced quite profound changes as far as the macronutrient composition of the respective diets was concerned. While the subjects in the non-dairy groups, regardless of whether they received a calcium supplement or placebo, cut back on all the three major macronutrients, the requirement to incorparate three servings of dairy into their meal-plan, alone appeared to suffice to keep the protein intake of the dairy group at a reasonably high level (~72g; which would be 0.96g/kg body weight). The protein intake of the two non-dairy groups, on the other hand dropped to 57g (0.75g/kg) and 54g (0.7g/kg) for the calcium and placebo supplemented groups, respectively.

Figure 2: Changes in body composition and measures of insulin sensitivity after 12-weeks on the high dairy, calcium supplemented or placebo supplemented diets (data calculated based on Smilowitz. 2011)

In view of the facts that the subjects had to stick to the calorically restricted diet for 12 weeks, it should not surprise you that all of them lost a statistically significant amount of body weight (cf. figure 1) and improved their insulin sensitivity (as indicated by reduced insulin levels and HOMA-IR values).What should yet strike your eye are the increased reductions in body fat and waist circumference and the greater increase in lean mass-% in the high dairy group. Now, you will probably assume that this was a result of the higher protein intake, and that may in fact have been the case, as one of my beloved model calculations by which scientists "adjust" their data for whatever they want (usually until the result is in accordance with their hypothesis ;-) revealed that

Dairy product consumption was found to be significantly associated with reduced WC [waist circumference] and %BF [percent body fat], however, these relationships were no longer significant after adjustment [my emphasis ;-] for protein and energy intake and physical activity.

Figure 3: Scatterplot of the partial correlations between reported 12-week mean dietary fat intake expressed as % of total energy and changes in lean body mass (LM) and body fat % (taken directly from Smilowitz. 2011)

Assuming that this "adjustment" yielded valid results it is all the more interesting what a subsequent analysis of the "adjusted" data revealed:

When expressed as a percent of total energy, dietary fat composition was correlated with changes in anthropometrics. Reported MUFA at 12 wk was inversely and positively associated with changes in % LM and % BF, respectively.

Or, in the words of the layman: The greater the relative monounsaturated fatty acid (MUFA) content of the subjects' diets, the more lean mass was lost and the more body fat was retained during the study period (cf. figure 3). Similarly, a higher intake of polyunsaturated fatty acids (PUFA) was associated with lower reductions in waist circumference, and while  the scientists claim that the n3:n6 ratio did not matter, it should make you wonder if it could actually be coincidental that the n6:n3 ratio in the dairy group was 6.6, while the ones in the calcium and placebo groups were 8.7 and 7.9, respectively.

And what about saturated fats? 

Moreover, the USDA scientists mention only "in the small print" that most fundamental (and statistically significant) distinguishing feature of the dairy group, who unquestionably had more favorable weight loss results despite an overall greater caloric intake, was (and I am quoting this from the paper) "a significantly higher intake of SFA [saturated fats] and lower intakes of MUFA and PUFA compared with the calcium supplement and placebo groups". Now, guess where this "bad" saturated fat came from? Well, probably from full-fat dairy! And guess why those "good" MUFAs and PUFAs were missing from the diets of the high dairy group. Well, probably because the subjects ate less "healthy vegetable oils"... ah, and did I already mention that the dairy group also ingested disproportionally (relative to their caloric intake) higher amounts of biotin, vitamin B12, vitamin D and - God forbid! - cholesterol?

Image 2: Even if you like animals, eating their eggs and full-fat dairy products won't hurt them.

So, while the scientists do their best to conceal that all those "bad things", like a high protein intake and nutrient dense real non-processed animal products with their original (saturated) fat, cholesterol and micronutrient content left untouched, are the true driving forces of successful weight loss (and, you bet, also maintenance), I am quite confident that you, as a diligent student of the SuppVersity, would not have needed the doctored... ah, pardon me, ... I obviously meant the well-adjusted results of this study to know that. After all, you are probably just enjoying a rib-eye steak with some delicious melted butter from grass-fed cows, right?

Fat Loss Principles That Work: 10g+ of EAAs W/ Every Meal. Do Energetic Costs of Protein Synthesis Trigger This Effect?

EAAs beyond whey: It may not necessarily look like this, but this salad (repicecorner) is an EAA power horse with cheddar cheese (25% protein, 0.49 EAA / P ratio), tuna (in oil, 29%,  0.45) and kidney beans (9%, 0.45). You see, it does not always have to be chicken breasts or whey to get beyond the 10g+ EAA threshold, I have repeatedly suggested as one of the fundamental rules of dieting for weight loss, maintenance and muscle gain.

Many people take it for granted that you become fat, when you get old. If you look at the statistics, you could even make a point that obesity has some protective effects with esp. with respect to CVD mortality. Scientists call this the "obesity paradox" (Kastorini. 2012). What's particularly paradox, at least in my humble opinion, is yet not the phenomenon itself, but rather the fact that it gets smart scientists derailed from working on useful dietary and exercise interventions to prevent the development of heart disease, cancer, metabolic syndrome etc. in early years. Instead, they argue ex-post, i.e. when the baby has already been thrown out with the bathtub by comparing sick lean (in parts even cachectic) and sick "obese" people, why their statistical shenanigan that's based on the useless BMI produces paradoxical results. And that, when studies such as the one Jacobs et al. did in 2010 clearly show that 50+ year old men and women with waist circumference >120cm and >110cm, respectively, have 2x higher all-cause mortality risk than their lean peers - irrespective of BMI (Jacobs. 2010)!

To get lean and stay lean, yet not thin and skinny fat is therefore a challenge everyone...

... from the child in the Kindergarten to the obese granny in the nursing home is facing. Against that background a previous study by Loenneke et al. comes to mind. The results of their analysis, which were published in Nutrition and Metabolism in January 2012 clearly show that the amount of times people eat meals with a 10g+ EAA content per day was inversely related to percent central abdominal fat (Loenneke. 2012). In previous studies EAAs have also been shown to improve glucose clearance without increases in insulin and in the absence of effects on the fat burnin and health promoting expresion of AMPK-alpha2 in skeletal muscle tissue (see "EAAs Stimulate Muscle Glucose Uptake by Exponentiating Insulin's Effect on GLUT4 Expression"). With the advanced publication of a study by Coker, Miller, Schutzler, Deutz and Wolfe in the online verison of the Nutrition Journal a couple of days ago, the notion that EAAs have a particularly beneficial effect on fat loss - in this case in obese elderly individuals - gets further support from a well-controlled randomized trial (Cooker. 2012).

EAA-rich protein increases fat loss to a greater extent than low EAA protein

The researchers from the Center for Translational Research in Aging and Longevity and the University of Arkansas for Medical Sciences in Little Rock, AR, USA randomized 12 elderly individuals (mean age 69 years) to an 8 week, caloric restriction diet utilizing equivalent caloric meal replacements (~850 kcal/day; the exact nutrient composition can be found in figure 1) + ~400kcal from solid foods (total intake: ~1,250kcal/day; the subjects were free to chose their solid meals but were provided with a list of examples the should pick from, if possible).

Figure 1: Macronutrient composition of the meal replacements used in the study (Cooker. 2012)

The diet was designed to induce a 7% weight loss in two months. And while both,  the rate of weight loss (~1.6lbs per week), as well as the relatively high caloric deficit are certainly appropriate for someone with a 30+ BMI and ~40% body fat, leaner people will fare better with a less pronounced kcal deficit or (alternatively) have to add some strategically planned refeeds to the equation in order to minimize the loss of lean mass and, more importantly, avoid the ensuing reduction in energy expenditure (for the obese, the latter is actually less of the problem, because the downsides of being calorically deprived are at least partly counglucose tolerance and leptin sensitivity with every gram of body can actually help the body recognize that there is still plenty of energy that has just not been available (glucose) or "visible" (fat) before).

Figure 2: Changes in lean and fat mass (kg, left) and fractional protein synthesis rates (FSR) in participants receiving iso-caloric meal replacements with identical macronutrient compositions (see figure 1), but different amounts of essential amino acids (EAAs) content (Coker. 2012)

As the data in figure 2 goes to show you even the obese individuals in the study at hand lost a non-negligible amount of lean mass - unfortunately the body composition was measure with a sophisticated, but still body impedance based device, the trends are still accurate, but it is questionable in how much we are actually talking about ~2 and 2.5kg of muscle mass (figure 2, left), because somebody's "lean body mass" does obviously include more than just skeletal muscle.

When it comes to supplements, we are often like children on Christmas eve. About all the new stuff we get we tend to forget our former favorite and often way more fun to play with toys. Don't make this mistake and ditch your PWO whey (personally, I like a ~1.5:1 whey + micellar casein mixture) for EAAs, they don't come close... read more

Be that as it may - since the before and after values were taken with the same device the changes should be correct, so that both the slightly yet not statistically significantly ameliorated loss of lean body mass and, more importantly, the significantly higher degree of body fat loss in the EAA meal replacement (EAAMR) group speak in favor of the 5 servings of a the 170 kcal, 6g EAA per day. Moreover, "the sparing influence of muscle loss might have been demonstrated with a larger sample size", so that you can take it for granted that the preservation of precious muscle mass is an advantage of being choosy with your protein sources and preferring those with higher over those with lower essential amino acid contents.

On a related note: I don't know if you noticed, but with a total energy content of 850kcal and 30g EAA these 5 meal replacements did in fact have exactly those 10g+ of essential amino acids, I have repeatedly recommended to have with each of the 3 meals most people consume in the course of the day.

In all fairness, it should also be mentioned that despite not being significantly different at baseline, the body fat percentage of the subjects in the EAA meal replacement group was ~3% higher to begin with.This may seem irrelevant, since figure 2 compares lean mass and fat mass as absolute changes and not their percentages, but in the end, the amount of fat you you can drop within a given time-frame decreases with lower body fat percentages.

Do the energetic costs of protein synthesis drive fat loss?

Another interesting observation Coker et al. made is the close association between fat loss, on the one hand, and increased protein synthesis (55%), on the other hand. The researchers take this as an incentive to do one of the of the much loved calories in vs. calories out calculation and come up with the following hypothesis:

"Acute administration of EAAMR did promote a significant increase in skeletal muscle protein FSR compared to CMR. Assuming that the energy cost of protein synthesis is 3.6 kJ/g and the baseline GAIA-derived lean tissue mass was 56.4 kg for EAAMR and 54.4 kg for the CMR, we can extrapolate that the overall energy discrepancy between the two groups was roughly equivalent to 27,170 kcal or 3.5 kg of weight loss across the entire caloric restriction-based weight loss paradigm. Based on the amount of total lean mass in each group, this value takes into account a consistent intervention structure of five servings/day across an eight week period. In short, these calculations suggest that differences in the source of intact protein/formulation of EAA may have a significant influence on diet-induced energy expenditure that coincides closely with the greater reduction of adipose tissue in EAAMR compared to CMR." (my emphasis in Coker. 2012)

I usually discard fallacious calculations like this one if they are not highlight the stupidity of trying to eat exactly as much as some funky formula + the figure on your treadmill, pedometer, heart rate monitor or whatever fancy tool you may use to "measure" your energy expenditure suggest you would have burned in the last 24h. In this case, however, I made an exception, because I feel that the notion that protein quality is one of the myriad of parameters that are missing from this foolish calculation is important, for lean and obese people from all age groups who are trying to shed body fat.

Bottom line: The take away message of the study is in the end identical to the previously mentioned study by Loenneke et al.: Make sure you hit the 10g EAA threshold with each and every of your meals, if being lean and muscular not skinny yet fat is your goal.

References:

• Coker RH, Miller S, Schutlzer S, Deutz N, Wolfe RR. Whey protein and essential amino acids promote the reduction of adipose tissue and increased muscle protein synthesis during caloric restriction-induced weight loss in elderly, obese individuals. Nutr J. 2012 Dec 11;11(1):105. [Epub ahead of print]
• Jacobs EJ, Newton CC, Wang Y, Patel AV, McCullough ML, Campbell PT, Thun MJ, Gapstur SM. Waist circumference and all-cause mortality in a large US cohort. Arch Intern Med. 2010 Aug 9;170(15):1293-301.
• Kastorini CM, Panagiotakos DB. The obesity paradox: methodological considerations based on epidemiological and clinical evidence--new insights. Maturitas. 2012 Jul;72(3):220-4.
• Loenneke JP, Wilson JM, Manninen AH, Wray ME, Barnes JT, Pujol TJ. Quality protein intake is inversely related with abdominal fat. Nutr Metab (Lond). 2012 Jan 27;9(1):5.

Chromium Picolinate Worsens Insulin Sensitivity in Healthy, Non-Diabetic, Non-Obese Individuals by Up to 25%

The more supplements you take the more likely you are to get way more than the 200mcg of chromium of which previous studies have shown that they are useless for healthy people, but at least not detrimental (cf. Lukaski 1996 & 2007; Vincent. 2007). Especially people who like the  'poly-supplementary' approach are yet at risk of getting so much of a this trace mineral that it will hamper not improve their insulin sensitivity.

I don't have to tell you that you would already be dead if you were following all the bro-scientific advice that's out there on the Internet and still I usually recognize a certain reluctance to give up on what X suggests and Y has tried an what has worked so well for Z. One of the instances, where I have hitherto been missing a 100% convincing argument to argue that this is just another instance where common wisdom would in fact be better called "common stupidity" is the "insulin mimetic" or "insulin sensitizer" (or whatever your favorite bro-expert may call it) chromium picolinate. With the recent publication of the result of a study on the effects of chromium supplementation in healthy individuals there is now finally a human study that confirms that chromium, which has never been an "insulin sensitizer", but rather an "insulin release amplifier" that reduced blood glucose in diabetics by simply having them produce even more insulin is not a supplement any healthy man or woman, let alone athlete should consider a staple of his or her regimen.

The long and short: Chromium hampers insulin sensitivity in normoglycemic individuals

For their experiment lead author Umesh Masharani and his colleagues from the UCSA recruited a group of 27 non-obese, non-diabetic, healthy subjects between the ages of 20 and 50 with a body mass index of less than 27 kg/m² and <24 kg/m² for subjects with Asian heritage (the cut-off limits were set so that they would be below a BMI that has not yet been shown to be an independent risk factor for insulin resistance; cf. Clausen. 1996; Newell-Morris. 1998).

To evaluate whether chromium picolinate (ChrPic) supplements, which contributed with $150,000,000 to the revenue of the supplement industry in 1996 (Nielsen. 1996), could come up to the claims that they would exert beneficial effects on glucose tolerance and insulin sensitivity, the study participants were randomized to take either a placebo or a high dose 500µg CrPic supplement twice daily for 4 months (the dosage was selected in view of previews studies reporting greater benefits of 1,000 vs. 200mcg of CrPic in - you already guessed it - diabetic subjects; cf. Morris. 2000).

Figure 1: Insulin sensitivity measured by euglycemic clamp before and after the 16 week intervention (left); change in insulin sensitivity of the individual subjects plotted against serum chromium levels at the end of the study (Masharani. 2012)

As the data in figure 1 goes to show, the results of the CrPic intervention were more or less the exact opposite of what the ~10 million US consumers of respective supplements probably expect from the pills many of them are taking almost religiously. Despite the fact that all subjects had very low chromium levels at the beginning of the study, the previously non-significant minimally benificial relation between both serum and urinary chromium, on the one hand, and insulin sensitivity (r = 0.24, p=0.1; r=0.08, p=0.79 respectively), on the other hand, had turned into a very significant negative correlation between high(er) urinary and serum chromium concentrations and lower insulin sensitivity at the end of the 16 week intervention period (figure 1, right).

"Due to the apparent variation in the degree of chromium absorption between subjects, we examined the relationship between serum chromium and change in insulin resistance. After controlling for baseline patient characteristics, results of a multiple regression analysis showed a strong association between serum chromium and worsening of insulin–mediated glucose disposal (β= -0.83, p<0.01), where subjects with the highest serum chromium had a decline in their insulin sensitivity. To further explore the association between chromium absorption and insulin resistance, patients within the chromium group were divided (based on  a medial split at 3.10 µg/L) into a high (n=6) and low (n=8) serum chromium group [...] There were no group differences at baseline; however, at post-assessment participants in the high serum chromium group (> 3.1  µg/L) were more insulin resistant than participants in the low serum chromium group (≤3.1  µg/L) or the placebo group (p=0.02, p=0.05 respectively) (Figure 3)." (my emphases in Masharani. 2012)

Due to the fact that the scientists did not observe any differences between the placebo and low serum  chromium groups (on a side note, contrary to many other studies insulin Masharani et al. measured the insulin sensitivity in a very reliable way with an euglycemic hyperinsulinemic clamp; cf. Defronzo. 1979), the scientists also conducted a post-hoc analysis to identify potential confounding factors that may have influenced the outcome of the trial. Neither changes in triglycerides levels LDL, BMI, or truncal fat were yet associated with the differences they observed between the supplemented and non-supplemented participants. Interactions that would reduce the significance of the observed correlations were likewise absent:

"Furthermore, when changes in triglycerides, LDL, BMI, and truncal fat were individually added to the model, none were independent significant predictors of change in insulin sensitivity, and chromium absorption remained a significant predictor of reduced insulin sensitivity in each model." (Masharani. 2012)

Against that background the scientists conclude that there must be a "direct effect of chromium on changes in insulin action". A mechanism, by the way, which is totally independent of classic markers of insulin resistance such as high serum lipids and abdominal / truncal adiposity .

Being healthy is a good predictor of increased chromium absorption and more pronounced negative effects, so if you are healthy and want to stay this way don't even think of taking high dose chromium supplements.

Despite the fact that the changes in insulin resistance did not depend on changes in serum lipids and other markers of metabolic health, Masharani and his colleagues were able to show that the increase in chromium levels in response to supplementation did. With the already mentioned statistically significant correlation between increases in serum chromium levels (higher response to supplementation = higher increase), on the one hand, and the worsening of insulin sensitivity, on the other hand, this means that the healthiest subjects, namely ...

"[...] subjects with lower triglycerides, and those with lower levels of homocysteine [who had] a greater likelihood of being in the high absorption group" (Masharani. 2012)

... were at the same time those who were at the greatest risk of the ill side-effects high dose chromium supplements exert on the insulin tolerance of healthy, non-diabetic, normal-weight individuals.

No matter if it may have helped you produce insulin back in your obese days, once you have accomplished this you better avoid high dose or multiple (hidden) sources of supplemental chromium like a plague - unless you can't afford new jeans, of course ;-)

Bottom line: Unless you are not a type II diabetic or feel the urgent desire to become one, you better steer clear of exuberant amounts of supplemental chromium the RDA is enough. This is particularly true, if you are already taking a multi (which is almost guaranteed to have 200mcg in it), or any BB-style supplements. After all, "broscience" wants it that chromium is in everything that's even remotely related to insulin / nutrient uptake or whatever. With the use of only one of these products and 200mcg of supplemental dietary chromium per day, you may still argue that it probably won't do much harm. When you add another 200mcg from your "nutrient partitioner" on top of the 200mcg you get from your multi and the 200mcg of which you probably did not even realize yet that they are part of your pre-workout supplement, however, you can hardly complain about simply not being able to tolerate carbohydrates - I mean, what's your body supposed to do if you are dumb enough to believe in the promises of fat loss and lean mass increases that have been debunked in the late 1990s, already (cf. Lukaski 1996 & 2007; Vincent. 2007), and simply chose to ignore the latest scientific evidence that chromium picolinate supplements are not just useless, but actually detrimental to your health?


References:

• Clausen JO, Borch-Johnsen K, Ibsen H, Bergman RN, Hougaard P, Winther K, Pedersen O. Insulin sensitivity index, acute insulin response, and glucose effectiveness in a population-based sample of 380 young healthy Caucasians. Analysis of  the impact of gender, body fat, physical fitness, and life-style factors.  J Clin Invest. 1996;  98(5):1195– 1209.
• Defronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979; 237:E214–E223. 
• Lukaski HC, Bolonchuk WW, Siders WA, Milne DB. Chromium supplementation and resistance training: effects on body composition, strength, and trace element status of men. Am J Clin Nutr. 1996 Jun;63(6):954-65.
• Lukaski HC, Siders WA, Penland JG.  Chromium picolinate supplementation in women: effects on body weight, composition, and iron status. Nutrition. 2007; 23(3):187– 195.
• Masharani U, Gjerde C, McCoy S, Maddux BA, Hessler D, Goldfine ID, Youngren JF. Chromium supplementation in non-obese non-diabetic subjects is associated with a decline in insulin sensitivity. BMC Endocr Disord. 2012 Nov 30;12(1):31.
• Morris BW, Kouta S, Robinson R, MacNeil S, Heller S. Chromium supplementation improves insulin resistance in patients with Type 2 diabetes mellitus.  DiabetMed. 2000; 17(9):684–685.
• Newell-Morris LL, Treder RP, Shuman WP, Fujimoto WY. Fatness, fat distribution, and glucose tolerance in second-generation Japanese-American (Nisei) men. Am J Clin Nutr. 1989; 50(1):9–18.
• Nielsen FH. Controversial Chromium: Does the superstar minearal of the mountebanks receive appropriate attention from clinicians and nutritionists?  Nutr Today. 1996; 31(6):226–233.
• Vincent JB: The nutritional biochemistry of chromium (III). Amsterdam, Boston: Elsevier. 2007.

Docosahexaenoic Acid (DHA) Blunts Negative Side Effects of Conjugated Linoleic Acid (CLA) W/out Hampering Its Effects on Body Fat Loss & the Expression of Obesity Genes

She already knew what scientists have recently discovered and now confirmed: You better stack CLA and DHA if you want lean and health offspring ;-)

Conjugated linoleic acid (CLA) is not only an omega-6 fatty acid, it's also a trans-fat (though a natural one) and still even scientists believe that it could contribute to the solution of the diabesity epidemic, if it (a) finally yielded the same extreme fat loss (yep, just the blubber, nothing else) results in human beings as in rodents (cf. "CLA Annihilates Body Fat and Increases Endurance") and (b) anywhere near appropriate doses would not hold he risk of inducing fatty liver disease and insulin resistance (Clément. 2002). At least with respect to (b) a "bodybuilding approach" to CLA supplementation which is based on the "if hammering your head against the wall hurts, you better make sure you wear a helmet" principle of stacking CLA and PUFAs, esp. the long-chain omega-3 fatty acid DHA, has already yielded some promising results in a study that has been published earlier this year (Fedor. 2012a).

Since, the deposition of fat in the liver in response to CLA supplementation is in the end only the logical consequence of CLA's lipolytic (=fat releasing) and anti-lipogenic (=inhibition of fat storage) effects in the adipose tissue, the absence of adequate data on the amount of fat in adipose tissue and muscle or the fatty acid composition of liver, adipose tissue, and muscle, nor did we monitor the changes in the expression of genes involved in fatty acid metabolism in adipose tissue and muscle in the respective study did not allow for the conclusion that the co-supplementation of DHA would not blunt the beneficial fat loss effects of CLA, as well.

Is it possible that high dose DHA blunts the negative and the positive effects of CLA?

In a paper that's going to be published in the next issue of Metabolic Syndrome And Related Disorders Dawn M. Fedor et al. describe the results of a follow up study, which dealt with this very question and I guess I am not giving away more than what you will already inferred from the headline of this post, when I tell you that the answer to the question in the subheading is "No, DHA does not blunt the beneficial effects of conjugated linoleic acid on adipose tissue!"

Figure 1: Relative body weight, liver weight, periuterine fat mass, muscle weigh, liver total lipid weight, adipose total lipid weight, and muscle total lipid content of the mice after 4 weeks on a 0.5% CLA, 0.5% CLA + 1.5% DHA or 1.5% DHA diets expressed relative to respective data from mice on the standard chow (Fedor. 2012b)

If you take a closer look at the data in figure 1 you will realize that the provision of a diet that contained 0.5% CLA (only the "active", but potentially hazardous t10, c12 isomer was used in the study) and 1.5% DHA did not blunt the beneficial effects on total and periuterine body fat mass in eight-week-old, pathogen-free female C57BL/6N mice. On the other hand, it did mitigate the negative effects on liver weight and (and this is actually quite remarkable) had identical beneficial effects on liver fat as the DHA only diet.

DHA + CLA = perfect synergists

Although the "equation" above may sound as if I had taken it right from one of those shiny adds in a muscle mags, it does in fact look, as if the combination of CLA + DHA was the silver bullet for healthy body fat (and I repeat only body fat not lean mass!) reductions in the absence of any dietary and/or exercise interventions.

Figure 2: Expression of selected genes involved in the synthesis, storage and release of fatty acids from the adipose tissue; the respective values (in a.u.) of the control group were all 100, so you can thing of these as percentages, as well (Fedor. 2012)

Moreover, the analyses of the expression of pro- and anti-obesity genes in the adipose tissue does actually support this claim:

"CLA significantly decreased the expression of LXRb, PGC1a, PPARg, SREBP1C, ACOX1, and CD36 adipose mRNA when compared to the control group. We also observed a trend for CLA to decrease the expression of HSL (P=0.08). DHA was not able to prevent any of these decreases in gene expression. CLA significantly increased UCP2 mRNA expression when compared to control group; DHA again had no effect." (Fedor. 2012b)

If we translate all these acronyms the scientists use to describe the data I've plotted for you in figure 2 into plain cause and effect relations, we could simply state: CLA induced changes in the expression of genes in the adipose tissue of the rodents that would prevent the maturation of adipocytes and the synthesis and accumulation of fatty acids, while increasing their release into circulation,  and DHA did not effect these changes.

DHA takes care of the energy that's released / not stored in fat cells

What the co-administration of DHA did, however, was to prevent the deposition of the energy that was released, respectively not even stored in the adipocytes in the liver -- and it did that so effectively that the overall weight of the liver of the mice in the CLA + DHA group was not greater than the the liver weight of the rodents in the control group.

Figure 3: Liver fatty acid composition (µmol/g) and omega-3 : omega-6 ratio after 4 weeks on regular (control), 0.5% CLA, 0.5% CLA + 1.5% DHA and 1.5% DHA diets (Fedor. 2012b)

In fact, the co-administration of conjugated linoleic acid and DHA did even reduce the total fatty acid content of the liver (not to a statistically significant degree, though) and brought about profound changes in its fatty acid content - most prominently, a whopping +975% increase in the omega-3 : omega-6 ratio (see small graph in figure 3) that were even slightly more pronounced in the CLA + DHA group than in the DHA only group (you do remember that CLA is an omega-6 trans-fat, right?).

Finally a stack that works -- but will it work in humans, as well? 

I don't know if it dawned on you, already, but dairy and butter from grass cows already has both CLA and DHA in it - what a lucky coincidence, isn't it? Still, there is one downside: You simply cannot eat enough of it to get anywhere close to the human equivalents of the amounts that are used in rodent studies.

Now, although both the changes in body fat levels in the CLA + DHA group were consistent with those observed in the CLA only group and the effects of the combination treatment on the changes in hepatic fatty acid composition were consistent with those observed in the DHA only group, there is still one question we have to answer: Are we going to see similar esults in humans?

To be honest, I still cannot answer this question, but if you take into consideration that no previous human trial used dosages in the 20-30g range simply because that would be unethical given the associated side effects, we may soon get an answer to this question - as soon as scientists dare to slowly escalate the dosage, trusting on the ability of supplemental DHA to blunt the negative, while conserving the beneficial effects of CLA.


References:

• Clément L, Poirier H, Niot I, Bocher V, Guerre-Millo M, Krief S, Staels B, Besnard P. Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse. J Lipid Res. 2002 Sep;43(9):1400-9.
• Fedor DM, Adkins Y, Mackey BE, et al. Docosahexaenoic Acid prevents trans-10, cis-12-conjugated linoleic Acid-induced nonalcoholic Fatty liver disease in mice by altering expression of hepatic genes regulating fatty acid synthesis and oxidation.Metab Syndr Relat Disord. 2012a;10:175–180
• Fedor DM, Adkins Y, Newman JW, Mackey BE, Kelley DS. The Effect of Docosahexaenoic Acid on t10, c12-Conjugated Linoleic Acid-Induced Changes in Fatty Acid Composition of Mouse Liver, Adipose, and Muscle. Metab Syndr Relat Disord. 2012b Nov 21.

Reduced Exertion High Intensity Training - A Minimalist 2x20s HIIT Protocol For The Male Convenience Generation.

Image 1: Looks like humans are not the only lazy creatures, in these days of unhealthy convenience.

Laziness, it seems, is utterly human. If you look around, these days, it appears as if we were genetically programmed to be bone idle. And, from an evolutionary perspective, we may actually be. After all, moving around, hunting and gathering was an obligatory part of our lives in 99% of the human history. It was thus only consistent that our genes would tell us to sit down at the fireplace and relax, once we had found enough to eat on a given day... (un-)fortunately things have changed since those early days. Not only have we moved out of our caves, we have also found ways to radically reverse the ratio of activity to inactivity in our lives.

"Convenience" is the buzzword of the modern western civilization and the obesity epidemic is its unwanted consequence.

A consequence, which is yet by no means inevitable. After all, we all know that getting our behinds off our couches and into the gym, and setting the dietary recommendations of the (fast-)food industry, ahh... pardon, the government at naught would solve the problem, if ... yeah, if there was not this aforementioned genetically programmed laziness that makes the couch so much more appealing to us than the hard benches in the gym...

Sacrifice 30min per week of your TV-time and live to see your grandchildren graduate

A recent study from scientists from the United Kingdom does yet show that you could still spend more than enough time in front of your beloved television set, if you just performed what what Richard S. Metcalfe and his colleagues from the United Kingdom call the "minimal amount of exercise for improving metabolic health" (Metcalfe. 2011) - a 3x per week 10min exercise regimen with no more than two (yes, only 2x!) all-out sprints.

Figure 1: Outline of the training protocol, the black bars indicate all-out sprints at a breaking force equivalent to 7.5% of the individuals body weight (directly adapted from Metcalfe. 2011. Fig. 1)

As you can see in the outline of the experimental protocol, the 29 healthy and normal-weight, but sedentary young (~23y) men (n=13) and women (n=16) did not even have to start with 2x20s sprints. They rather built up to it, by starting out with a single 10s all-out cycle-ergometer sprint at a braking force equivalent to 7.5% of their body weight in the first week of the 6-week study period and built their exercise capacity from there.

Image 2: "Cardio" does not have to be steady state.

Note: If you have not read my previous blogposts on HIIT, you may have missed the information that interval training (not necessarily at the maximal intensity, though) is suitable for everyone - even heart disease patients (cf. Interval, not Steady State Aerobics is the Way to Go - Even for Patients with Myocardial Infarctions!). This has been confirmed only recently by Neil A. Smart et al. who found that "[i]ntermittent exercise may improve functional capacity [of congestive heart failure patients] to a greater extent than continuous exercise" (Smart. 2011) - and that despite the fact that both continuous (30min), as well as interval training (60min, 1 min cycling, 1 min rest) were performed at the same low intensity.

The rest of the 10-min exercise sessions, the subjects were pedaling along at 60W, which is about as much as it takes so that you do not fall off the bike, because of the lack of resistance that is required to stabilize yourself on the bike. The latter would have been tragic, at least if you are a man, because that would have counteracted the surprisingly (not for who has read about the magic of HIIT here at the SuppVersity before) profound effects this regimen, for which the scientists coined the name "reduced exertion high intensity training" (REHIT), had on the glucose homeostasis of the male subjects.

Figure 2: Changes in VO2Max, glucose and insulin area under the cure in response to oral glucose tolerance test in men and women after 6 week of "reduced exertion high intensity training" (data calculated based on Metcalfe. 2011)

As the data in figure 2 shows, the statistically more than significant decreases in the area under the glucose (-12%) and insulin (-39%) curve (AUC) measured during an oral glucose tolerance test was exclusive to the 13 male participants - and that despite the fact that both, male as well as female study participants exhibited similar improvements in their individual VO2Max (+15% in men; +12% in women).

(RE)HIIT only for men?

As far as the underlying reasons for these gender differences are concerned, the scientists are pretty much at a loss, stating that this could be due to "the low statistical power of our study, with only eight female subjects performing the REHIT", " differences in metabolic perturbations during the brief high-intensity cycle sprints",  and the 3-day delay after the last HIIT session before the glucose tolerance test was done (as a SuppVersity reader you will be familiar with the notion that the "anabolic barn door" is wide open for 24-48h), so that "insulin sensitivity was improved in female subjects at an earlier time-point". Now, I do not want to sound like a himbo, but I would say that another observation the scientists made, provides a much better explanation:

[...] we observed that some of the female volunteers struggled with the transition from 60 W to the all-out sprints, and were unable to substantially increase their pedal frequency, and thus their power output during the sprints. This may have increased the aerobic contribution to energy supply and reduced glycogen depletion.

In other words, what was supposed to be a sprint turned out to be a sluggish ordeal. The slightly, but statistically significantly higher rates of perceived exertion (+10%) in the female study participants corroborates the assumption that the women simply did not burn enough glycogen. If we do now also consider the results of a 2008 study by Hagobia et al. who report that

[...] in women, exercise altered energy-regulating hormones in a direction expected to stimulate energy intake, regardless of energy status. In men, the response to exercise was abolished when energy balance was maintained.

It appears obvious that an increase in pedaling frequency by adapting the resistance to the individual fitness levels and dietary controls may be necessary to render this minimalist "REHIT" protocol productive for the fairer sex.

Figure 2: Comparison of changes in VO2Max, glucose and insulin area under the cure in response to oral glucose tolerance test subsequent to 6 weeks of REHIT, or 10 months of "classic cardio" exercise, or dietary intervention (data calculated based on Metcalfe. 2011 and Dengel. 1996)

The comparison of this 6 week exercise program with the results of a 10 months intervention program in likewise healthy sedentary, but older men (45y) who exercised 3x a week for 40min (steady state) at 75-85% of their maximal heart rate, goes to show that it would well be worth making the REHIT protocol work for women, as well (Dengel. 1996). After all, the steady state endurance protocol in the Dengel study was not only four times more time-consuming (plus, the intervention period was 6.6x longer) than the modified HIIT protocol in the Metcalfe study, it also failed to improve the glucose response to the oral glucose tolerance test and produced less pronounced improvements in insulin sensitivity (cf. insulin AUC in figure 3). The mild caloric reduction (-300-500kcal/day) that was imposed on another group of the study participants, on the other hand, yielded similar reductions in glucose and insulin AUCs as the REHIT protocol in the Metcalfe study that was accompanied by a body weight reduction of ~10%, a reduction in body-fat of -5.8% and essentially no loss in fat free mass!

Note: Unfortunately, Metcalfe et al. did not measure the body composition of the study participants. In view of the results of the Whyte study (Whyte. 2010), I cited in the Intermittent Thoughts on Healthy Weight Loss, where the participants lost -2.4cm of their allegedly obese bellies within no more than 2 weeks of doing HIIT, as well as the well-established correlation between insulin resistance and the size of your beer-belly, it is very well possible that the male participants in the Metcalfe study will have lost some body fat doing no more than 8.67 minutes of all out cycling spread across 18 training sessions in 6 weeks... and if they didn't their diet probably was still too convenient ;-)

The (in-)convenient truth about your future

Taken together the results of these studies suggest that a) steady state aerobic exercise is pretty pointless, b) even a minimalist HIIT regimen goes a long way, as long as c) you really hit it hard and d) adhere to your regular (hopefully non-convenient) diet, or even better e) introduce a slight calorie deficit. In other words, without at least some "inconveniences" as far as nutrition and exercise are concerned, chances are that YOU will either remain or become one of the 34,004,946 obese human beings that are now populating a planet where the US alone spend 1,550,566$ per day on the detrimental health consequences of the"convenience" of its citizens (data from Obesity Statistics).

The Counterintuitive Catabolic & Pro-Diabetic Effects of Leucine Supplementation in Rodents on Corticosteroids

Not the mice from this study, but still a nice example of the effects of dexamethasone on skeletal muscle (right; Quin. 2012)

"Leucine-laced water + stress = insulin resistance" - This simple equation is the net result of a recent study by Nelo Eidy Zanchi and his colleagues from the Laboratory of Applied Nutrition and Metabolism at the School of Physical Education and Sports of the University of Sao Paulo in Brazil. Inspired by previous research which clearly indicated that leucine does not only have pro-anabolic, but also insulin sensitizing effects, Zanchi et al. speculated that the provision of adequate amounts of leucine would blunt the catabolic and pro-diabetic effects of 7 days of intraperitoneally injections of  dexamethasone, an artificial corticosteroid that's used to treat all sorts of inflammatory diseases.

Remember SuppVersity Rule of Smart Supplementation No. 2? Right. Specificity!

In order to test their hypothesis that leucine supplementation either in low doses in the drinking water or as higher dosed oral gavage would ameliorate the negative side effects of DEXA treatment, the scientists randomized groups of 10 male Wistar rats to six groups receiving either low dose or high dose leucine supplements with and without dexmethasone.

"During  the duration of the experiment, which lasted  seven  days,  DEXA (a synthetic glucocorticoid analogue that does not bind to plasma binding proteins) was given daily (at 9:00 a.m.) through intraperitoneal injection (5 mg/kg/day); control groups received  an equivalent volume of saline (0.9% NaCl). As DEXA was reported to decrease food intake, all groups were  fed the same amount of food (in terms of caloric intake) equal to the DEX group. Thus, differences among groups did not originate from different food intakes. We measured the caloric content of our standard chow (16.32 kJ/g) as well as leucine (25 kJ/g) in a calorimetric bomb (FTT Oxygen Bomb Calorimeter) in  order to avoid differences in the caloric ingestion between experimental groups and observed that the total caloric consumption was not statistically different among groups." (Zanchi. 2012)

The leucine was administered either in dosages of 0.068g/kg body weight per day (low dose) or 1.35 g/kg per day (high-dose) twice daily at 8:00  a.m. and  2:00  p.m. through gavage over seven days. And while the scientists had selected the high dose (LH) "to induce a maximal increase in muscle protein synthesis and insulin plasmatic levels", the dosage in the LL (=low leucine) group was too low to increase either muscle protein synthesis or plasma insulin levels. The third, non-supplemented control group received an NaCl (sodium) placebo, the volume of which was identical to the supplement to make sure that any possible volume-induced effects of oral gavage that could for example be induced by gastric expansion would not skew the study results.

"But leucine has been shown to be anabolic! So it must help."

Aside from the usual basal fasting glucose, insulin, tryacilglycerol (TAG) and HOMA-IR values, the scientists did also assess the motor performance of the animals by the means of two standardized strength and ambulation tests (Kennel. 1996; Anderson. 2004; Viera. 2008).

Figure 1: Effect of 7 days of low (LL) and high (LH) dose leucine supplementation with and with out dexamethasone on total body mass, soleus (slow twitch) and EDL (fast twitch) muscle mass in male Wistar rats (left; values expressed relative to non-supplemented control) and corresponding changes in mean ambulation and grip strength (right; Zanchi. 2012)

As you can see in figure 1 the supplemental leucine failed to reduce the negative side effects of dexamethasone. As far as the total body weight and the fast-twitch muscle mass (EDL) are concerned, you could even argue that the high dose treatment (DEX-LH) did even amplify the catabolic effects of the synthetic corticosteroid:

"Thus, leucine supplementation at both low and high doses did not counteract body weight loss in both food restricted (control groups) and DEXA-treated animals. Soleus muscle mass did not differ among groups. Leucine supplementation at  high doses  attenuated food  restriction-induced EDL muscle loss (CON-LH group) when compared with the CON-NS group  (p < 0.05). All DEXA-treated animals presented reduced EDL muscle mass when compared with the CON-NS group (p < 0.05), and leucine supplementation at both low and high doses of amino acid did not attenuate it." (Zanchi. 2012)

Now, you may well argue that the mere fact that the muscle weight was "statistically significant" reduced, this does not mean that these reductions would be physiologically significant and that the minimal differences between the DEX groups would not matter, anyway. If you just go by the data on the left side of figure 1, this is certainly right, if you do yet also consider the significant reductions in muscle function (figure 1, right) and the fact that all that happened within no more than 7 days, the overall result should actually remind you of the "Three Simple Rules of Smart Supplementation" - and here specifically the 2nd one: Specificity!

Figure 2: Time course of the dexamethasone-induced detoriations in fed serum glucose levels and ameliorative effect of low and high dose leucine supplementation (left) and effects of the treatment on fasting insulin levels and HOMA-IR (index of insulin resistance) at the end of the study (Zanchi. 2012)

In fact, the data in figure 2 only confirms the notion that things that you cannot define "good and bad", "black and white" and "beneficial or detrimental" without a context and the outcome you are expecting. If you are trying to keep the postprandial blood sugar in check, for example he addition of an effective (high dose) of leucine to the diet would appear to be a good idea. If, on the other hand, you are more concerned about insulin resistance, you would be better advised to use minimal amounts of leucine or simply refrain from supplementation altogether.

Figure 3: If the ingestion of bolus amounts of leucine is not helpful, lacing the water of the rodents DEXA treated rodents with leucine turned them into full-blown diabetics (Zanchi. 2012)

As these results clearly demonstrate the provision of additional leucine is not useful to counter the negative side-effects of synthetic corticosteroids. On the contrary, the negative effects on insulin resistance are apparently even augmented and the muscle function is further compromised by the purpotedly anabolic high dose leucine supplement.

And while the overall effects of the bolus administration may still be negligible, the scientists ingenious idea that the provision of similar amounts of leucine in the drinking water in a second follow-up experiment turned out to be "capable of inducing a massive diabetic state" (Zanchi. 2012; see figure 3 for the ensuing surge in fasting blood glucose levels) while decreasing the mass of the fast-twich EDL muscles even further.

Bottom line: Overall these results only confirm the simple, but often neglected truth that inductive reasoning is a futile undertaking in the realms of exercise and nutrition sciences: What is good for an athlete is rarely optimal for an obese person, the same diet that helps the obese lose weight, will make the athlete feel miserable, and lacing the drinking water of rodents on corticosteroids with the exact same amount of leucine that has had highly beneficial effects on the insulin sensitivity of diabetic rodents in previous studies (Guo. 2010) will not only fail to ameliorate the glucocorticoid-induced detoriations in blood glucose, it will even exasperate them.

So, does that mean you should not take your whey protein or BCAAs any longer? No, if you did that you would make the exact same mistake as someone who laces his water with leucine in order to avoid the catabolic effects of the synthetic corticosteroid he is taking for medical reasons. On the other hand, the results of the study at hand should make you re-evaluate the necessity and even benefits of guzzling BCAAs all-day long, at least if the reason for doing so is that you believe that you are so stressed that you would otherwise fall into a catabolic black hole.

That said, there may even be implications for the average pre-diabetic inhabitant of the Western hemisphere who is eating his hamburger and French fries on the parking lot of the local fast food restaurant, because he cannot make room to prepare and consume a real meal somewhere in his busy and stressful schedule. I mean, despite the fact that the aforementioned specificity principle does not allow for anything but a still to be verified hypothesis, it does at least appear not to far-fetched that this chronic endogenous stress, despite being very different from the "stress" that's induced by the administration of a synthetic corticosteroid that does not bind to serum proteins, could have similar negative modulatory effects on the purported benefits of chronic leucine supplementation ... but as I've said before, this would be something to investigate in another study. So unless you are actually taking dexamethasone for medical reasons, you are probably not at risk of developing diabetes due to a high amount of leucine in your diet.

In the unfortunate case that you are actually on synthetic corticosteroids, a previous study by the same group of scientists, in the same rodent model does suggests that three workouts with three sets of squats (10 reps each) per week may offer the protection against corticosteroid induced muscle loss decreased skeletal muscle GLUT-4 expression and insulin resistance, leucine does not have to offer.... well, at least as long as you abstain from leucine supplementation, because the latter had the exact same detrimental effects in the 2011 study where it was administered to one of the experimental groups in conjunction with resistance training as it had in these more recent experiments in the absence of any type of workout (Nicastro. 2011). 

References:

• Anderson,  K.D.; Abdul, M.; Steward, O. Quantitative assessment of deficits and recovery of
  forelimb motor function after cervical spinal cord injury in mice.  Exp. Neurol.  2004,  190,
  184–191.
• Kennel,  P.F.; Fonteneau, P.; Martin, E.;  Schmidt,  J.M.; Azzouz, M.; Borg, J.; Guenet,  J.L.;
  Schmalbruch, H.; Warter, J.M.; Poindron, P. Electromyographical and motor performance studies
  in the pmn mouse model of neurodegenerative disease. Neurobiol. Dis. 1996, 3, 137–147.
• Nicastro H, Zanchi NE, da Luz CR, de Moraes WM, Ramona P, de Siqueira Filho MA, Chaves DF, Medeiros A, Brum PC, Dardevet D, Lancha AH Jr. Effects of leucine supplementation and resistance exercise on dexamethasone-induced muscle atrophy and insulin resistance in rats. Nutrition. 2012 Apr;28(4):465-71. Epub 2011 Nov 12.
• Qin J, Du R, Yang YQ, Zhang HQ, Li Q, Liu L, Guan H, Hou J, An XR. Dexamethasone-induced skeletal muscle atrophy was associated with upregulation of myostatin promoter activity. Res Vet Sci. 2012 Aug 29.
• Vieira, N.M.; Bueno,  C.R., Jr.; Brandalise, V.; Moraes,  L.V.; Zucconi, E.; Secco, M.; Suzuki, M.F.; Camargo, M.M.; Bartolini, P.; Brum, P.C.; Vainzof, M.; Zatz, M. SJL dystrophic mice express a significant amount of human muscle proteins following systemic delivery of human adipose-derived stromal cells without immunosuppression.  Stem Cells  2008,  26, 2391–2398.  
• Zanchi NE, Guimarães-Ferreira L, de Siqueira-Filho MA, Felitti V, Nicastro H, Bueno C, Jr, Lira FS, Naimo MA, Campos-Ferraz P, Nunes MT, Seelaender M, de Oliveira Carvalho CR, Blachier F, Lancha AH, Jr. Dose and Latency Effects of Leucine Supplementation in Modulating Glucose Homeostasis: Opposite Effects in Healthy and Glucocorticoid-Induced Insulin-Resistance States. Nutrients. 2012; 4(12):1851-1867.

Sleep to Grow, Train to Sleep: How Strength and Endurance Training Effect Your Sleep Patterns & Exercise Performance and May Help or Hinder Fat Loss & Muscle Gains

Image 1: As a toddler you already knew - "Sleep is the most anabolic agent there is"; Sleep - Train - Eat, repeat! Remember that ;-)

If you like Dave Palumbo's Heavy Muscle Radio, you will probably have heard an advertisement that (a few other questionable statements aside) contains a real gem of wisdom: "Sleep is the most anabolic agent there is!" But how come? Well, if you remember the comments I made on the way your muscles grow by both, increasing mononuclear domain sizes (protein synthesis) and the accumulation of new myonuclei, you will probably also remember that, next to estrogen, nitric oxide and a handful of other factors, growth hormone, in general, and the IGF-1 (and MGF-1) that is locally released in response to its secretion, are the primary drivers of satellite cell driven muscle hypertrophy (and possibly hyperplasia)... now, guess when your body produces the lion share of growth hormone (and downstream IGF-1?) in a given day?

You got it, in those cosy (hopefully) ~8 hours you are snorkeling away in between your sheets (Cauter. 1998) - it is in these hours, that your GH levels spike at 600% of their daytime average and your cortisol levels plummet into the abyss. As studies show, this is yet not the only thing on which you are missing out if you do not get your share of quality sleep day in, day out: Even short-term (let alone chronic) sleep deprivation has been shown to significantly increase rates of perceived exertion in athletes and - and this may be even more detrimental - decrease insulin sensitivity and glucose tolerance (VanHelder. 1989). So that after nights and nights of low-quality or insufficient sleep, your secret weapon against tiredness, your pre-workout high-carb-get-me-going shake will no longer get you going in the gym, but rather out of the gym and right to your doctor to ask him for a script for some Metformin to get your blood sugar levels back to normal.

Assuming that I now got your full attention, I want to share the results of two very recent studies with you. One on the differential effect of strength and endurance training in the morning (10am) on sleep quality and duration in 15 healthy trained men (Roveda. 2011) and a second one on the beneficial effects even a single session of resistance training (at 60%RM) has on the sleep pattern of 22 65-85 year old men (Viana. 2011).

Always remember: Sleep is the most anabolic agent there is

One thing upfront: A reasonable amount of physical activity will - regardless of your age and fitness level - make it easier to fall asleep, lengthen the time you spent in bed actually sleeping and not tossing and turning, and contribute to an overall improvement in sleep quality.

Figure 1: Relative changes (compared to baseline) in assumed and actual sleep on day 1 and day 2 after a 10am strength (bench press 4x80RM + 10 min warm up)or endurance training (10min warm-up, 30min 80%VO2max, 10min cool-down) session in 15 healthy young men (data calculated based on Roveda. 2011).

As figure 1 goes to show there was a distinct effect of both strength and endurance training on the time spend in bed (assumed sleep) and the actual sleep time on the first day after the physical activity. In that, it is particularly noteworthy that the actual sleep time increased by +8% and +12.5% and thusly ~2% more than the time the subjects spent in bed. This increase in sleep quality is something we also see in the older subjects of the Viana study, whose REM latency, i.e. the time it took them to enter into the valuable rapid eye movement phase of their sleep, decreased by a whopping -48%, on days on which they had performed their 3 sets of 12 reps (60%RM) of chest presses, leg presses, vertical tractions, leg curls, biceps curls, abdominal crunches, arm extension, and lower back exercises.

Figure 2: Relative changes in sleep efficiency and sleep latency on day 1 and day 2 after a 10am strength or endurance training session in 15 healthy young men (data calculated based on Roveda. 2011).

Now, while we see a "rebound" effect (a decrease in sleep time) in the 2nd night after the morning exercise in the young subjects (comparative data were not collected in the Viana study), the increase in sleep efficiacy, i.e. the amount of time the young men spent in bed vs. the amount of time they actually sleep persisted (cf. figure 2)! And the sleep latency, i.e. the time it took the subjects to fall asleep was still significantly reduced on day 2 after the respective physical activities.

Although there probably is no doubt that physical activity may benefit sleep quality and sleep quality in turn may benefit not only the performance during the former, but also its effects on your metabolic health and body composition (cf. image 1), it is still a matter of constant debate how much, is too much - after all, both forms of overtraining, the sympathetic form, which puts you into a chronic fight and flight mode and will wreak havoc on both your sleep quality and its duration (usually associated with higher intensity training than the bench pressing session 10min warm-up + 4x80%RM the Rovenda subjects performed) and the parasympathetic form, which is what people usually refer as "burnout syndrome" and will have you sleep hours after hours waking totally unrefreshed, produce quite distinct, yet of many athletes carelessly overlooked sleeping patterns, which - and here lies the culprit, still appear to be one of the best, yet by far not "objective" measures of whether you are "hitting your sweet spot" or are just digging a deep black hole by keep pushing and pushing, when your batteries have long run out of energy (Urhausen. 2002)... but this, my friends is a topic for another blog post ;-)