Sunday, February 26, 2017

BCAAs Mess W/ Vegan Glucose Management, Human Study Says - Do You Have to Stay Away From BCAAs, Now?

Are vegan athletes who supplement their low BCAA baseline diet with amino acid powders making an unhealthy mistake? At first sight a recent study from Poland suggests just that. Upon closer scrutiny, however, the practical relevance of the results appear less and less convincing.
It seems (and I have to admit that I fell for that logic, too) only logical that vegans, unlike omnivores and lactovegetarians run the risk of not getting enough BCAAs from their diet. After all, their diets allow the neither the consumption of dairy nor many of the other wonderful high BCAA protein sources.

Against that background, I would venture the guess that many vegan athletes spike their diets with copious amounts of the ubiquitous BCAA supplements, supplement vendors all around the globe are pushing on unsuspecting customers who have no clue that a new study claims that these supplements may ruin one of the often-heard benefits of vegan diets: improved glucose management and reduced diabetes risk (eg. -62% in Tonstad et al. 2013).
You can learn more about BCAAs & other amino acids at the SuppVersity

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Based on the observation that BCAAs will reduce the glucose clearance rates in healthy human beings, in some (Tremblay 2005 | glucose uptake ↓ by 33%; Robinson 2015 | glucose uptake ↓ by 40% and 23% at low and high insulin levels, respectively), but not all (Everman 2015) pertinent studies and in view of the fact that
Bad news for BCAA-junkies | more
"[d]ata on the effect of a chronic supplementation with BCAA in humans are still limited making it impossible to clarify whether increased dietary BCAA themselves are sufficient to trigger IR-related diseases or whether the perturbations in BCAA levels only reflect an already developed insulin resistant state [here, the authors refer to the observation that people with metabolic syndrome have, across the board, significantly elevated BCAA levels in the blood]" (Gojda. 2017)
the authors speculated that supplementing healthy subjects with 20g of BCAAs (female subjects received only 15g to make up for their lower body weight) and comparing the results of vegan (=low BCAA intake) and omnivore (=high BCAA intake) subjects would yield valuable insights into the 'true' effects of BCAAs on human glucose metabolism.
Don't rejoice too early, omnivores: If you're an omnivore you may still be concerned about the literally 'depressing' effects of BCAAs - a supplement of which most research shows that it is useless if you have a high intake of quality protein, anyway.
Now, while I cannot tell in how far a single 12-week study can do that, i.e. contribute valuable insights into the 'true' effects of BCAAs on human glucose metabolism, I can tell you that the results Gojda et al. present in the European Journal of Clinical Nutrition will make at least the vegans in the SuppVersity audience sit up and question their use of BCAA supplements... at least for as long as they didn't read the rest of the article ;-)
Figure 1: At first sight, the changes in the subjects' basal glucose levels and their ability to clear glucose during the hyperinsulinemic euglycemic clamp test clearly suggest that 20g/15g/day BCAAs are bad for vegans (Gojda 2017).
It stands out of question, a -28% decrease in glucose clearance during the scientists' two-hour hyperinsulinemic euglycemic clamp test is quite a significant negative effect (the effect size, here, is d = 0.99; anything >0.8 is considered a "large" effect size). Before you freak out, however, it must be said that the metabolic rate of glucose clearance per unit of insulin, which is what I would consider a much better measure of insulin sensitivity, was decreased by a statistically highly non-significant, practically (check out the standard deviation in Figure 2) irrelevant 3%, only (addendum: I calculated the effect size, which is d = 0.08 and would thus confirm the lack of practical relevance of this finding, after all, anything < 0.2 is already considered a "small" effect size - 0.08 is thus quasi no effect).
Figure 2: Unlike the absolute glucose infusion rates during the hyperinsulinemic euglycemic clamp, the rates per unit of insulin were not affected by 3 months on 20/15g of BCAAs per day (Gojda 2017).
Nevertheless, the scientists are still confident to conclude that "[a] chronic increase in BCAA intake led to a decrease of IS only in vegans" (Gojda 2017) - and that despite the fact that they did not observe the typical increases in serum BCAAs seen in obese / metabolically diseased subjects during the supplementation period (only the levels of leucine increased from the 20g of BCAAs that contained leucine, valine, and isoleucine at a ratio of 4:1:1) and admit that previous studies in metabolically deranged people show "an improvement of glucose uptake after a long term high-BCAA protein supplementation" (Gojda 2017).

Obviously, the last mentioned real-world (i.e. meals vs. insulin clamp + glucose infusion as in the study at hand) effects may obviously be a mere result of an increased release of insulin in the otherwise insulin resistant subjects when they were fed cod and whey protein, the "high-BCAA protein sources" in Ouellet, et al. (2007) and Jakubowicz, et al. (2013), the two studies Godja et al. are referring to in the previously cited statement. With nothing but eventually elusive evidence from a single lab test with conditions that hardly resemble our everyday dietary glucose exposure, I would still be hesitant to jump on the 'BCAAs mess with your glucose metabolism'-train - and that's despite the fact that I have been very critical in previous articles about BCAA supplementation.
What's the message for the omnivores? There are two things omnivores should take away from the study: (a) the increased clearance of glu-cose in the hyperinsulinemic euglycemic clamp test the scientists observed in the omnivores is as misleading as the decrease in the vegan subjects, because it was likewise not complemented by an increased rate of glucose disposal per unit of insulin; and the former was (b) probably a mere result of an increased production of insulin (+63% in the omnivore subjects of the study at hand; p < 0.05) and thus the insulinotropic effect of BCAAs that has been pre-viously observed in both, healthy and (pre-)diabetic subjects, whose glucose levels improve with the consumption of high BCAA proteins merely due to an increase in insulin production. In conjunction with the hitherto not discussed omnivore-exclusive increase in the ex-pression of lipogenic genes FASN and DGAT-2, as well as corresponding increases in two additional lipogenic genes, PPARγ and SCD-1, the increased insulinemia with extra BCAAs in omnivores is in fact the only substantially 'bad news' of a study that, initially, appears to hold bad news only for vegans.
So what's the verdict, then? The practical significance of the study at hand is much lower than headlines like "BCAAs mess with vegans' glucose metabolism" would suggest - and that's despite its relatively long intervention period and the inclusion of a follow-up.

So why is it too early to freak out? Well, for one, the scientists "conclusion that BCAA could have a direct negative impact on IS in healthy humans" is based on a test the practical relevance of which remains questionable: the hyperinsulinemic euglycemic clamp test has little to nothing to do with the metabolic response to a complex meal; and even if we accept its results as reliable indicators of real-world changes in glucose sensitivity, there's still the lack of changes in the metabolic clearance rates for glucose on a per unit of insulin base. And while the scientists address the non-significance of this data in the limitations section of their paper, where they declare that the "statistical power of our study to show differences of MCR/I after the intervention was therefore only 7%", that doesn't explain that the MCR/I dropped by only 3% and thus 50% of the standard deviation.

Furthermore, the scientists did not observe the 'classic' changes in BCAA metabolism gene expression that have been observed in the previously hinted at studies that link a high serum BCAA level to insulin resistance (Newgard 2012). And it's not just genes that are involved in BCAA metabolism that didn't change in the vegans: the same goes for all other genes the scientists tested, as well.

No effect on MCR/I, no effect on the expression of metabolically relevant genes (including insulin receptor and glucose transporter expression), this leaves us with the 4% increase in serum glucose of which even a layman can see that it's very unlikely a result of the BCAA supplementation... if it was, the glucose level should not increase by another 8% after the three months supplementation period, should it? No, it shouldn't and you shouldn't freak out if you read elsewhere that "a recent study shows that BCAAs decrease your insulin sensitivity" | Comment!
  • Everman, Sarah, et al. "Effects of acute exposure to increased plasma branched-chain amino acid concentrations on insulin-mediated plasma glucose turnover in healthy young subjects." PloS one 10.3 (2015): e0120049.
  • Gojda, J., et al. "Chronic dietary exposure to branched chain amino acids impairs glucose disposal in vegans but not in omnivores." European Journal of Clinical Nutrition (2017).
  • Jakubowicz, Daniela, et al. "Incretin, insulinotropic and glucose-lowering effects of whey protein pre-load in type 2 diabetes: a randomised clinical trial." Diabetologia 57.9 (2014): 1807-1811.
  • Newgard, Christopher B. "Interplay between lipids and branched-chain amino acids in development of insulin resistance." Cell metabolism 15.5 (2012): 606-614.
  • Robinson, Matthew M., et al. "High insulin combined with essential amino acids stimulates skeletal muscle mitochondrial protein synthesis while decreasing insulin sensitivity in healthy humans." The Journal of Clinical Endocrinology & Metabolism 99.12 (2014): E2574-E2583.
  • Tonstad, S., et al. "Vegetarian diets and incidence of diabetes in the Adventist Health Study-2." Nutrition, Metabolism and Cardiovascular Diseases 23.4 (2013): 292-299.
  • Tremblay, Frédéric, et al. "Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability." Diabetes 54.9 (2005): 2674-2684.
  • Ouellet, Véronique, et al. "Dietary cod protein improves insulin sensitivity in insulin-resistant men and women." Diabetes Care 30.11 (2007): 2816-2821.