Leucine Supplementation Exemplifies Potential Downsides of Non-Specific Insulin Sensitizers on a Hypercaloric Diet / Bulk

Adelfo's latest progress pics speak for themselves. Maybe that consoles you for the missing update!?

Another Thursday and ... no post from your's truly Adelfo Cerame. In fact, Adelfo shot me an email earlier today, that he won't be able to submit a blogpost this week if he wanted to get some sleep this night (remember we are living in different time zones) And while this was in fact a problem for me, since I am pretty pressed on time, today and did actually allocate the time I usually spend writing these blogposts, I agreed to cover his a** and step into the breach (so please ignore the surplus of typos, mistakes an missing words, please ;-). I mean, what could I say? We all know about the importance of sleep to bring in your best physique possible and I don't want to be the one who could be blamed in the very unlikely case that he won't finally take away his pro-card on his upcoming competition in March, right?

SuppVersity Science Round-Up Sneak Peak

Apropos sleep, I guess sleep is going to be one of the topics Carl and I are going to talk about on today's SuppVersity Science Round-Up (check out all previous installments and the respective Seconds, here), other topics I've got on my list here, are the Aspartame causes cancer study that resurfaced as of late on the pertinent "science websites" as if it had been released yesterday, and a couple of other news, e.g.

• The thrifty phenotype - Is it an effect of "healthy calorie restriction" during gestation?
• Fish protein & glucose metabolism - More evidence that a little can go a long way
• Eat more fruits & vegetables! - Why "more" is not specific enough
• Vitamin D - Convincing evidence that the obesity connection is a one-way street
• BPA and prostate cancer - Changes in aromatase and 5α-reductase increase malignancy
• Night shift & breast cancer - Meta analysis finds 30%+ increased risk

Even if you are not interested in any of these (btw. there will be more on obesity & healthy eating than the first two ;-), you should know by now that there are usually side-tracks, follow up an "on the other hands" that often lead the discussion into a completely new direction. So make sure you don't forget to tune in live - 1PM (EST) on the Super Human Radio Network. As usual, a podcast and the Seconds with everything that did not make it into the show will be available tomorrow.

Chronic leucine supplementation + hypercaloric diet = ???

The subheading actually summarizes pretty well, what the scientists from the School of Public Health at the Huazhong University of Science and Technology, the Department of Nutrition at the University of North Carolina at Chapel Hill and one colleague from the Hubei University of Medicine in the People's Republic of China wanted to find out, when they bought a group of male Sprague-Dawley rats, and kept them in eight groups of 10 animals for 24 weeks on one of the following dietary regimen

normal chow diet (3.78 kcal/g)	hypercaloric "high fat"(54%) diet  (5.20 kcal/g)
+ 0%, 1.5%, 3.0% or 4.5% leucine	+ 0%, 1.5%, 3.0% or 4.5% leucine

The animals had free access to food and water. The body weight and average food intake were recorded once a week. And if you take a peek at the graph on the left hand side of figure 1 it does not take a rocket scientists to recognize that any effects the supplementation may have had was "negligible" at best, with higher weight gain in the high leucine (3% an 4.5%) and minimally lower weight gain in the medium leucine supplementation group (1.5%) for the normal diet and higher weight gain for all leucine supplemented diets in the HFD group (1.5% > 3.0% > 4.5%)

Figure 1: Body weight development (remember the food intake was identical) and perirenal fat depot weight at the end of the study (Lee. 2013)

In view of what leucine is hailed for in the fitness and bodybuilding community, the explanation should be obvious: "Of course are those glutenous rodents simply gaining more muscles." The anabolic prowess of leucine makes it possible. They are ..." I am not going to repeat the superlatives with which the supplement industry is going head over heels to explain why they have just ramped up their BCAA product from a 2:1:1 to a  5:1:1 and from there to whatever ratio, as you will by now already have realize that what the rodents gained was not mere muscle, but a significant amount of body fat. So much in fact that the total boy weight to fat ratio was skewed (in other words, the body fat % increased):

[T]he perirenal white adipose tissue was −1.20% of the total body weight in animals on ND [nromal diet]. HFD alone increased the perirenal fat to 1.62% (p<0.05). Chronic supplementation of leucine (1.5 and 3.0%) increased the percentage of the perirenal white adipose tissue to 2.01–2.03% in animals on HFD (p<0.05). [...] These results show that chronic supplementation of leucine increases the ratio of white fat over total body weight in rats on HFD." (Li. 2013)

Interestingly, this increase in adiposity went hand in hand with a decrease in the expression of TNF-alpha and various inflammatory cytokines in the adipose tissue of the rodents. The picture of leucine that emerges here is therefore one of a "healthy growth factor". unfortunately one that obviously does not make a difference between muscle and fat tissue.

Leucine as a non-selective growth promoter and insulin sensitizer

Whether the decrease in inflammatory cytokines is the chicken or the egg here cannot be said for sure. What is pretty certain though is that the combination of decreased inflammation → increased adipose tissue insulin sensitivity → increase energy uptake by the fat tissue may lead to a healthier, but certainly not smaller adipose organ and does thus go against what the usual muscle head would be looking for, when he or she buys a product that claims to provide lean mass gains.

Figure 3: HOMA-IR and Area Under the Curve (AUC) of the glucose response in a glucose challenge (Lee. 2013)

In fact, the data in figure 2 hints at a classic dilemma I have alluded to in various contexts before. Many of the purported insulin mimetics or insulin sensitizers are non-tissue specific, which means that the increase in insulin sensitivity happens in the adipose tissue as well. This allows for lower blood glucose levels, but only because the energy can be stashed away in the fat cells. For a diabetic that probably does not matter much, as his or her first concern would be to get the blood glucose levels back in check. If that happens at the cost of yet another midriff bulge that may be unaesthetic, but better than the progression from type II to type III diabetes aka Alzheimer's or the advent of other side effects of chronically elevated blood glucose levels.

Figure 3: Plasma insulin response to the ingestion of 0.7g/kg CHO, 0.7g/kg CHO + 0.3g/kg WPH, and the former with additional 0.1g/kg leucine in type II diabetics and healthy controls (Manders. 2006)

What's more from previous human trials in type II diabetics, we already know that the addition of leucine to a whey protein hydrolysate does not augment its beneficial effects on postprandial glucose clearance. While statistically non-significant, the data from a 2006 study by Manders et al. rather suggests that it has a negative effect on the benefits of the 0.3g/kg whey protein hydrolysateof which the scientists were able to show that it reduced the plasma glucose response by 15% (vs. only 12% with 0.3g/kg whey + 0.1g/kg leucine; cf. Manders. 2006). Moreover, this was no diabetes specific "problem". In fact, the unnecessary insulin overshoot from the added leucine was even more pronounced in the healthy controls of the Manders study (see data in figure 3).

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Bottom line: You could in fact argue that leucine works much like the diabetes drug rosiglitazone. While the underlying mechanism it totally different, the outcome is very similar. Both increase the insulin sensitivity by reducing adipose tissue inflammation and allowing for greater energy storage in the fat tissue. Good or bad thing? Well, I guess for the majority of SuppVersity readers of whom I hope that they are not type II diabetics an only battling with one or another unaesthetic, but totally healthy pound of body fat, this is bad news.

Even if it was not for the non-specific and potentially obesogenic insulin sensitizing effects of leucine, the increased protein anabolic response to whey hydrosolate compared to free form amino acids is another thing that speaks against the use of leucine or other free-form amino acis in isolation. After all, you would be missing out on the anabolic effects of the peptides in whole proteins (read more).

When you are dieting and there is no energy surplus to stored, you don't have to bother. When you are bulking, on the other hand, and trying to do yourself a favor by adding some "highly anabolic" leucine to each and every meal, you better watch out what it is you are "building" here - is it going to be the intended lean mass or is it going to be a pot belly? I obviously don't have an answer to that question, but in view of the fact that previous trials with "leucine only" supplementation (Balage. 2010) and the provision of leucine as part of an already leucine rich protein shake (Koopman. 2008) did fail to produce superior gains, it's actually not worth trying.

If you also take into consideration the latest SuppVersity post on the non-insulin dependent increase in skeletal-muscle glucose uptake from isoleucine, the #3 in the original branch-chain amino acid concert (leucine, valine, isoleucine; read more), you better keep away from bulk supplies of l-leucine and "superior high leucine BCAA powders" and stick to the tried and proven.

References:

• Balage M, Dardevet D. Long-term effects of leucine supplementation on body composition. Curr Opin Clin Nutr Metab Care. 2010 May;13(3):265-70.
• Koopman R, Verdijk LB, Beelen M, Gorselink M, Kruseman AN, Wagenmakers AJ, Kuipers H, van Loon LJ. Co-ingestion of leucine with protein does not further augment post-exercise muscle protein synthesis rates in elderly men. Br J Nutr. 2008 Mar;99(3):571-80. Epub 2007 Aug 13.
• Li X, Wang X, Liu R, Ma Y, Guo H, Hao L, Yao P, Liu L, Sun X, He K, Cao W, Yang X. Chronic leucine supplementation increases body weight and insulin sensitivity in rats on high-fat diet likely by promoting insulin signaling in insulin-target tissues. Mol Nutr Food Res. 2013 Feb 13.
• Manders RJ, Koopman R, Sluijsmans WE, van den Berg R, Verbeek K, Saris WH, Wagenmakers AJ, van Loon LJ. Co-ingestion of a protein hydrolysate with or without additional leucine effectively reduces postprandial blood glucose excursions in Type 2 diabetic men. J Nutr. 2006 May;136(5):1294-9.