HIGH BRANCHED-CHAIN AMINO ACIDS (BCAAs)- LINKED TO OBESITY AND DIABETES. Beware Valine the Villain!
By Steve Blechman
There’s an overwhelming amount of evidence over the years that elevated branched-chain amino acids are associated with obesity and insulin resistance. A study in the Journal of Physiology (February 2018) suggests that a diet low in BCAAs may help weight loss and prevent the metabolic problems that occur in diabetes and obesity. “We’ve identified an unanticipated role for dietary BCAAs in the regulation of energy balance, and we show that a diet with low levels of BCAAs promotes leanness and good control of blood sugar,” according to an article in Nutraingredients-USA.com, dated December 21, 2017.
“…branched-chain amino acids, or BCAA, had been identified in 2009 as a robust marker of obesity and insulin resistance in humans by Duke researchers led by Christopher Newgard, the director of the Duke Molecular Physiology Institute,” according to ScienceDaily on May 17, 2018 and most recently published, in addition to findings by Duke University researchers in Cell Metabolism also on May 17, 2018. “The association between BCAA and insulin resistance had been present in the literature dating back to a 1969 study that appeared in the New England Journal of Medicine. And they have since been shown to be highly predictive of future diabetes development by the landmark Framingham Heart study.”
“This helps to explain how and why BCAAs are associated with disordered fat metabolism that can lead to type 2 diabetes,” said Newgard, who has worked on BCAA in metabolic disease for more than a decade.
Two large human population studies showed an association of estimated dietary BCAA intake with T2D risk (Int J Epidemiol, 2016; Br J Nutr 2017). Other studies have reported that high BCAA intake along with a high animal protein diet contributes to the development of insulin resistance and interfering with the intracellular insulin signaling pathway (Cell Metab 2009; 9: 311-26; Diabetes 2005; 54: 2674-84). In a most recent study published in the prestigious journal The Lancet Public Health (August, 2018), Harvard researchers found that when individuals exchanged carbohydrates for animal protein such as beef, lamb, pork or chicken – their mortality risk increased. When carbs were exchanged for plant-based proteins, from sources including vegetables, nuts and whole grains, mortality risks decreased. This study was a meta-analysis of eight cohort studies that included more than 400,000 participants from 20 countries. The authors of the study said, “There are several possible explanations for our main findings. Low carbohydrate diets have tended to result in lower intake of vegetables, fruits, and grains and increased intakes of protein from animal sources as observed in the ARIC cohort, which has been associated with higher mortality. It is likely that different amounts of bioactive dietary components in low carbohydrate versus balanced diets, such as branched-chain amino acids, fatty acids, fibre, phytochemicals, haem iron, and vitamins and minerals are involved.”
Because of the concern of BCAAs and their potential effect in diabetes, a governmental clinical trial has been underway entitled, The Effects of Branched Chain-Amino Acids in Glucose Tolerance Obese Pre-Diabetic Subjects (BCAA) (February 12, 2018, US Nat Libr of Med ClinicalTrials, gov Identifier: NCT02684565). The mechanisms underlining the role of dietary BCAAs on the risk of insulin resistance are not fully understood.
Research has shown that elevated levels of valine are present in the blood of diabetic rats, mice and humans. (Nat Rev Endocrinol, 2014) When the mice were fed a diet without valine insulin sensitivity improved after only one day. Mice on the valine-free diet lasting an entire week decreased in blood glucose levels, indicating that there was improved insulin function. (Metabolism, 2014) It was reported in the journal Nature Medicine, 2015 that valine catabolite 3-hydroxyisobutyrate (3-HIB) promoted the accumulation of fat within muscle tissue by directly stimulating fatty uptake in the muscle. The intramuscular fat activates certain signaling cascades within the muscle cell that diminish insulin signaling, leading to insulin resistance. This study also found that inhibiting the production of 3-HIB prevented the uptake of fat. Other studies support the negative effect of 3-HIB on insulin signaling with elevated 3-HIB in the muscle of human subjects with diabetes. (J Lipid Res, 1989; Diabetologia, 2015) An article titled Insulin Resistance, And What May Contribute To It by Lila Abassi and published on the American Council on Science & Health website March 14, 2016 reported on “… a study published in Nature Medicine, [that] scientists have discovered that 3-hydroxyisobutyrate (3-HIB), one of the intermediate products in the breakdown of the BCAA valine, plays a role in the transport of fatty acids into skeletal muscle cells, which creates fatty muscles — a contributor to insulin resistance.” Abassi also also states, “Thus far, it has been a relative mystery as to how BCAAs play a role in insulin resistance. Skeletal muscles display resistance to insulin when there is excess fat inside their cells.” In closing of the article, Abassi said, “What the researchers found was that 3-HIB acted as a shuttle in muscle cells, allowing blood vessels in skeletal muscle tissue to move fat into skeletal muscle. The more 3-HIB, the more fat was transported — and conversely, when scientists blocked 3-HIB from being made, there was less uptake of fat into skeletal muscle.”
One of the authors of the study, Dr. Zoltan Arany, said to Abassi: “In this study we showed a new mechanism to explain how 3-HIB, by regulating the transport of fatty acids in and out of muscle, links the breakdown of branched-chained amino acids with fatty acid accumulation, showing how increased amino acid flux can cause diabetes.”
More recent studies have confirmed that the branched-chain amino acid valine metabolite 3-HIB is involved in the pathogenesis of insulin resistance in skeletal muscle and might be involved in insulin resistance in humans (Diabetes, July 2017; EbioMedicine, 2018; J Diab Rsch, 2018). Unlike valine, leucine has been shown to improve insulin function. Leucine consumption alone has been shown to rescue insulin-signaling deficiency (PLoS, 2011). A most recent study (Exp Clin Endocrinol Diabetes, 2018) has found that oral administration of leucine improved endothelial function in healthy individuals when infused with glucose. Acute hyperglycemia impairs endothelial function in healthy individuals. This study found that leucine administration prevented hyperglycemia-mediated endothelial function. Unlike leucine, which avoids insulin resistance by increasing mitochondrial-driven fat loss, valine does not encourage mitochondrial biogenesis. “Impaired mitochondrial function in skeletal muscle is one of the major predisposing factors to metabolic diseases, such as insulin resistance, type 2 diabetes and cardiovascular disease.” Leucine supplementation increases insulin sensitivity by activating SIRT1 activity. SIRT1 is known to “promote mitochondrial biogenesis and oxidative capacity and prevent the mitochondrial dysfunction in skeletal muscle.” (Journal of Nutrition and Metabolism, 2014) Leucine may also attenuate adiposity and promote weight loss during energy restriction (Nutrition 2006, Diabetes, 2007). These effects are in part by activating the SIRT1-dependent pathway, stimulating mitochondrial biogenesis and increased oxygen consumption (Nutrition Metabolism, 2008). Mitochondrial biogenesis and SIRT1 expression in skeletal muscle has also been shown to increase lifespan in middle-aged mice (Cell Metabolism, 2010). As far as isoleucine is concerned, unlike valine, it has been shown to improve insulin sensitivity by increasing glucose into muscle cells (Am J Physiol Endocrinol Metab, 2007).
Leucine is an essential amino acid that serves as a building block for muscle protein synthesis. Leucine is a powerful anabolic trigger— it’s the most potent branched-chain amino acid (BCAA) and a key activator of the mTOR pathway that is critical for muscle protein synthesis that promotes muscle growth. So, it is likely that consuming leucine after exercise would be more effective (and cheaper) than consuming BCAAs. The addition of isoleucine and valine may hinder the benefits. In the March 2018 issue of the International Journal of Sports Nutrition and Exercise Metabolism, it was reported that men fed 6 grams of whey protein supplemented with leucine, isoleucine and valine observed less protein synthesis than whey protein supplemented with just leucine!
For best results as an anabolic trigger, take 5 grams of leucine (on an empty stomach) 15-30 minutes before a post-workout meal. A meta-analysis (Nutrition, 2017) that combined the results of seven studies showed that BCAA supplements are best taken after exercise, not before, or during exercise (intra-workout).
Leucine, not branched-chain amino acids (BCAAs), is the most important chemical that turns on the mTOR pathway, so it is likely that consuming leucine after exercise would be more effective (and cheaper) than consuming BCAAs. The BCAAs share the same active transport system into cells and muscle cells. Indeed, isoleucine and valine have been shown to inhibit absorption of leucine (Nutrition, 2017; Biochem J, 1966; Int J of Sp Nutr & Exer Metab, 2018).
Robert R. Wolfe, noted amino acid researcher, says in the Journal of the International Society of Sports Nutrition (2017) that “BCAAs also compete with other amino acids for transport, including phenylalanine, and this competition could affect the intramuscular availability of other EAAs. As a result of competition for transporters, it is possible that leucine alone, for example, could have a transitory stimulatory effect on muscle protein synthesis where the BCAAs fail to elicit such response.”
By taking pure leucine on an empty stomach, you will get a better spike in blood levels than if you take leucine with food, because food can slow leucine’s absorption. The addition of isoleucine and valine may hinder the benefits of leucine due to competition for transport into muscle cells. When leucine is taken on an empty stomach, it’s a powerful metabolic switch that turns on protein synthesis. Leucine increases mTOR activity for several hours after training. When leucine is taken after resistance exercise and before a post-workout, protein-containing meal rich in essential amino acids, it triggers greater protein synthesis for improved recovery and greater gains.
In conclusion, “There's growing evidence to suggest that BCAAs isn't just a passive marker of diabetes but may actually play a role in driving the disease,” Gerszten said. “It gives us the motivation to test whether changes in the amino acid intake in our diets would be worth exploring.”
It’s clear based on scientific research that high-circulating BCAAs are associated with obesity and diabetes. The latest available literature has shown that the branched-chain amino acid valine (catabolite 3-HIB) might be the villain!
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