PLUS, BREAKING NEWS!

L-NORVALINE CAN BE TOXIC TO THE BRAIN!

By Steve Blechman

A most recent study published in the journal Metabolife (January 14, 2019) found a strong association between branched-chain amino acids (BCAAs) and the risk of incidents for type 2 diabetes in China. The branched-chain amino acid valine had the highest risk prediction of incidents of type 2 diabetes! These findings could aid in diabetes risk assessment in the Chinese and global population!

There’s an overwhelming amount of evidence over the years that elevated branched-chain amino acids are associated with obesity and insulin resistance. A most recent meta-analysis study (Acta Diabetologica, November 9, 2018) found that oral BCAA elevates circulating dietary BCAA intake and were positively and inversely related to type 2 diabetes, mellitus and overweight/obesity risk respectively! The researchers said, “Eight articles on randomized clinical trials of oral BCAA supplementation and seven articles on dietary BCAA intake and type 2 diabetes/obesity risks were eligible for inclusion in our meta-analysis.”

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 showed decreased blood glucose levels, indicating that there was improved insulin function (Metabolism, 2014). It was reported in the journal Nature Medicine in 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 and Health website on 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 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 her 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.”

In a most recent study in the journal Nutrients (January 5 2019, Nutrients) valine intake in 12 healthy lean men was not shown to be effective on weight loss, satiety or blood glucose levels. Unlike valine, leucine has been shown to improve blood glucose levels and insulin function.

Leucine consumption alone has been shown to rescue insulin-signaling deficiency (PLoS, 2011). A recent study (Exp Clin Endocrinol Diabetes, 2018) 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,” the study authors noted.

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 life span 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). Research has shown that leucine amplifies the effect of the diabetic drug metformin on insulin sensitivity and glycemic control in diet-induced obesity. Adding leucine to metformin has been shown to be synergistic, enabling a 65% to 80% metformin reduction with no loss of diabetic efficacy and a 40% metformin dose reduction in a recent clinical trial (Diabetes, June 12, 2016; Metabolism 2016 and Alimentary Pharmacology & Therapeutics, 2018). Metformin has been approved by the FDA for over 25 years as an anti-diabetic drug and has recently been reviewed as a possible FDA-approved anti-aging drug. Recent research has also shown that metformin can lower elevated valine levels in diabetics. 

“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) is the probable cause!

It is my recommendation to take leucine by itself. The research shows that leucine is a powerful anabolic trigger and enhances protein synthesis and can promote muscle growth and recovery. Also, leucine supplementation can improve mitochondrial biogenesis and function, increase insulin sensitivity and may also enhance fat loss and improve lean body mass.

BREAKING NEWS!

L-NORVALINE CAN BE TOXIC TO THE BRAIN!

A recent report by ScienceDaily released on February 7, 2019 shows that the L-norvaline, used in many bodybuilding pre-workout supplements as a nitric oxide activator, could be bad for the brain! A study performed by the University of Technology in Sydney, Australia shows that L-norvaline may be linked to neurodegenerative diseases. Norvaline is an analog of the amino acid L-valine. Don’t confuse norvaline with the amino acid L-valine. L-valine is an essential amino acid; norvaline is not.

One of the researchers, Kate Samardzic, spoke to ScienceDaily about the April 2019 article that appears in the journal Toxicology in Vitro.

"Some non-protein amino acids are toxic because they can mimic protein amino acids and deceive the body into making faulty proteins; a property used by some plants to kill predators.

"Some plants can even release non-protein amino acids into the soil to kill other plants so that they can have access to all the nutrients. Chemical warfare among plants is a well-known phenomenon. Since there was evidence that L-norvaline has antimicrobial and herbicidal activity we examined its toxicity in human cells," Samardzic said.

ScienceDaily also reported, “This is the first study that investigates the toxicity of L-norvaline in human cells, specifically testing its effect on the health of brain cells arising from its ability to mimic protein amino acids.”

Associate Professor Ken Rodgers, who led the research, said the study revealed that L-norvaline, while it might initially allow cells to produce more energy, after a while the machinery of the cell that generates the energy is damaged. “People are taking supplements such as this without really knowing much about what the long-term consequences might be,” Rodgers said.

The amino acid L-norvaline may cause damage to brain cells by reducing cell viability and induced necrotic cell death, increase mitochondrial fragmentation and bioenergetic dysfunction. Stick with proven safe and effective nitric oxide activators such as citrulline, citrulline malate, beetroot, grapeskin polyphenols and folic acid.

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