Do BCAAs Cause Cancer and Diabetes?

Do BCAAs Cause Cancer and Diabetes?

For well over a decade, branched-chain amino acid (BCAA) supplements have been the de facto intra-workout and intra-meal supplement of many a gym rat looking to increase performance, stave off catabolism, and boost muscle protein synthesis. High in leucine, valine, and isoleucine, BCAA supplements were, and still remain, a cash cow for the supplement industry, but recently, there’s been an all-out assault on BCAA from multiple fronts.

Bolstered by suspect research and a host of fear-mongering, so-called “gurus” have begun stating that BCAA supplements are “useless” in moderate cases, and in the more extreme circumstances, say that they can cause cancer and diabetes.

Related - BCAAs vs EAAs: Which Are Better?

Let’s take a look at these claims, along with the “evidence” these alleged know-it-alls have put forth, and discuss this idea that BCAAs are the cause of cancer and diabetes.

But first…

Before we get into the weeds of the research (and trust us, it’s going to get heavy), let’s take a moment to make one thing very, very clear.

Correlation does NOT equal causation.

This statement simply means that a correlation between two variables (i.e. BCAA and diabetes) does not imply that one causes the other.

This is a common fault of most epidemiological studies, and it’s led to more than a few things initially being labeled as harmful (i.e. red meat, eggs, dietary fat), yet upon closer inspection were.

As we go forth into the research, put aside your biases, keep an open mind, and view the research for what it actually says, not what you want to believe or what your favorite insta-famous fitness “guru” professes.

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BCAA and Diabetes

One of the more recent claims being bandied about involves the idea BCAA's cause diabetes.

Taking a cursory glance, it’s easy to be misled into thinking that BCAA supplements cause insulin resistance and Type 2 Diabetes due to several studies showing a link between elevated levels of BCAA and insulin resistance/diabetes.

But, remember, correlation does not imply causation.

So, let’s take a look at some of the specifics of what the researchers had to say exactly about the link between BCAA and diabetes/insulin resistance.

The first study we’ll look at comes courtesy of the journal Nutrients. Titled “The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism”, the study delved into the link between high levels of BCAA and type 2 diabetes noting:

“The expression of the genes encoding the enzymes of BCAA metabolism was reduced in muscle and liver tissue of patients with T2DM [80,81]. Similar findings were made in rats [82]. In contrast, liver BCKDH activity is actually increased and could compensate for the decreased activity in adipose tissue [83]. Therefore, the resulting plasma BCAA levels are either elevated or unchanged, depending on the enzymatic activity in other organs.” [1]

“Recent work also exhibited using untargeted metabolomics that BCAA levels were not elevated in a UC Davis (UCD)-T2DM rat model until six months post-onset of diabetes. These suggested that the increase of BCAAs level is not enough to elicit IR and T2DM in rat model systems. Impairment of BCAA metabolism also contributes to increased levels of BCAAs in insulin-resistant subjects.”

"However, whether BCAAs are simply markers of insulin resistance, or whether they are direct contributors to insulin resistance remains uncertain.” [1]

To put the researchers' words in plain English that we all can understand:

Obesity, type 2 diabetes, and insulin resistance affect the expression of genes that impact your body’s ability to break down (catabolize) branched-chain amino acids.

As a result of this “dysmetabolism,” blood levels of BCAA rise.

Previous animal studies suggest that increased levels of BCAA are not enough on their own to cause insulin resistance or type 2 diabetes.

Now, let’s take a closer look at how the body metabolizes BCAAs.

BCAA Catabolism Up Close

The first step in the breakdown of BCAA is catalysed by the enzyme branched-chain-amino-acid transaminase, or BCAT(m) for short. BCAT(m) is encoded by the BCAT2 gene. [4]

Animal studies have noted that when the BCAT2−/− is missing (“deleted”) it prevents metabolites of the BCAA from forming in peripheral tissues. In other words, when the BCAT2 gene is absent or malfunctioning, the ability to break down BCAA is severely compromised. As a result, this is one means that could lead to elevated levels of BCAA in the blood.

But, we’ve only begun to scratch the surface of BCAA catabolism…

The next step in the breakdown of branched-chain amino acids is prompted by the multienzyme mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC), which irreversibly catabolizes BCAAs to their respective ketoacids.

The “products” resulting from the activity of BCKDC are are branched-chain acyl-Coenzyme A (CoA) species. These “species” are subsequently metabolized by several mitochondrial-matrix enzymatic steps, ultimately resulting in the formation of ketogenic, lipogenic, or gluconeogenic substrates, such as acetyl-CoA, acetoacetyl-CoA, and propionyl-CoA. [4]

Research has noted that the expression and activity of BCKDC, as well as other enzymes involved in the metabolism of BCAA, can be changed by numerous metabolic factors, including those linked to obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. [4]

Additionally, researchers have noted that BCAA metabolism is interorgan dependent, such that if one organ can’t metabolize BCAA, another one can “pick up the slack” so to speak.

A problem arises though when multiple organs and tissues have altered gene expression/mitochondrial dysfunction, as in the case of obesity, insulin resistance, and type 2 diabetes. As a result, due to the impairment of BCAA metabolism across multiple systems blood levels of BCAA increase.

In other words, the reason diabetics and people with insulin resistance have elevated levels of BCAAs in the blood goes back to poor metabolism and absorption of the amino acids in their muscles and organs.

As further proof that BCAAs are not the cause of diabetes and insulin resistance, consider the Takayama study, which followed 13,525 people over a 20 year period, to study the link between BCAA intake and the risk for diabetes. [2]

“A high intake of BCAAs in terms of percentage of total protein was significantly associated with a decreased risk of diabetes in women after controlling for covariates...” [2]

Within the paper researchers point out another study, conducted by McCormack et al., which documented that plasma BCAA level, but not dietary BCAA intake, was associated with obesity and insulin resistance. [5]

Again, this serves as evidence that BCAA consumption is not at fault, but impaired BCAA metabolism as a result of overfeeding.

To further bolster this point, consider another recently published study in the Molecular Nutrition & Food Research journal investigating BCAA Metabolism and Insulin Sensitivity, which observed: [3]

"However given the available data, it appears as though the following statements can be made: (1) consistent correlations between elevated circulating BCAAs and metabolic disease in humans (especially insulin resistance) seem to exist; (2) while experimental evidence is inconclusive, chronic excess energy/dietary fat intake or chronic adiposity are likely contributors of dysregulated BCAA catabolism, thereby promoting BCAA accumulation; and (3) given ample data from health and athletic populations, dietary sources of BCAAs are unlikely to be independently sufficient to cause metabolic disease in otherwise healthy populations. Proposed metabolic benefits of supplemental BCAAs are based largely on in vitro experiments and have yet to be demonstrated consistently in human trials, and therefore require further validation." [3]

In other words:

There is a link between elevated levels of BCAA and metabolic disease
Eating too much food and being obese impair your ability to break down BCAA
It is highly unlikely that supplementing with BCAA will cause metabolic disease in healthy individuals.

For even more proof that BCAAs are not the cause of diabetes and insulin resistance, consider this recent 2018 study that showed that BCAA supplementation in patients with hepatitis C DECREASED insulin resistance and improved health-related quality of life. The authors go on to state BCAA supplementation could be a tool to help COMBAT diabetes. [6]

FYI, the patients in this study were consuming upwards of 30 grams of BCAAs per day, and typically in a fasted state. [6] Even the most hardcore gym bro who’s sipping on BCAAs all day in his gallon jug doesn’t really approach those levels.

As a final point, various studies have noted that supplementing with either leucine or isoleucine on its own has led to improvements in diet-induced obesity as well as glucose and cholesterol metabolism. [7][8][9]

Suffice it to say, that it is NOT BCAA that are causing diabetes or insulin resistance, but the genetic and enzymatic changes that occur as a result of obesity, diabetes, metabolic syndrome, and insulin resistance (all of which are related to overfeeding in one form or another) that lead to elevated levels of BCAAs.

Now, let’s take a look at the belief that BCAAs cause cancer.

BCAAs and Cancer

Cachexia is characterized by muscle wasting and involuntary weight loss that usually occurs in cancer patients. It’s also associated with increased rates of morbidity and mortality.

Another way to view this is that muscle tissue serves as a “protector” of sorts when you’re sick. The more you have of it, the longer you can survive while fending off a disease. Conversely, the less lean mass you have, and the faster you lose it, the more likely you are to die quickly when facing illness and disease.

Due to this, doctors use both BCAA and isolated leucine supplementation in the treatment of cachexia for a variety of cancers as well as other diseases including movement disorders, anorexia, genetic diseases, and liver diseases. The reason for using BCAA and/ or free form leucine is due to their ability to slow muscle loss and treat poor appetite.

Upon initial inspection, this would seem like a great idea. BCAA supplements can spare muscle tissue, increase muscle protein synthesis, and enhance your chances for survival. However, research has shown that they (BCAA or leucine) may also enhance the progression of cancer as well, due to the fact that protein synthesis rates increase significantly more in tumor cells than in muscle cells in certain forms of cancer. [10][14] 

Additionally, cancer researchers have noted that enzymes (BCAT1 and BCAT2) catalyzing the initial step in BCAA metabolism are overexpressed in many cancers.

But, it’s not as simple as stating that “BCAAs are cancer fuel.” Researchers themselves have stated that additional studies are needed to determine the true diagnostic value of markers such as BCAT1 and BCAA levels in monitoring and diagnosing cancers.

Yes, BCAA administration has been shown to increase disease progression in certain cancers, but, in reality, a number of factors influence any potential impact BCAA may have on the treatment or progression of cancer including: [10][11][12][13][18]

  • The type of cancer present
  • The organ that cancer is present
  • Any one of a number of genetic mutations that occur as a result of cancer
  • Whether the subject is lean or obese

Furthermore, there have been several studies, particularly in patients with liver cancer, that have shown that BCAA supplementation actually increased survival rates and reduced complications associated with treatment. [15][16][17]

In the end, researchers are at a crossroads, having to choose between depriving individuals of BCAA, so as to “starve” the cancer cells, and providing BCAA supplementation to support lean muscle mass.

This is best summarized in a 2013 study by Thomas M. O’Connell that concluded:

“The challenge of using the BCAAs as biomarkers comes with the multitude of competing energetic and proliferative demands present in both healthy and disease states [79]. Furthermore, the stage of the disease and in the case of cancer, the location of the tumor, will also affect how the levels of BCAAs are affected. The ultimate utility for BCAAs in diagnosing, predicting or monitoring disease will depend upon the presence of additional information that will place these levels in the context of the entire phenotypic condition.” [10]

In other words, BCAAs can offer utility as a metric for diagnosing and tracking cancer, but it is not THE SOLE marker. Levels of BCAAs (and their metabolites and enzymes) are one piece of a much more complex puzzle.

And before we go, while we’re in the groove of debunking these myths around BCAAs, let’s take a moment to again address the whole issue of EAAs vs BCAAs.

EAAs vs BCAAs... One Last Time

The etiology of this whole EAA vs BCAA debate was sparked in large part due to a review by Robert Wolfe[19], which stated that “BCAA supplements alone do not promote muscle anabolism.”

However, upon further inspection, there are some “issues” that need to be brought up regarding this study.

Robert Wolfe is a co-inventor (along with Dr. Arny Ferrando) of a patent consisting of a proprietary blend of essential amino acids.

Since this study was published, Wolfe has since licensed the patented EAA blend for use to several companies.

Wolfe “conveniently” forgot to disclose these facts (or any other inherent biases) in his review.

Clearly there is a conflict of interest at play here, which casts a shadow on the integrity and quality of the paper.

But there’s more fodder in this EAA vs BCAA debate.

A 2016 study by Moberg et al.,[20] stated:

“In summary, EAA ingestion appears to stimulate translation initiation more effectively than the other supplements, although the results also suggest that this effect is primarily attributable to the BCAA...However, after 180 min of recovery this difference between EAA and BCAA had disappeared...Unfortunately, we were not able to accurately assess protein synthesis, as evidenced by the very large variations in FSR (fractional synthetic rate) values in all four trials.”

Basically what the researchers are saying, is that the reason EAA are superior to BCAAs has to do with phosphorylating translation and initiation factors that impact muscle protein synthesis.

But here’s the interesting thing...the authors specifically attribute these effects to the BCAAs, which, as you probably realize are contained within EAAs. Additionally, after three hours had elapsed there was minimal difference between the effects of BCAA or EAA.

So in other words, EAA are better stimulating muscle protein synthesis, but the effect is mostly due to the three BCAA. And, after three hours, the difference between the two is negligible.

Furthermore, the study shows that the average increase of fractional muscle protein synthesis was greater with BCAA consumption compared to EAA. There was also no significant difference in maximal muscle protein synthesis between the group consuming EAAs and those ingesting BCAAs.

Nevermind the fact that researchers biased the setup of the trial in favor of the EAA group by having the subjects fast for 17 hours prior to the testing.

Why is this important?

To assess whether EAA or BCAA are superior, daily intake of protein must be controlled. Forcing the subjects to fast reduces plasma amino acid levels which nullifies control variable, which is protein intake. This results in a very complicated and confounded analysis.

When protein is controlled for, we see that there is no difference in muscle protein synthesis between EAA and BCAAs. Plus, no one is really advocating the use of BCAA following a prolonged fast, nor are they claiming that BCAA will build muscle in the absence of a proper muscle building diet, high in complete protein sources.

Takeaway

There is a distinct lack of evidence in the present body of research proving that BCAA or BCAA supplements cause cancer or diabetes. To promote the idea that three amino acids are the cause for these chronic diseases, is nothing but pure fear mongering.

Again, remember that correlation is not the same as causation. Just because two things are found together does NOT mean one causes the other.

Additionally, leucine and isoleucine have both been shown to enhance glucose uptake in skeletal muscle through different means, making it illogical to say that BCAA cause diabetes or insulin resistance.

At the end of the day, making such blanket statements, such as “BCAA are cancer fuel” or “BCAA cause insulin resistance” demonstrates a gross negligence of understanding of the available scientific research and does little to educate the uninformed consumer.

Instead of trying to grab a headline or add more followers on your insta-face accounts, try providing honest information, sans the salacious, fear-mongering commentary. The average consumer will thank you.

References
1) Yoon M-S. The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism. Nutrients. 2016;8(7):405. doi:10.3390/nu8070405.
2) Chisato Nagata, Kozue Nakamura, Keiko Wada, Michiko Tsuji, Yuya Tamai, Toshiaki Kawachi; Branched-chain Amino Acid Intake and the Risk of Diabetes in a Japanese Community: The Takayama Study, American Journal of Epidemiology, Volume 178, Issue 8, 15 October 2013, Pages 1226–1232, https://doi.org/10.1093/aje/kwt112
3) Gannon, N. P., Schnuck, J. K., & Vaughan, R. A. (2018). BCAA Metabolism and Insulin Sensitivity – Dysregulated by Metabolic Status? Molecular Nutrition & Food Research, 62(6), 1700756. https://doi.org/10.1002/mnfr.201700756
4) Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nature reviews Endocrinology. 2014;10(12):723-736. doi:10.1038/nrendo.2014.171.
5) McCormack SE, Shaham O, McCarthy MA, et al. Circulating Branched-chain Amino Acid Concentrations Are Associated with Obesity and Future Insulin Resistance in Children and Adolescents. Pediatric obesity. 2013;8(1):52-61. doi:10.1111/j.2047-6310.2012.00087.x.
6) Ocaña-Mondragón A, Mata-Marín JA, Uriarte-López M, et al. Effect of branched-chain amino acid supplementation on insulin resistance and quality of life in chronic hepatitis C patients. Biomedical Reports. 2018;8(1):85-90. doi:10.3892/br.2017.1012.
7) Binder E, Bermúdez-Silva FJ, André C, Elie M, Romero-Zerbo SY, et al. (2013) Leucine Supplementation Protects from Insulin Resistance by Regulating Adiposity Levels. PLOS ONE 8(9): e74705. https://doi.org/10.1371/journal.pone.0074705
8) Masako Doi, Ippei Yamaoka, Mitsuo Nakayama, Shinji Mochizuki, Kunio Sugahara, Fumiaki Yoshizawa; Isoleucine, a Blood Glucose-Lowering Amino Acid, Increases Glucose Uptake in Rat Skeletal Muscle in the Absence of Increases in AMP-Activated Protein Kinase Activity, The Journal of Nutrition, Volume 135, Issue 9, 1 September 2005, Pages 2103–2108, https://doi.org/10.1093/jn/135.9.2103
9) Doi, M., Yamaoka, I., Fukunaga, T., & Nakayama, M. (2003). Isoleucine, a potent plasma glucose-lowering amino acid, stimulates glucose uptake in C2C12 myotubes. Biochemical and Biophysical Research Communications, 312(4), 1111–1117.
10) O’Connell TM. The Complex Role of Branched Chain Amino Acids in Diabetes and Cancer. Metabolites. 2013;3(4):931-945. doi:10.3390/metabo3040931.
11) Ananieva EA, Wilkinson AC. Branched-chain amino acid metabolism in cancer. Current Opinion in Clinical Nutrition and Metabolic Care. 2018;21(1):64-70. doi:10.1097/MCO.0000000000000430.
12) Zhang, S., Zeng, X., Ren, M., Mao, X., & Qiao, S. (2017). Novel metabolic and physiological functions of branched chain amino acids: a review. Journal of Animal Science and Biotechnology, 8(1), 10. https://doi.org/10.1186/s40104-016-0139-z
13) Vickie E. Baracos, Michelle L. Mackenzie; Investigations of Branched-Chain Amino Acids and Their Metabolites in Animal Models of Cancer, The Journal of Nutrition, Volume 136, Issue 1, 1 January 2006, Pages 237S–242S, https://doi.org/10.1093/jn/136.1.237S
14) Fearon K, Arends J, Baracos V: Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol. 2013, 10: 90-99.
15) Nojiri S, Fujiwara K, Shinkai N, et al. Effects of branched-chain amino acid supplementation after radiofrequency ablation for hepatocellular carcinoma: a randomized trial. Nutrition 2017; 33:20–27.
16) Park JG, Tak WY, Park SY, et al. Effects of branched-chain amino acids (BCAAs) on the progression of advanced liver disease: a Korean nationwide, multicenter, retrospective, observational, cohort study. Medicine (Baltimore) 2017; 96:e6580.
17) Shiozawa S, Usui T, Kuhara K, et al. Impact of branched-chain amino acid-enriched nutrient on liver cirrhosis with hepatocellular carcinoma undergoing transcatheter arterial chemoembolization in Barcelona Clinic Liver Cancer Stage B: a prospective study. J Nippon Med Sch 2016; 83:248–256.
18) Liu, K. A., Lashinger, L. M., Rasmussen, A. J., & Hursting, S. D. (2014). Leucine supplementation differentially enhances pancreatic cancer growth in lean and overweight mice. Cancer & Metabolism, 2(1), 6. https://doi.org/10.1186/2049-3002-2-6
19) Wolfe, R. R. (2017). Branched-chain amino acids and muscle protein synthesis in humans: myth or reality? Journal of the International Society of Sports Nutrition, 14(1), 30.
20) Moberg, M., Apro, W., Ekblom, B., van Hall, G., Holmberg, H.-C., & Blomstrand, E. (2016). Activation of mTORC1 by leucine is potentiated by branched-chain amino acids and even more so by essential amino acids following resistance exercise. American Journal of Physiology. Cell Physiology, 310(11), C874-84. https://doi.org/10.1152/ajpcell.00374.2015
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