HIGH BLOOD LEVELS OF BRANCHED-CHAIN AMINO ACIDS ARE LINKED TO OBESITY, AND DIABETES: IS VALINE TO BLAME?
By Robert A. Schinetsky
For well over a decade, branched-chain amino acids (BCAA) have been a mainstay ingredient in pre, intra, and post workout supplements.
The main reason for this is due to the fact that BCAAs (primarily leucine) have been noted to stimulate muscle protein synthesis, reduce protein breakdown, and mitigate central fatigue (thereby allowing individuals to complete more work before succumbing to fatigue).[1,2]
However, regarding exercise outcomes (increased performance, greater muscle gain, reduced DOMS), the research on BCAAs is very mixed.
Essentially, when individuals consume sufficient amounts of dietary protein, consuming extra BCAAs does not seem to confer any additional benefits in regards to muscle growth, recovery from exercise, or a decrease in delayed onset muscle soreness (DOMS).
Despite these conflicting findings many individuals (and supplement companies) continue to preach the gospel of BCAAs as being an “essential” supplement (even though that by definition is a contradiction) to getting results.
When you step beyond the realm of sports nutrition and dive headlong into the general population, you will find some rather intriguing studies surrounding BCAAs.
Namely, a link between BCAAs and several chronic diseases.
There’s an overwhelming amount of evidence that elevated blood levels of branched-chain amino acids are associated with obesity, insulin resistance, and type 2 diabetes.[3,4,5,6]
This is all the more concerning when you realize that 34.2 million people have diabetes and another 34.5% of the population (~88 million people) have prediabetes.
Now, exercise of all kinds is typically recommended as one of the most effective means for improving glucose utilization and insulin sensitivity, thereby helping keep type 2 diabetes and metabolic syndrome at bay.
However, recent animal data suggests that hyperglycemic individuals may derive less benefit from exercise than those whose blood sugar levels are normal. While this doesn’t mean that exercise is useless in the fight against diabetes and insulin resistance, it does drive home that point that you “can’t out-exercise a bad diet.”
At this point, it’s worth mentioning that studies to date merely note a correlation between elevated levels of BCAAs and insulin resistance, type 2 diabetes, etc. And, as you’re hopefully aware, correlation does not necessarily mean causation.
Still, there’s a large enough body of evidence concerning elevated levels of BCAA and poor metabolic health to warrant further inspection.
And with that said, let’s look a little deeper into the link between BCAA, insulin resistance, and type 2 diabetes.
BCAAs, Diabetes, & Insulin Resistance
As we mentioned above, there is a formidable body of research noting a link between elevated BCAA levels in the blood (valine, in particular) and insulin resistance, most notably in overweight and obese individuals.[3,4,6,8]
Research has also shown that elevated levels of valine are present in the blood of diabetic rats, mice and humans.
When the mice were fed a diet sans valine, insulin sensitivity improved after only a single day.
Upon further inspection though, it’s not as simple as saying BCAAs or valine cause diabetes or insulin resistance.
In fact, animal data points to BCAAs exerting anti-obesity effects.
Further insight can be gained from a study published in the journal, Nutrients, titled: “The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism.”
As the title indicates, the study investigates 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 . In contrast, liver BCKDH activity is actually increased and could compensate for the decreased activity in adipose tissue . Therefore, the resulting plasma BCAA levels are either elevated or unchanged, depending on the enzymatic activity in other organs.”
“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.”
Essentially, chronic diseases including obesity, Type 2 Diabetes, and insulin resistance affect the expression of genes that impact the body’s ability to breakdown BCAAs. As a result of this impaired metabolism, blood levels of BCAA rise.
And, previous animal studies indicate that increased levels of BCAA are not enough on their own to cause insulin resistance or Type 2 diabetes.
There’s also some interesting data indicating that higher dietary BCAA intake is associated with lower prevalence of overweight status/obesity among healthy middle-aged adults.
And, let’s not forget the famous Takayama study, which followed 13,525 people over a 20 year period, to study the link between BCAA intake and the risk for diabetes.
“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...”
Nevertheless, research continues to be published, even as recent as 2019-2020 that the circulating valine levels might be a biomarker for type 2 diabetes and restoring the level of valine might be a potential strategy for diabetes therapy.
Perhaps, at this point, it would be beneficial to examine what happens during the breakdown of BCAAs in the body.
Breaking Down BCAAs
The first step in the catabolism of BCAA is initiated by the enzyme branched-chain-amino-acid transaminase (BCAT(m)), which is encoded by the BCAT2 gene.
Animal studies have noted that when the BCAT2−/− gene is deleted it prevents metabolites of the BCAA from forming in peripheral tissues.
Basically, when the BCAT2 gene is missing or not functioning properly, the body’s ability to break down branched-chain amino acids is severely compromised, which could lead to elevated levels of BCAAs in the blood.
The next step in the catabolism of BCAAs is brought on by the mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC), which irreversibly catabolizes BCAAs to their respective ketoacids.
The by-products resulting from the activity of BCKDC are branched-chain acyl-Coenzyme A (CoA) species.
These “species” are then broken down by several mitochondrial-matrix enzymatic steps, leading to the formation of ketogenic, lipogenic, or gluconeogenic substrates, such as acetyl-CoA, acetoacetyl-CoA, and propionyl-CoA.
Research indicates the expression and activity of BCKDC, as well as other enzymes involved in the metabolism of BCAA, can be modified by numerous metabolic factors, including those linked to insulin resistance, obesity, metabolic syndrome, and type 2 diabetes.
As if the waters weren’t murky enough, BCAA metabolism is interorgan dependent, meaning that if one organ has difficulty metabolizing BCAA, another one can “pick up the slack” (in a manner of speaking).
However, complications arise when multiple tissues and/or organs have modified gene expression / mitochondrial dysfunction, as is the case with individuals who are obese, insulin resistant, and/or diabetic. As a result, systemic dysmetabolism of BCAA leads to increases in blood BCAA levels.
When viewed in this light, it’s not necessarily the BCAA that are causing obesity, insulin resistance, etc. It is the inability to effectively metabolize these amino acids by organs and tissues that leads to elevated levels in the blood.
One consequence of this impaired metabolism not discussed frequently is that elevated levels of circulating BCAAs could potentially compete with the uptake of amino acid precursors of dopamine (tyrosine) and 5-hydroxytryptamine (5-HTP) in the brain, which could then contribute to poorer mood and increased risk of depression in the obese.[11,12]
Should You Supplement with BCAAs?
By and large, the average individual that consumes enough protein does not stand to benefit from consuming additional BCAA.
A recent study in the journal Nutrients found that valine supplementation in lean, healthy people did not have a significant effect on weight loss, satiety or blood glucose levels.
Unlike valine, leucine has been shown to improve blood glucose levels and insulin function. And, leucine alone has been noted to rescue insulin-signaling deficiency.
A 2019 study also found that oral administration of leucine improved endothelial function in healthy individuals when infused with glucose.
This is all the more notable when you understand that hyperglycemia impairs endothelial function, even in otherwise healthy individuals.
The same cannot be said for valine, since it does not encourage mitochondrial biogenesis -- something that leucine does.
It should be mentioned that both leucine, and its little brother isoleucine, each have been shown to lead to improvements in diet-induced obesity as well as glucose and cholesterol metabolism.[19,20,21]
Moreover, leucine has been shown to prevent intracellular muscle lipid accumulation and storage in skeletal muscle, outcomes typically observed in obese individuals which leads to mitochondrial damage.
And, when you factor in that some research notes that the valine metabolite 3-hydroxyisobutyrate (3HIB) promotes fat accumulation within muscle tissue by directly stimulating fatty uptake in the muscle, it doesn’t make a whole lot of sense to mega-dose BCAA supplements (especially if you’re already consuming enough protein).
For these reasons, and many more, Advanced Molecular Labs does not advocate the use of supplemental BCAAs or include them in any supplement.
AML™ Post Workout does contain 5 grams of leucine, as it is a powerful switch that turns on protein synthesis and increases mTOR activity for several hours after training.
We recommend consuming AML Post Workout on an empty stomach immediately following resistance training and 15-30 minutes before a post-workout meal.
This allows for a greater spike in blood levels of leucine than if you were to take it in combination with a mixed meal.
- Blomstrand E, Eliasson J, Karlsson HK, Köhnke R. Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. J Nutr. 2006;136(1 Suppl):269S-73S. doi:10.1093/jn/136.1.269S
- VanDusseldorp TA, Escobar KA, Johnson KE, et al. Effect of Branched-Chain Amino Acid Supplementation on Recovery Following Acute Eccentric Exercise. Nutrients. 2018;10(10):1389. Published 2018 Oct 1. doi:10.3390/nu10101389
- Asghari G, Farhad Nejad H, Teymoori F, Mirmiran P, Tohidi M, Azizi F. High dietary intake of branched-chain amino acids is associated with an increased risk of insulin resistance in adults [published correction appears in J Diabetes. 2019 Nov;11(11):920]. J Diabetes. 2018;10(5):357-364. doi:10.1111/1753-0407.12639
- Lu J, Gu Y, Liu H, et al. Daily Branched-Chain Amino Acid Intake and Risks of Obesity and Insulin Resistance in Children: A Cross-Sectional Study. Obesity (Silver Spring). 2020;28(7):1310-1316. doi:10.1002/oby.22834
- 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.
- 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
- Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2020
- Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014;10(12):723-736. doi:10.1038/nrendo.2014.171
- Qin LQ, Xun P, Bujnowski D, et al. Higher branched-chain amino acid intake is associated with a lower prevalence of being overweight or obese in middle-aged East Asian and Western adults. J Nutr. 2011;141(2):249-254. doi:10.3945/jn.110.128520
- Liao, X., Liu, B., Qu, H., Zhang, L., Lu, Y., Xu, Y., Zheng, H. (2019). A High Level of Circulating Valine Is a Biomarker for Type 2 Diabetes and Associated with the Hypoglycemic Effect of Sitagliptin. Mediators of Inflammation, 2019, 8247019. https://doi.org/10.1155/2019/8247019
- Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005;135:1539S–1546S.
- Crandall EA, Fernstrom JD. Effect of experimental diabetes on the levels of aromatic and branched-chain amino acids in rat blood and brain. Diabetes. 1983;32:222–230.
- 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
- MacDonald, T.L., Pattamaprapanont, P., Pathak, P. et al. Hyperglycaemia is associated with impaired muscle signalling and aerobic adaptation to exercise. Nat Metab (2020). https://doi.org/10.1038/s42255-020-0240-7
- Elovaris RA, Fitzgerald PCE, Bitarafan V, Ullrich SS, Horowitz M, Feinle-Bisset C. Intraduodenal Administration of L-Valine Has No Effect on Antropyloroduodenal Pressures, Plasma Cholecystokinin Concentrations or Energy Intake in Healthy, Lean Men. Nutrients. 2019;11(1):99. Published 2019 Jan 5. doi:10.3390/nu11010099
- Macotela, Y Emanuelli, B, Bang, AM et al. (2011) Dietary leucine – an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS One 6, e21187
- Argyrakopoulou G, Kontrafouri P, Eleftheriadou I, et al. The Effect of the Oral Administration of Leucine on Endothelial Function, Glucose and Insulin Concentrations in Healthy Subjects. Exp Clin Endocrinol Diabetes. 2019;127(8):505-510. doi:10.1055/a-0597-8985
- Liu R, Li H, Fan W, et al. Leucine Supplementation Differently Modulates Branched-Chain Amino Acid Catabolism, Mitochondrial Function and Metabolic Profiles at the Different Stage of Insulin Resistance in Rats on High-Fat Diet. Nutrients. 2017;9(6):565. Published 2017 Jun 2. doi:10.3390/nu9060565
- 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
- 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
- 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.
- Wu H, Dridi S, Huang Y, Baum JI. Leucine decreases intramyocellular lipid deposition in an mTORC1-independent manner in palmitate-treated C2C12 myotubes. American Journal of physiology. Endocrinology and Metabolism. 2020 Feb;318(2):E152-E163. DOI: 10.1152/ajpendo.00241.2019.
- Nilsen, M. S., Jersin, R. Å., Ulvik, A., Madsen, A., McCann, A., Svensson, P.-A., … Dankel, S. N. (2020). 3-Hydroxyisobutyrate, a Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism. Diabetes, db191174. https://doi.org/10.2337/db19-1174