Branched chain amino acids leucine, isoleucine and valine are essential nutrients and important building blocks of muscle proteins and sources of energy that are obtained from the diet, primarily from meat and dairy. Past studies in humans, however, have linked excess BCAA consumption with obesity and insulin resistance and thus increased susceptibility to diabetes, cancers and cardiovascular diseases.
“Our results showed that discrepancies between human studies and animal studies may reflect errors in the ways human studies were designed and conducted,” the researchers wrote recently in the journal Communications Medicine. “As a result, these human studies may provide a flawed picture of BCAA effects that could mislead efforts developing novel therapeutics.”
Addressing the inconsistencies
The study noted the challenges in quantifying individual BCAA effects on metabolism and health and disease because of the high correlation between circulating leucine, isoleucine and valine concentrations.
“This correlation reflects shared enzymes governing synthesis and degradation as well as dietary patterns in which BCAAs are typically consumed together,” they wrote. “Despite these high correlations, BCAA intermediates and final metabolites differ, motivating studies examining whether individual BCAAs harbor distinct metabolic effects.”
To explore these inconsistencies, the investigation used the newer Mendelian statistical method coupled with data from the long-term UK Biobank study initiated in 2006 to account for confounding from shared lifestyle and genetic factors.
The data set included 97,468 men and women of European ancestry with an average age of 56.7 years, 67% of whom were classified as overweight or obese and 4.6% as having type 2 diabetes. Causal effects of the three BCAAs were estimated on a total of 441 phenotypes spanning 17 categories, simultaneously quantifying 249 metabolite biomarkers.
Distinct and opposing effects
Of the 117 phenotypes with evidence of a statistically significant total causal effect for at least one BCAA, 52 were associated with only one BCAA, including total causal effects of valine on diabetic eye disease, valine on albuminuria (a sign of kidney disease) and isoleucine on angina (heart attack or stroke risk). Only two (beta blocking agents and drugs affecting bone structure and mineralization) showed evidence of a total causal effect with leucine only.
To illustrate the constraints of bias that result from failing to address confounding factors, the researchers cited a recent Harvard meta-analysis that associated higher circulation levels of isoleucine, leucine and valine with type 2 diabetes risk.
“In contrast, by estimating BCAA total causal effects, our results suggested a different picture: that valine significantly increased type 2 diabetes, leucine significantly decreased type 2 diabetes, and isoleucine had no significant effect,” they reported, adding that these discrepancies observed for type 2 diabetes paralleled the study’s overall findings.
As explanation, the study suggested that each BCAA differentially activates a key regulator of cell growth and metabolism (mTORC1) and highlighted differences in intermediate and final end-products of BCAA metabolism that can either promote or improve insulin resistance.
“At best the assumed homogeneity of effects may lead to ineffective therapies,” the researchers concluded. “At worst, assumed homogeneity may lead to unintended impacts where combined BCAA therapies have directionally opposing effects.”
They also noted that the threats to validity are not limited to BCAA studies and that other observational studies governed by shared factors could benefit from causal inference approaches.
Source: Communications Medicine
“Branched chain amino acids harbor distinct and often opposing effects on health and disease”
doi: doi.org/10.1038/s43856-023-00382-x
Authors: Christie L. Avery et al.