BCAAs May Be Newest Marker for Type 2 Diabetes

Women with a history of gestational diabetes who are poor metabolizers of branched-chain amino acids might develop type 2 diabetes at a greater rate later in life.

With Deirdre Tobias, ScD, Caroline Apovian, MD, and J. Michael Gonzalez-Campoy, MD, PhD

While the risk of developing type 2 diabetes (T2D) is five times higher in women who have had gestational diabetes (GD),1 the reasons remain unsettled. Those who do develop it may be inefficient at metabolizing branched-chain amino acids (BCAAs),2 according to study findings published in Clinical Chemistry.

In the general population, BCAAs have been associated with a higher risk of diabetes and cardiovascular disease (CVD) down the road,2,3 according to lead study author Deirdre Tobias, ScD, assistant professor at Harvard Medical School and an epidemiologist at Brigham & Women's Hospital, Boston.

Women with gestational diabetes who cannot metabolize BCAAs may be at greater risk for T2D.

"We looked at this high-risk group [with a history of GD] particularly and we found this association was even stronger,'' she told EndocrineWeb; it's the elevated plasma levels, not the dietary intake, that relate to future diabetes risk.2

"Even if a patient with a history of GD has had a high intake BCAAs in her diet, she would only have an elevated risk for T2D if her circulating levels of these essential amino acids were also high," she said about the study findings. 

Evaluating the Role of BCAA as Marker of T2D

Dr. Tobias and her team evaluated the blood samples from 347 women with a history of gestational diabetes.2 The participants were pooled from women in the Nurses' Health Study II,4 who provided plasma samples from 1996-99. The Harvard researchers compared data from 172 women who developed type 2 diabetes later against 175 women who did not develop T2D despite having a history of GD.2

An estimation of the dietary intake of the three most essential BCAAs—isoleucine, leucine, and valine—was derived from self-reported food intake questionnaires.2 Dr. Tobias et al also analyzed the BCAA levels in the blood of all study subjects. Conditional logistic regression models were used to estimate odds ratios across the quartiles of BCAA intake, adjusting for age, body mass index (BMI), physical activity, family history, and other relevant risk factors.2

The researchers found that dietary and plasma BCAA concentrations were positively associated with incident type 2 diabetes: Quartile (Q) 4 of diet versus Q1, (OR =4.6, CI=1.6, 13.4); and, plasma Q4 versus Q1 (OR = 4.4, CI = 1.4, 13.4.) 2

The researchers modeled the joint association, finding that higher dietary BCAA levels were linked to type 2 diabetes when plasma concentrations were also higher (OR=6.0, CI-2.1, 17.2) but not when they were lower (OR=1.6, CI=0.61, 4.1).2 Conversely, Dr. Tobias said the results indicated that higher plasma BCAA levels were associated with increased T2D in women with either higher or lower dietary BCAA levels.2

Clinical Assessment and Value of Findings

"People who have a hard time breaking down BCAAs from dietary sources appear to have higher circulating branched-chain amino acids, and therefore higher BCAA blood levels, and it is these higher blood levels that show a strong association with increased insulin resistance or an impaired ability to break down BCAAS seem to be a sign of insulin resistance," Dr. Tobias said. Regardless of intake, the inability to metabolize the BCAAs raises risk.2

It is likely that the underlying impaired metabolism may begin several years before the onset or diagnosis of type 2 diabetes,2 Dr. Tobias and her colleagues concluded in the paper.

Uncovering the role of dietary and/or plasma BCAAs in T2D pathophysiology may help improve the identification of high-risk individuals as well as lead to effective therapeutic interventions to lessen the risk for women with gestational diabetes.

And follow-up studies could determine if current interventions for prediabetes, including lifestyle modification, might lead to reduced BCAA levels and, in the process, lessen the risk of progression to type 2 diabetes.2

Second Study Points to Link Between BCAAs and Cardiovascular Risk

In a second study, Dr. Tobias and her colleagues examined the association between BCAAs and cardiovascular disease (CVD) risk to assess whether BCAA levels were dependent on an intermediate diagnosis of type 2 diabetes.This study was published in Circulation: Genomic and Precision.

The researchers analyzed blood samples from more than 27,000 women participants in the Women's Health Study,5 finding that higher blood levels of BCAAs are predictive of future risk of cardiovascular disease in a similar extent as LDL cholesterol does.

There were 2,207 confirmed CVD events over the mean of 18.6 years of follow-up.Total BCAAS were positively associated with CVD (per SD: HR 1.13, 95% CI, 1.08-1.18, comparable to LDL with CVD (per SD: HR, 1.12, 95% CI, 1.07-1.17).3

The association between BCAAs and cardiovascular disease was greater (P interaction = 0.036) among women who developed T2D before CVD (HR, 1.20, 95% CI, 1.08-1.32) versus women without T2D (HR, 1.08, 95% CI, 1.03-1.14).3

Adjusting for hemoglobin A1c (HbA1c) and insulin resistance eliminated the BCAA—CVD findings.3 It could be, the researchers concluded, that impaired BCAA metabolism ''may capture the long-term risk of the common cause underlying T2D and CVD."

What Might Clinicians Take Away from These Studies?

Diets rich in BCAAs ''often have been associated as having positive effects on body weight reduction, body composition, muscle protein synthesis and glucose homeostasis," 6 said Caroline Apovian, MD, FACE, FACP, professor of medicine and pediatrics at Boston University School of Medicine, and president of the Obesity Society. 

Dr. Apovian told EndocrineWeb, ''despite the positive effects [of BCAA-enriched diets] on metabolic health, this paper adds to the evidence to support our understanding that along with blood sugar, insulin levels, and blood inflammatory markers, increased fasting concentrations of BCAAs are associated with an elevated risk of type 2 diabetes.”2

“The first study looked at dietary BCAA levels as well as circulating levels of BCAA in women with gestational diabetes and found that indeed the highest risk of T2D occurred In women both high dietary intake of BCAAs and high blood levels of BCAAs.Yet, high dietary intake of BCAA was not associated with T2D risk among women with low blood levels of BCAA,” she added.

''The authors hypothesized that the high levels of BCAA in the blood increased toxic metabolites which may interfere with β cell mitochondrial function, leading to type 2 diabetes,'' Dr. Apovian said, and ''that perhaps obesity contributes to decreased BCAA metabolism in adipose tissue such that BCAA may be a component of the causal pathway between obesity and T2D.''

"In essence, it is possible that an increase in BCAA in blood is a marker of insulin dysfunction, but not the cause,” she said.

Another expert, J. Michael Gonzalez-Campoy, MD, PhD, FACE, medical director and CEO of the Minnesota Center for Obesity, Metabolism, and Endocrinology, in Egan, Minnesota, took a more cautious view, telling EndocrineWeb that while the research came from a reputable institution, there were some study limitations to consider.

"Although it was a large cohort study,2 the number of women was small, the authors estimated dietary intake of BCAAs from self-reported questionnaires, and the best they could offer was an association," so the findings are not sufficient to inform patient management.

However, Dr. Apovian said, ''the researchers went further in the second study [BCAAs and CVD] and showed that if women develop type 2 diabetes before heart disease the association was stronger.''3

In the BCAA and CVD study,3 when the data was adjusted for HbA1c and insulin resistance, ''there was no association between BCAAs and heart disease which means the association is attributable to diabetes," she said.

So the question remains: What is it about the BCAAs that may lead to type 2 diabetes? Among the most interesting possible explanations, Dr. Apovian told EndocrineWeb is that ''somehow there is some kind of defect in metabolism that impairs the breakdown or clearance of BCAAs," suggesting that the elevated BCCAs offer a viable marker for increased risk of T2D, at least in women with a history of gestational diabetes.

None of the experts had any relevant financial disclosures.

Continue Reading:
Fat Intake Before Pregnancy and Its Effect on Gestational Diabetes
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