Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism.

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Abstract

Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear.

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Plasma amino acid levels and insulin secretion in obesity.

Philip Felig, Errol B Marliss, George F. Cahill (1969)

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Branched-Chain and Aromatic Amino Acids Are Predictors of Insulin Resistance in Young Adults

Peter Würtz, Pasi Soininen, Antti Kangas … (2013)

OBJECTIVE Branched-chain and aromatic amino acids are associated with the risk for future type 2 diabetes; however, the underlying mechanisms remain elusive. We tested whether amino acids predict insulin resistance index in healthy young adults. RESEARCH DESIGN AND METHODS Circulating isoleucine, leucine, valine, phenylalanine, tyrosine, and six additional amino acids were quantified in 1,680 individuals from the population-based Cardiovascular Risk in Young Finns Study (baseline age 32 ± 5 years; 54% women). Insulin resistance was estimated by homeostasis model assessment (HOMA) at baseline and 6-year follow-up. Amino acid associations with HOMA of insulin resistance (HOMA-IR) and glucose were assessed using regression models adjusted for established risk factors. We further examined whether amino acid profiling could augment risk assessment of insulin resistance (defined as 6-year HOMA-IR >90th percentile) in early adulthood. RESULTS Isoleucine, leucine, valine, phenylalanine, and tyrosine were associated with HOMA-IR at baseline and for men at 6-year follow-up, while for women only leucine, valine, and phenylalanine predicted 6-year HOMA-IR (P < 0.05). None of the other amino acids were prospectively associated with HOMA-IR. The sum of branched-chain and aromatic amino acid concentrations was associated with 6-year insulin resistance for men (odds ratio 2.09 [95% CI 1.38–3.17]; P = 0.0005); however, including the amino acid score in prediction models did not improve risk discrimination. CONCLUSIONS Branched-chain and aromatic amino acids are markers of the development of insulin resistance in young, normoglycemic adults, with most pronounced associations for men. These findings suggest that the association of branched-chain and aromatic amino acids with the risk for future diabetes is at least partly mediated through insulin resistance.

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Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice.

Giuseppe D'Antona, Maurizio Ragni, Annalisa Cardile … (2010)

Recent evidence points to a strong relationship between increased mitochondrial biogenesis and increased survival in eukaryotes. Branched-chain amino acids (BCAAs) have been shown to extend chronological life span in yeast. However, the role of these amino acids in mitochondrial biogenesis and longevity in mammals is unknown. Here, we show that a BCAA-enriched mixture (BCAAem) increased the average life span of mice. BCAAem supplementation increased mitochondrial biogenesis and sirtuin 1 expression in primary cardiac and skeletal myocytes and in cardiac and skeletal muscle, but not in adipose tissue and liver of middle-aged mice, and this was accompanied by enhanced physical endurance. Moreover, the reactive oxygen species (ROS) defense system genes were upregulated, and ROS production was reduced by BCAAem supplementation. All of the BCAAem-mediated effects were strongly attenuated in endothelial nitric oxide synthase null mutant mice. These data reveal an important antiaging role of BCAAs mediated by mitochondrial biogenesis in mammals. Copyright © 2010 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (iso-abbrev): Mol Metab

Title: Molecular metabolism

Publisher: Elsevier BV

ISSN (Print): 2212-8778

Publication date (Electronic): Oct 2016

Volume: 5

Issue: 10

Affiliations

[1 ] Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Endocrinology Department, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona 08950, Spain.

[2 ] Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.

[3 ] Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.

[4 ] Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.

[5 ] Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.

[6 ] Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.

[7 ] Metabolon, Inc., Durham, NC 27723, USA.