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Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.

Publication ,  Journal Article
White, PJ; McGarrah, RW; Herman, MA; Bain, JR; Shah, SH; Newgard, CB
Published in: Mol Metab
October 2021

BACKGROUND: A strong association of obesity and insulin resistance with increased circulating levels of branched-chain and aromatic amino acids and decreased glycine levels has been recognized in human subjects for decades. SCOPE OF REVIEW: More recently, human metabolomics and genetic studies have confirmed and expanded upon these observations, accompanied by a surge in preclinical studies that have identified mechanisms involved in the perturbation of amino acid homeostasis- how these events are connected to dysregulated glucose and lipid metabolism, and how elevations in branched-chain amino acids (BCAA) may participate in the development of insulin resistance, type 2 diabetes (T2D), and other cardiometabolic diseases and conditions. MAJOR CONCLUSIONS: In human cohorts, BCAA and related metabolites are now well established as among the strongest biomarkers of obesity, insulin resistance, T2D, and cardiovascular diseases. Lowering of BCAA and branched-chain ketoacid (BCKA) levels by feeding BCAA-restricted diet or by the activation of the rate-limiting enzyme in BCAA catabolism, branched-chain ketoacid dehydrogenase (BCKDH), in rodent models of obesity have clear salutary effects on glucose and lipid homeostasis, but BCAA restriction has more modest effects in short-term studies in human T2D subjects. Feeding of rats with diets enriched in sucrose or fructose result in the induction of the ChREBP transcription factor in the liver to increase expression of the BCKDH kinase (BDK) and suppress the expression of its phosphatase (PPM1K) resulting in the inactivation of BCKDH and activation of the key lipogenic enzyme ATP-citrate lyase (ACLY). These and other emergent links between BCAA, glucose, and lipid metabolism motivate ongoing studies of possible causal actions of BCAA and related metabolites in the development of cardiometabolic diseases.

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Published In

Mol Metab

DOI

EISSN

2212-8778

Publication Date

October 2021

Volume

52

Start / End Page

101261

Location

Germany

Related Subject Headings

  • Protein Phosphatase 2C
  • Protein Kinases
  • Obesity
  • Liver
  • Lipogenesis
  • Keto Acids
  • Insulin Resistance
  • Insulin
  • Humans
  • Disease Models, Animal
 

Citation

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White, P. J., McGarrah, R. W., Herman, M. A., Bain, J. R., Shah, S. H., & Newgard, C. B. (2021). Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street. Mol Metab, 52, 101261. https://doi.org/10.1016/j.molmet.2021.101261
White, Phillip J., Robert W. McGarrah, Mark A. Herman, James R. Bain, Svati H. Shah, and Christopher B. Newgard. “Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.Mol Metab 52 (October 2021): 101261. https://doi.org/10.1016/j.molmet.2021.101261.
White PJ, McGarrah RW, Herman MA, Bain JR, Shah SH, Newgard CB. Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street. Mol Metab. 2021 Oct;52:101261.
White, Phillip J., et al. “Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.Mol Metab, vol. 52, Oct. 2021, p. 101261. Pubmed, doi:10.1016/j.molmet.2021.101261.
White PJ, McGarrah RW, Herman MA, Bain JR, Shah SH, Newgard CB. Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street. Mol Metab. 2021 Oct;52:101261.
Journal cover image

Published In

Mol Metab

DOI

EISSN

2212-8778

Publication Date

October 2021

Volume

52

Start / End Page

101261

Location

Germany

Related Subject Headings

  • Protein Phosphatase 2C
  • Protein Kinases
  • Obesity
  • Liver
  • Lipogenesis
  • Keto Acids
  • Insulin Resistance
  • Insulin
  • Humans
  • Disease Models, Animal