Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.
Journal Article (Journal Article;Review)
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.
Full Text
Duke Authors
- Bain, James R.
- Herman, Mark A.
- McGarrah III, Robert W.
- Newgard, Christopher Bang
- Shah, Svati Hasmukh
- White, Phillip James
Cited Authors
- White, PJ; McGarrah, RW; Herman, MA; Bain, JR; Shah, SH; Newgard, CB
Published Date
- October 2021
Published In
Volume / Issue
- 52 /
Start / End Page
- 101261 -
PubMed ID
- 34044180
Pubmed Central ID
- PMC8513145
Electronic International Standard Serial Number (EISSN)
- 2212-8778
Digital Object Identifier (DOI)
- 10.1016/j.molmet.2021.101261
Language
- eng
Conference Location
- Germany