Elevated Plasma Levels of 3-Hydroxyisobutyric Acid Are Associated With Incident Type 2 Diabetes

EBioMedicine. 2018 Jan:27:151-155. doi: 10.1016/j.ebiom.2017.12.008. Epub 2017 Dec 7.


Branched-chain amino acids (BCAAs) metabolite, 3-Hydroxyisobutyric acid (3-HIB) has been identified as a secreted mediator of endothelial cell fatty acid transport and insulin resistance (IR) using animal models. To identify if 3-HIB is a marker of human IR and future risk of developing Type 2 diabetes (T2D), we measured plasma levels of 3-HIB and associated metabolites in around 10,000 extensively phenotyped individuals. The levels of 3-HIB were increased in obesity but not robustly associated with degree of IR after adjusting for BMI. Nevertheless, also after adjusting for obesity and plasma BCAA, 3-HIB levels were associated with future risk of incident T2D. We also examined the effect of 3-HIB on fatty acid uptake in human cells and found that both HUVEC and human cardiac endothelial cells respond to 3-HIB whereas human adipose tissue-derived endothelial cells do not respond to 3-HIB. In conclusion, we found that increased plasma level of 3-HIB is a marker of future risk of T2D and 3-HIB may be important for the regulation of metabolic flexibility in heart and muscles.

Keywords: 3-Hydroxyisobutyric acid (3-HIB); Branched-chain amino acids (BCAAs); Insulin resistance; Insulin secretion; T2D.

MeSH terms

  • Adipose Tissue / pathology
  • Amino Acids, Branched-Chain / blood
  • Biological Transport
  • Body Mass Index
  • Diabetes Mellitus, Type 2 / blood*
  • Endothelial Cells / metabolism
  • Fatty Acids / metabolism
  • Humans
  • Hydroxybutyrates / blood*
  • Incidence
  • Metabolome
  • Microvessels / pathology


  • Amino Acids, Branched-Chain
  • Fatty Acids
  • Hydroxybutyrates
  • 3-hydroxyisobutyric acid