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.
Adil Mardinoglu  1 ,  Silvia Gogg  2 ,  Luca A Lotta  3 ,  Alena Stančáková  4 ,  Annika Nerstedt  5 ,  Jan Boren  6 ,  Matthias Blüher  7 ,  Ele Ferrannini  8 ,  Claudia Langenberg  9 ,  Nicholas J Wareham  10 ,  Markku Laakso  11 ,  Ulf Smith  12
Affiliations
  • 1. Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden; Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden. Electronic address: [email protected].
  • 2. Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: [email protected].
  • 3. MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. Electronic address: [email protected].
  • 4. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland. Electronic address: [email protected].
  • 5. Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: [email protected].
  • 6. Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: [email protected].
  • 7. University of Leipzig, Department of Medicine, Leipzig, Germany. Electronic address: [email protected].
  • 8. CNR Institute of Clinical Physiology, Pisa, Italy. Electronic address: [email protected].
  • 9. MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. Electronic address: [email protected].
  • 10. MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. Electronic address: [email protected].
  • 11. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland. Electronic address: [email protected].
  • 12. Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: [email protected].
PMID: 29246479 DOI: 10.1016/j.ebiom.2017.12.008
Abstract

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.
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