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

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Mardinoglu A ; Gogg S ; Lotta LA ; Stancáková A ; Nerstedt A ; Boren J ; Blüher M ; Ferrannini E ; Langenberg C ; Wareham NJ ; Laakso M ; Smith U (2018)
  • Publisher: Elsevier BV
  • Journal: volume 27, pages 151-155 (issn: 2352-3964, eissn: 2352-3964)
  • Related identifiers: pmc: PMC5828558, doi: 10.1016/j.ebiom.2017.12.008, doi: 10.17863/CAM.20736
  • Subject: Endothelial Cells | Fatty Acids | Body Mass Index | 3-Hydroxyisobutyric acid (3-HIB) | T2D | Adipose Tissue | Medicine | Insulin secretion | Hydroxybutyrates | Biological Transport | Microvessels | R | Diabetes Mellitus, Type 2 | Amino Acids, Branched-Chain | Branched-chain amino acids (BCAAs) | Research Paper | Insulin resistance | Humans | Incidence | Metabolome

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.
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