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

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

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

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

Adil Mardinoglu et al. EBioMedicine. 2018 Jan.

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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Figures

Fig. 1
Fig. 1
Plasma levels of 3-HIB are strongly related to BMI. A) Catabolism of branched-chain amino acids (BCAAs) including valine (val), leucine (leu) and isoleucine (Ile). B) Plasma levels of metabolites involved in BCAA catabolism in lean and obese subjects in RISC study. The Spearmen correlation of BMI, OGIS and the plasma levels of metabolites involved in BCAA metabolism before (C) and after eliminating the effect of BMI (D) in the RISC study. Correlation of BMI, IS and the plasma levels of metabolites involved in BCAA metabolism before (E) and after eliminating the effect of BMI (F) in the METSIM study. G) The plasma level of the metabolites involved in BCAA metabolism in healthy subjects and T2D patients in the EPIC-Norfolk study. (*P-value < 0.05).
Fig. 2
Fig. 2
Fatty acid transport in human microvascular and cardiac-derived endothelial cells. A) Fatty acid transport in human adipose tissue-derived microvascular endothelial cells show no effect of preincubating the cells for up to 24 h with 5 mM 3-HIB while preincubation with oleic acid (OA) (300 μM) increased fatty acid uptake. B) However, fatty acid uptake by cardiac-derived endothelial cells was significantly increased by 3-HIB.
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