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

Journal article
Authors A. Mardinoglu
Silvia Gogg
L. A. Lotta
A. Stancakova
Annika Nerstedt
Jan Borén
M. Bluher
E. Ferrannini
C. Langenberg
N. J. Wareham
M. Laakso
Ulf Smith
Published in Ebiomedicine
Volume 27
Pages 151-155
ISSN 2352-3964
Publication year 2018
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 151-155
Language en
Links dx.doi.org/10.1016/j.ebiom.2017.12....
Keywords 3-Hydroxyisobutyric acid (3-HIB), Branched-chain amino acids (BCAAs), T2D, Insulin resistance, Insulin, insulin sensitivity, glucose-tolerance, cardiovascular-disease, metabolic signature, mannose levels, resistance, obesity, risk, General & Internal Medicine, Research & Experimental Medicine
Subject categories Clinical Medicine

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.

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