Open AccessCorrelation of plasma metabolites with glucose and lipid fluxes in human insulin resistance
Author(s) -
Hartstra Annick V.,
Groot Pieter F.,
Mendes Bastos Diogo,
Levin Evgeni,
Serlie Mireille J.,
Soeters Maarten R.,
Pekmez Ceyda T.,
Dragsted Lars O.,
Ackermans Mariette T.,
Groen Albert K.,
Nieuwdorp Max
Publication year - 2020
Publication title -
obesity science and practice
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.654
H-Index - 14
ISSN - 2055-2238
DOI - 10.1002/osp4.402
Subject(s) - insulin resistance , metabolomics , medicine , metabolite , lipolysis , endocrinology , insulin , type 2 diabetes , glycemic , diabetes mellitus , biology , bioinformatics , adipose tissue
Summary Objective Insulin resistance develops prior to the onset of overt type 2 diabetes, making its early detection vital. Direct accurate evaluation is currently only possible with complex examinations like the stable isotope‐based hyperinsulinemic euglycemic clamp (HIEC). Metabolomic profiling enables the detection of thousands of plasma metabolites, providing a tool to identify novel biomarkers in human obesity. Design Liquid chromatography mass spectrometry–based untargeted plasma metabolomics was applied in 60 participants with obesity with a large range of peripheral insulin sensitivity as determined via a two‐step HIEC with stable isotopes [6,6‐ 2 H 2 ]glucose and [1,1,2,3,3‐ 2 H 5 ]glycerol. This additionally enabled measuring insulin‐regulated lipolysis, which combined with metabolomics, to the knowledge of this research group, has not been reported on before. Results Several plasma metabolites were identified that significantly correlated with glucose and lipid fluxes, led by plasma (gamma‐glutamyl)citrulline, followed by betaine, beta‐cryptoxanthin, fructosyllysine, octanylcarnitine, sphingomyelin (d18:0/18:0, d19:0/17:0) and thyroxine. Subsequent machine learning analysis showed that a panel of these metabolites derived from a number of metabolic pathways may be used to predict insulin resistance, dominated by non‐essential amino acid citrulline and its metabolite gamma‐glutamylcitrulline. Conclusion This approach revealed a number of plasma metabolites that correlated reasonably well with glycemic and lipolytic flux parameters, measured using gold standard techniques. These metabolites may be used to predict the rate of glucose disposal in humans with obesity to a similar extend as HOMA, thus providing potential novel biomarkers for insulin resistance.