Metabolic modeling of muscle metabolism identifies key reactions linked to insulin resistance phenotypes

Molecular Metabolism
Christopher NogiecMary-Elizabeth Patti

Abstract

Dysregulated muscle metabolism is a cardinal feature of human insulin resistance (IR) and associated diseases, including type 2 diabetes (T2D). However, specific reactions contributing to abnormal energetics and metabolic inflexibility in IR are unknown. We utilize flux balance computational modeling to develop the first systems-level analysis of IR metabolism in fasted and fed states, and varying nutrient conditions. We systematically perturb the metabolic network to identify reactions that reproduce key features of IR-linked metabolism. While reduced glucose uptake is a major hallmark of IR, model-based reductions in either extracellular glucose availability or uptake do not alter metabolic flexibility, and thus are not sufficient to fully recapitulate IR-linked metabolism. Moreover, experimentally-reduced flux through single reactions does not reproduce key features of IR-linked metabolism. However, dual knockdowns of pyruvate dehydrogenase (PDH), in combination with reduced lipid uptake or lipid/amino acid oxidation (ETFDH), does reduce ATP synthesis, TCA cycle flux, and metabolic flexibility. Experimental validation demonstrates robust impact of dual knockdowns in PDH/ETFDH on cellular energetics and TCA cycle flux in cult...Continue Reading

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Citations

Apr 30, 2015·Metabolites·Mark T Mc AuleyStephen J Wilkinson
Sep 15, 2015·PloS One·Leanne S Whitmore, Ping Ye
Jun 21, 2016·Current Diabetes Reports·Alba Gonzalez-FranquesaMary-Elizabeth Patti
Oct 1, 2016·Molecular Metabolism·Carles LerinMary-Elizabeth Patti
Apr 27, 2018·Endocrine Reviews·Reuben L SmithRiekelt H Houtkooper
Mar 20, 2018·Alternatives to Laboratory Animals : ATLA·Zeeshan AliJohn J Pippin
Jan 18, 2017·Bioscience Reports·Mark T Mc AuleyCarole J Proctor
Aug 18, 2018·Experimental and Therapeutic Medicine·Nikolaos GoutzourelasDemetrios Kouretas
Feb 8, 2018·Trends in Endocrinology and Metabolism : TEM·Alba Gonzalez-Franquesa, Mary-Elizabeth Patti
May 22, 2021·Cell Communication and Signaling : CCS·Mehrshad Sadria, Anita T Layton
Apr 27, 2016·Journal of Proteome Research·Sergio PolakofBlandine Comte

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Datasets Mentioned

BETA
GSE25462

Methods Mentioned

BETA
biopsy
biopsies

Software Mentioned

limma
R
GLPK
MATLAB

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