Chronic kidney disease attenuates the plasma metabolome response to insulin

Baback Roshanravan, Leila R. Zelnick, Daniel Djucovic, Haiwei Gu, Jessica A. Alvarez, Thomas R. Ziegler, Jorge L. Gamboa, Kristina Utzschneider, Bryan Kestenbaum, Jonathan Himmelfarb, Steven E. Kahn, Daniel Raftery, Ian H. de Boer

    Research output: Contribution to journalArticle

    6 Citations (Scopus)

    Abstract

    Chronic kidney disease (CKD) leads to decreased sensitivity to the metabolic effects of insulin, contributing to protein energy wasting and muscle atrophy. Targeted metabolomics profiling during hyperinsulinemic-euglycemic insulin clamp testing may help identify aberrant metabolic pathways contributing to insulin resistance in CKD. Using targeted metabolomics profiling, we examined the plasma metabolome in 95 adults without diabetes in the fasted state (58 with CKD, 37 with normal glomerular filtration rate [GFR]) who underwent hyperinsulinemic-euglycemic clamp. We assessed heterogeneity in fasting metabolites and the response to insulin to identify potential metabolic pathways linking CKD with insulin resistance. Baseline differences and effect modification by CKD status on changes with insulin clamp testing were adjusted for confounders. Mean GFR among participants with CKD was 37.3 compared with 89.3 ml/min per 1.73 m2 among controls. Fasted-state differences between CKD and controls included abnormalities in tryptophan metabolism, ubiquinone biosynthesis, and the TCA cycle. Insulin infusion markedly decreased metabolite levels, predominantly amino acids and their metabolites. CKD was associated with attenuated insulin-induced changes in nicotinamide, arachidonic acid, and glutamine/glutamate metabolic pathways. Metabolomics profiling suggests disruption in amino acid metabolism and mitochondrial function as putative manifestations or mechanisms of the impaired anabolic effects of insulin in CKD.

    Original languageEnglish (US)
    JournalJCI insight
    Volume3
    Issue number16
    DOIs
    StatePublished - Aug 23 2018

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    Metabolome
    Chronic Renal Insufficiency
    Insulin
    Metabolomics
    Metabolic Networks and Pathways
    Glucose Clamp Technique
    Glomerular Filtration Rate
    Insulin Resistance
    Anabolic Agents
    Amino Acids
    Ubiquinone
    Niacinamide
    Muscular Atrophy
    Glutamine
    Arachidonic Acid
    Tryptophan
    Glutamic Acid
    Fasting

    Keywords

    • Amino acid metabolism
    • Insulin
    • Metabolism
    • Mitochondria
    • Nephrology

    Cite this

    Roshanravan, B., Zelnick, L. R., Djucovic, D., Gu, H., Alvarez, J. A., Ziegler, T. R., ... de Boer, I. H. (2018). Chronic kidney disease attenuates the plasma metabolome response to insulin. JCI insight, 3(16). https://doi.org/10.1172/jci.insight.122219

    Chronic kidney disease attenuates the plasma metabolome response to insulin. / Roshanravan, Baback; Zelnick, Leila R.; Djucovic, Daniel; Gu, Haiwei; Alvarez, Jessica A.; Ziegler, Thomas R.; Gamboa, Jorge L.; Utzschneider, Kristina; Kestenbaum, Bryan; Himmelfarb, Jonathan; Kahn, Steven E.; Raftery, Daniel; de Boer, Ian H.

    In: JCI insight, Vol. 3, No. 16, 23.08.2018.

    Research output: Contribution to journalArticle

    Roshanravan, B, Zelnick, LR, Djucovic, D, Gu, H, Alvarez, JA, Ziegler, TR, Gamboa, JL, Utzschneider, K, Kestenbaum, B, Himmelfarb, J, Kahn, SE, Raftery, D & de Boer, IH 2018, 'Chronic kidney disease attenuates the plasma metabolome response to insulin', JCI insight, vol. 3, no. 16. https://doi.org/10.1172/jci.insight.122219
    Roshanravan B, Zelnick LR, Djucovic D, Gu H, Alvarez JA, Ziegler TR et al. Chronic kidney disease attenuates the plasma metabolome response to insulin. JCI insight. 2018 Aug 23;3(16). https://doi.org/10.1172/jci.insight.122219
    Roshanravan, Baback ; Zelnick, Leila R. ; Djucovic, Daniel ; Gu, Haiwei ; Alvarez, Jessica A. ; Ziegler, Thomas R. ; Gamboa, Jorge L. ; Utzschneider, Kristina ; Kestenbaum, Bryan ; Himmelfarb, Jonathan ; Kahn, Steven E. ; Raftery, Daniel ; de Boer, Ian H. / Chronic kidney disease attenuates the plasma metabolome response to insulin. In: JCI insight. 2018 ; Vol. 3, No. 16.
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