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

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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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