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Abstract: FR-OR130

CKD Attenuates the Plasma Metabolome Response to Insulin

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1302 Health Maintenance, Nutrition, and Metabolism: Clinical

Authors

  • Roshanravan, Baback, University of Washington - Kidney Research Institute, Seattle, Washington, United States
  • Zelnick, Leila R., Kidney Research Institute, Seattle, Washington, United States
  • Alvarez, Jessica A., Emory University SOM, Atlanta, Georgia, United States
  • Gamboa, Jorge, Vanderbilt University, Nashville, Tennessee, United States
  • Ziegler, Thomas, ASN, Lilburn, Georgia, United States
  • Utzschneider, Kristina M., University of Washington, Seattle, Washington, United States
  • Kahn, Steven E., University of Washington, Seattle, Washington, United States
  • Kestenbaum, Bryan R., University of Washington, Seattle, Washington, United States
  • Raftery, Daniel, University of Washington, Seattle, Washington, United States
  • de Boer, Ian H., Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, Washington, United States
Background

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 potential aberrant metabolic pathways contributing to insulin resistance among patients with CKD.

Methods

Using a targeted metabolomics profiling, we examined the plasma metabolome in 95 adults without diabetes in the fasted state (58 with moderate-severe CKD, 37 with normal glomerular filtration rate (GFR)) of whom 60 had plasma collected during a hyperinsulinemic-euglycemic clamp (40 with CKD). We assessed heterogeneity in fasting metabolites and the response to insulin to identify potential cellular metabolic pathways linking CKD with insulin resistance. Differences and changes in metabolite concentrations by CKD status and with insulin clamp testing were adjusted for potential confounders of age, sex, race/ethnicity (white versus non-white) and body weight. Pathway analysis was performed using Metaboanalyst

Results

Mean GFR among participants with CKD was 37.3 mL/min per 1.73m2compared to 89.3 ml/min per 1.73m2among controls. In the fasting state, differences between CKD and control subjects included significant abnormalities in tryptophan metabolism, ubiquinone biosynthesis, and the TCA cycle (Figure). Insulin infusion markedly decreased plasma 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 (Figure).

Conclusion

Targeted plasma metabolomics profiling suggests broad disruption in amino acid metabolism and mitochondrial function as putative manifestations or mechanisms of the impaired anabolic effects of insulin in CKD.

Comparison of fasting (left panel) and insulin clamp (right panel) metabolic pathway differences between CKD and controls.

Funding

  • NIDDK Support