Chronic kidney disease attenuates the plasma metabolome response to insulin

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.

Keywords: Amino acid metabolism; Insulin; Metabolism; Mitochondria; Nephrology.

Figure 1. Fold changes in fasting metabolites comparing CKD and controls (n = 93), adjusted for age, sex, race/ethnicity (European descent versus non–European descent), and weight.

Figure 2. Comparison of fasting metabolomic profiles and pathway differences between CKD and non-CKD participants (n = 93).

(A) Percent changes in TCA cycle metabolites and amino acid precursors to TCA cycle metabolites, comparing CKD (n = 58) and non-CKD (n = 35) participants. Fasting metabolomic pathways significantly different between CKD and controls. Blue represents glucogenic and ketogenic amino acids and green represents glucogenic amino acids. (B) Results from pathway enrichment analysis. Asterisks denote significance after adjustment for age, sex, race/ethnicity, body weight, and batch. PDH, pyruvate dehydrogenase; PC, pyruvate carboxylase; SDH, succinate dehydrogenase.

Figure 3. Comparison of metabolite concentrations before and during the insulin infusion as part of the hyperinsulinemic-euglycemic clamp procedure (n = 60).

(A) Volcano plot of fold change (FC) in metabolites with insulin infusion in entire cohort (n = 60). (B) Pathway analysis of changes with insulin infusion in the overall cohort (n = 60). (C) Pathway analysis of changes with insulin infusion comparing CKD (n = 40) with controls (n = 20). ALA, α linolenic acid; Ile, Isoleucine; L-Kyn, L-kynurenine; AA, arachidonic acid.

Figure 4. Comparison of adjusted mean percent change in metabolite subgroups from fasting to during the insulin infusion at euglycemia (n = 60).

Adjusted for age, sex, race/ethnicity, weight, and batch.