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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.

SUBMITTER: Roshanravan B

PROVIDER: S-EPMC6141172 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Chronic kidney disease attenuates the plasma metabolome response to insulin.

Roshanravan Baback B Zelnick Leila R LR Djucovic Daniel D Gu Haiwei H Alvarez Jessica A JA Ziegler Thomas R TR Gamboa Jorge L JL Utzschneider Kristina K Kestenbaum Bryan B Himmelfarb Jonathan J Kahn Steven E SE Raftery Daniel D de Boer Ian H IH

JCI insight 20180823 16

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 fil ...[more]

PMID: 30135309

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Project description:METHODS:A cross-over study within a split-plot design was performed using healthy (n = 10) and CKD cats [IRIS Stage 1 and 2; n = 10]. Cats were fed dry Prescription Diet® k/d® Feline with chicken, during a pre-trial period and then randomly assigned to two fiber treatments for 4 weeks each. Treatment foods were formulated similar to pre-trial food, with the exception that they contained 0.500% betaine, 0.586% oat beta glucan, and either 0.407% short chain fructooligosaccharides (scFOS) fiber or 3.44% apple pomace. Both foods had similar crude fiber percent (2.0 and 2.1% for scFOS and apple pomace, respectively) whereas soluble fiber was 0.8 and 1.6%, respectively. RESULTS:Plasma metabolites separated cats based on health status. At baseline, cats with CKD had significantly higher circulating concentrations of creatinine, urea, and some microbial and host tryptophan metabolites including several indole sulfates and kynurenate. Healthy cats had higher concentrations of the antioxidant α-tocopherol after consuming apple pomace; alternatively, they had higher concentrations of inflammatory sphingolipid metabolites after consuming scFOS, but not after consuming apple pomace. The CKD cats had higher concentrations of the more oxidized glutathione metabolites after consuming apple pomace compared with scFOS, as well as higher concentrations of inflammatory sphingolipid metabolites after consuming apple pomace, but not scFOS. After consuming scFOS, CKD cats had lower concentrations of the phenolic uremic toxins guaiacol sulfate and 4-vinylphenol sulfate compared with after consuming apple pomace. At baseline, there were five significant microbiota OTU differences in CKD cats compared with healthy cats. Overall, the OTUs in CKD cats were more resistant to change after feeding either fiber source. Counts of an unclassified genus in the family S24-7 in the order Bacteroidales (OTU 100296), were lower in CKD cats compared with healthy cats at baseline (P = 0.001), but increased after consumption of food containing scFOS (P = 0.006). Linear regression analysis showed that this genus had significant negative correlations with several microbial uremic toxins. None of the baseline differences in OTUs between healthy and CKD cats changed after CKD cats consumed food containing apple pomace. CONCLUSIONS:Health status impacts the influence of dietary fermentable fibers on the feline plasma metabolome and fecal microbiome. A more readily fermented fiber such as scFOS is preferable to apple pomace as a fiber source for cats with CKD.

Project description:BackgroundCorrection of metabolic acidosis (MA) with nutritional therapy or bicarbonate administration is widely used in chronic kidney disease (CKD) patients. However, it is unknown whether these interventions reduce insulin resistance (IR) in diabetic patients with CKD. We sought to evaluate the effect of MA correction on endogenous insulin action in diabetic type 2 (DM2) CKD patients.MethodsA total of 145 CKD subjects (83 men e 62 women) with DM2 treated with oral antidiabetic drugs were included in the study and followed up to 1 year. All patients were randomly assigned 1:1 to either open-label (A) oral bicarbonate to achieve serum bicarbonate levels of 24-28 mmol/L (treatment group) or (B) no treatment (control group). The Homeostatic model assessment (HOMA) index was used to evaluate IR at study inception and conclusion. Parametric and non-parametric tests as well as linear regression were used.ResultsAt baseline no differences in demographic and clinical characteristics between the two groups was observed. Average dose of bicarbonate in the treatment group was 0.7 ± 0.2 mmol/kg. Treated patients showed a better metabolic control as confirmed by lower insulin levels (13.4 ± 5.2 vs 19.9 ± 6.3; for treated and control subjects respectively; p < 0.001), Homa-IR (5.9[5.0-7.0] vs 6.3[5.3-8.2]; p = 0.01) and need for oral antidiabetic drugs. The serum bicarbonate and HOMA-IR relationship was non-linear and the largest HOMA-IR reduction was noted for serum bicarbonate levels between 24 and 28 mmol/l. Adjustment for confounders, suggests that serum bicarbonate rather than treatment drives the effect on HOMA-IR.ConclusionsSerum bicarbonate is related to IR and the largest HOMA-IR reduction is noted for serum bicarbonate between 24 and 28 mmol/l. Treatment with bicarbonate influences IR. However, changes in serum bicarbonate explains the effect of treatment on HOMA index. Future efforts are required to validate these results in diabetic and non-diabetic CKD patients.Trial registrationThe trial was registered at www.clinicaltrial.gov (Use of Bicarbonate in Chronic Renal Insufficiency (UBI) study - NCT01640119 ).

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Chronic kidney disease attenuates the plasma metabolome response to insulin.

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Chronic kidney disease attenuates the plasma metabolome response to insulin.

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