p-Cresyl glucuronide is a major metabolite of p-cresol in mouse: in contrast to p-cresyl sulphate, p-cresyl glucuronide fails to promote insulin resistance

The role of uraemic toxins in insulin resistance associated with chronic kidney disease (CKD) is gaining interest. p-Cresol has been defined as the intestinally generated precursor of the prototype protein-bound uraemic toxins p-cresyl sulphate (p-CS) as the main metabolite and, at a markedly lower...

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Bibliographic Details
Published in:Nephrology, dialysis, transplantation dialysis, transplantation, 2017-12, Vol.32 (12), p.2000-2009
Main Authors: Koppe, Laetitia, Alix, Pascaline M, Croze, Marine L, Chambert, Stéphane, Vanholder, Raymond, Glorieux, Griet, Fouque, Denis, Soulage, Christophe O
Format: Article
Language:English
Subjects:
Animals
Cresols - blood
Cresols - pharmacology
Glucuronides - blood
Glucuronides - pharmacology
Insulin - metabolism
Insulin Resistance
Life Sciences
Mice
Renal Insufficiency, Chronic - drug therapy
Renal Insufficiency, Chronic - physiopathology
Signal Transduction - drug effects
Sulfuric Acid Esters - blood
Sulfuric Acid Esters - pharmacology
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Summary:The role of uraemic toxins in insulin resistance associated with chronic kidney disease (CKD) is gaining interest. p-Cresol has been defined as the intestinally generated precursor of the prototype protein-bound uraemic toxins p-cresyl sulphate (p-CS) as the main metabolite and, at a markedly lower concentration in humans, p-cresyl glucuronide (p-CG). The objective of the present study was to evaluate the metabolism of p-cresol in mice and to decipher the potential role of both conjugates of p-cresol on glucose metabolism. p-CS and p-CG were measured by high performance liquid chromatography-fluorescence in serum from control, 5/6 nephrectomized mice and mice injected intraperitoneously with either p-cresol or p-CG. The insulin sensitivity in vivo was estimated by insulin tolerance test. The insulin pathway in the presence of p-cresol, p-CG and/or p-CS was further evaluated in vitro on C2C12 muscle cells by measuring insulin-stimulated glucose uptake and the insulin signalling pathway (protein kinase B, PKB/Akt) by western blot. In contrast to in humans, where p-CS is the main metabolite of p-cresol, in CKD mice both conjugates accumulated, and after chronic p-cresol administration with equivalent concentrations but a substantial difference in protein binding (96% for p-CS and
ISSN:0931-0509
1460-2385
DOI:10.1093/ndt/gfx089