Journal
NEPHROLOGY DIALYSIS TRANSPLANTATION
Volume 32, Issue 12, Pages 2000-2009Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ndt/gfx089
Keywords
CKD; insulin resistance; p-cresyl-glucuronide; p-cresyl-sulphate; uraemic toxin
Categories
Funding
- Fondation pour la Recherche Medicale
- Societe Francaise de Nephrologie
- French 'Ministere de l'Enseignement Superieur et de la Recherche'
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Institut National des Sciences Appliquees de Lyon (INSA-Lyon)
- Federation Nationale d'Aide aux Insuffisants Renaux (FNAIR)
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Background. 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 (pCG). 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 glucosemetabolism. Methods. 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. Results. 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 <6% for p-CG). p-CG exhibited no effect on insulin sensitivity in vivo or in vitro and no synergistic inhibiting effect in combination with p-CS. Conclusions. The relative proportion of the two p-cresol conjugates, i.e. p-CS and p-CG, is similar in mouse, in contrast to humans, pinpointing major inter-species differences in endogenous metabolism. Biologically, the sulpho-(i.e. p-CS) but not the glucuro- (i.e. p-CG) conjugate promotes insulin resistance in CKD.
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