Document Detail

p-Cresyl sulfate promotes insulin resistance associated with CKD.
MedLine Citation:
PMID:  23274953     Owner:  NLM     Status:  MEDLINE    
The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD.
Laetitia Koppe; Nicolas J Pillon; Roxane E Vella; Marine L Croze; Caroline C Pelletier; Stéphane Chambert; Ziad Massy; Griet Glorieux; Raymond Vanholder; Yann Dugenet; Hédi A Soula; Denis Fouque; Christophe O Soulage
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of the American Society of Nephrology : JASN     Volume:  24     ISSN:  1533-3450     ISO Abbreviation:  J. Am. Soc. Nephrol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-31     Completed Date:  2013-03-04     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  9013836     Medline TA:  J Am Soc Nephrol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  88-99     Citation Subset:  IM    
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MeSH Terms
Adipocytes / drug effects
Adipose Tissue, White / drug effects
Cresols / administration & dosage,  metabolism*
Disease Models, Animal
Extracellular Signal-Regulated MAP Kinases / metabolism
Glucose / metabolism
Hypercholesterolemia / chemically induced
Hyperglycemia / chemically induced
Insulin / metabolism
Insulin Resistance*
Lipid Metabolism / drug effects
Mice, Inbred C57BL
Muscle, Skeletal / drug effects,  metabolism
Renal Insufficiency, Chronic / complications,  metabolism*
Signal Transduction / drug effects
Sulfuric Acid Esters
Uremia / diet therapy
Reg. No./Substance:
0/4-cresol sulfate; 0/Cresols; 0/Insulin; 0/Prebiotics; 0/Sulfuric Acid Esters; 1MXY2UM8NV/4-cresol; EC Signal-Regulated MAP Kinases; IY9XDZ35W2/Glucose

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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