| p-Cresyl sulfate promotes insulin resistance associated with CKD. | |
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MedLine Citation:
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PMID: 23274953 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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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:
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Created Date: 2012-12-31 Completed Date: 2013-03-04 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 9013836 Medline TA: J Am Soc Nephrol Country: United States |
Other Details:
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Languages: eng Pagination: 88-99 Citation Subset: IM |
Affiliation:
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Hospices Civils de Lyon, Department of Nephrology, Hôpital E Herriot, Lyon, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adipocytes
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drug effects Adipose Tissue, White / drug effects Animals 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 Mice, Inbred C57BL Muscle, Skeletal / drug effects, metabolism Prebiotics Renal Insufficiency, Chronic / complications, metabolism* Signal Transduction / drug effects Uremia / diet therapy |
| Chemical | |
Reg. No./Substance:
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0/Cresols; 0/Insulin; 0/Prebiotics; 0/p-cresylsulfate; 1MXY2UM8NV/4-cresol; 50-99-7/Glucose; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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