Document Detail

Chronic exposure to ketone bodies impairs glucose uptake in adult cardiomyocytes in response to insulin but not vanadate: the role of PI3-K.
MedLine Citation:
PMID:  16960657     Owner:  NLM     Status:  MEDLINE    
There is a strong positive correlation between insulin resistance and cardiac diseases. We have already shown that chronic exposure to the ketone body beta-hydroxybutyrate (OHB) decreases insulin-mediated activation of protein kinase B (PKB) and glucose uptake in cardiomyocytes. To gain further insights into the mechanism underlying ketone body-induced insulin resistance, we examined whether OHB alters activation of the insulin-signaling cascade and whether the insulinomimetic agent vanadate could bypass insulin resistance and stimulate glucose uptake in these cells. Cardiomyocytes were incubated with 5 mM OHB, 50 microM vanadate or both for 16 h before the measurement of glucose uptake or the activation of insulin-signaling molecules. While chronic exposure to OHB did not alter insulin- or vanadate-mediated activation of the insulin receptor, it suppressed insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation in response to both agonists. Furthermore, this treatment decreased by 54 and 36% the phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-K) and PKB in response to insulin, whereas it did not alter vanadate-mediated activation of these enzymes. Although insulin did not significantly stimulate p38MAPK phosphorylation, vanadate increased it by 3.8-fold. Furthermore, chronic exposure to OHB potentiated vanadate's action, resulting in a 250% increase in enzyme activation compared to control cells. Though OHB induced a 2.1-fold increase of basal ERK1/2 phosphorylation, inhibition of this enzyme with the MEK inhibitor PD98059 demonstrated that ERK1/2 did not participate in OHB-induced insulin resistance. In conclusion, ketone bodies promote insulin resistance probably through decreased activation of the PI3-K/PKB signaling cascade. Furthermore, vanadate can bypass insulin resistance and stimulate glucose uptake in OHB-treated cardiomyocytes.
Amélie Pelletier; Annie Tardif; Marie-Hélène Gingras; Jean-Louis Chiasson; Lise Coderre
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Publication Detail:
Type:  Journal Article     Date:  2006-09-08
Journal Detail:
Title:  Molecular and cellular biochemistry     Volume:  296     ISSN:  0300-8177     ISO Abbreviation:  Mol. Cell. Biochem.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-03-05     Completed Date:  2007-07-18     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0364456     Medline TA:  Mol Cell Biochem     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  97-108     Citation Subset:  IM    
Montreal Diabetes Research Centre, Centre hospitalier de l'Université de Montréal (CHUM)-Hôtel-Dieu, 3850 St. Urbain, Montreal, Que., Canada, H2W 1T7.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / metabolism*
3-Hydroxybutyric Acid / metabolism*
Cells, Cultured
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases / metabolism
Glucose / metabolism*
Insulin / metabolism*
Insulin Receptor Substrate Proteins
Ketone Bodies / metabolism*
Myocytes, Cardiac / cytology,  metabolism*
Phosphoproteins / metabolism
Protein Subunits / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Rats, Sprague-Dawley
Receptor, Insulin / metabolism
Signal Transduction / physiology
Vanadates / metabolism*
p38 Mitogen-Activated Protein Kinases / metabolism
Reg. No./Substance:
0/IRS1 protein, human; 0/Insulin Receptor Substrate Proteins; 0/Irs1 protein, rat; 0/Ketone Bodies; 0/Phosphoproteins; 0/Protein Subunits; 0/Vanadates; 11061-68-0/Insulin; 300-85-6/3-Hydroxybutyric Acid; 50-99-7/Glucose; EC 3-Kinase; EC, Insulin; EC Proteins c-akt; EC Signal-Regulated MAP Kinases; EC Mitogen-Activated Protein Kinases

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

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