title: Chronic exposure to ketone bodies impairs glucose uptake in adult cardiomyocytes in response to insulin but not vanadate: the role of PI3-K.
abstract: 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.
authors.affiliation: Montreal Diabetes Research Centre, Centre hospitalier de l'Université de Montréal (CHUM)-Hôtel-Dieu, 3850 St. Urbain, Montreal, Que., Canada, H2W 1T7.
authors.forename: Amélie
authors.initials: A
authors.lastname: Pelletier
authors.forename: Annie
authors.initials: A
authors.lastname: Tardif
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Gingras
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Chiasson
authors.forename: Lise
authors.initials: L
authors.lastname: Coderre
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007657:Ketone Bodies / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D021122:Protein Subunits / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014638:Vanadates / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D007657:Ketone Bodies; D010750:Phosphoproteins; D021122:Protein Subunits; D014638:Vanadates; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose; D020155:3-Hydroxybutyric Acid