Chronic exposure to beta-hydroxybutyrate impairs insulin action in primary cultures of adult cardiomyocytes.
Type 1 and type 2 diabetic patients often show elevated plasma ketone body concentrations. Because ketone bodies compete with other energetic substrates and reduce their utilization, they could participate in the development of insulin resistance in the heart. We have examined the effect of elevated levels of ketone bodies on insulin action in primary cultures of adult cardiomyocytes. Cardiomyocytes were cultured with the ketone body beta-hydroxybutyrate (beta-OHB) for 4 or 16 h, and insulin-stimulated glucose uptake was evaluated. Although short-term exposure to ketone bodies was not associated with any change in insulin action, our data demonstrated that preincubation with beta-OHB for 16 h markedly reduced insulin-stimulated glucose uptake in cardiomyocytes. This effect is concentration dependent and persists for at least 6 h after the removal of beta-OHB from the media. Ketone bodies also decreased the stimulatory effect of phorbol 12-myristate 13-acetate and pervanadate on glucose uptake. This diminution could not be explained by a change in either GLUT-1 or GLUT-4 protein content in cardiomyocytes. Chronic exposure to beta-OHB was associated with impaired protein kinase B activation in response to insulin and pervanadate. These results indicate that prolonged exposure to ketone bodies altered insulin action in cardiomyocytes and suggest that this substrate could play a role in the development of insulin resistance in the heart.
Tardif
A
A
Department of Medicine, Research Center, Centre Hospitalier de l'Université de Montréal, University of Montreal, Montreal H2W 1T8, Canada.
Julien
N
N
Pelletier
A
A
Thibault
G
G
Srivastava
A K
AK
Chiasson
J L
JL
Coderre
L
L
D020155:3-Hydroxybutyric Acid / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006321:Heart / Q000187:drug effects*; D007329:Insulin Antagonists / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D007657:Ketone Bodies / Q000378:metabolism; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley
D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007329:Insulin Antagonists; D007657:Ketone Bodies; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; C495679:Slc2a1 protein, rat; C495694:Slc2a4 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D020155:3-Hydroxybutyric Acid