Chronic exposure to beta-hydroxybutyrate impairs insulin action in primarycultures of adult cardiomyocytes

Type 1 and type 2 diabetic patients often show elevated plasma ketone body concentrations. Because ketone bodies compete with other energetic substrat es 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 car diomyocytes. Cardiomyocytes were cultured with the ketone body beta -hydrox ybutyrate (beta -OHB) for 4 or 16 h, and insulin-stimulated glucose uptake was evaluated. Although short-term exposure to ketone bodies was not associ ated with any change in insulin action, our data demonstrated that preincub ation with beta -OHB for 16 h markedly reduced insulin-stimulated glucose u ptake in cardiomyocytes. This effect is concentration dependent and persist s for at least 6 h after the removal of beta -OHB from the media. Ketone bo dies also decreased the stimulatory effect of phorbol 12-myristate 13-aceta te and pervanadate on glucose uptake. This diminution could not be explaine d 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 cardiom yocytes and suggest that this substrate could play a role in the developmen t of insulin resistance in the heart.