Tardif A, Julien N, Pelletier A, Thibault G, Srivastava A K, Chiasson J L, Coderre L
Department of Medicine, Research Center, Centre Hospitalier de l'Université de Montréal, University of Montreal, Montreal H2W 1T8, Canada.
Am J Physiol Endocrinol Metab. 2001 Dec;281(6):E1205-12. doi: 10.1152/ajpendo.2001.281.6.E1205.
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.
1型和2型糖尿病患者的血浆酮体浓度常常升高。由于酮体与其他能量底物竞争并减少它们的利用，它们可能参与心脏胰岛素抵抗的发生发展。我们研究了酮体水平升高对原代培养的成年心肌细胞胰岛素作用的影响。将心肌细胞与酮体β-羟基丁酸酯（β-OHB）一起培养4或16小时，并评估胰岛素刺激的葡萄糖摄取。虽然短期暴露于酮体与胰岛素作用的任何变化无关，但我们的数据表明，用β-OHB预孵育16小时会显著降低心肌细胞中胰岛素刺激的葡萄糖摄取。这种作用是浓度依赖性的，并且在从培养基中去除β-OHB后至少持续6小时。酮体还降低了佛波酯12-肉豆蔻酸酯13-乙酸酯和过钒酸钠对葡萄糖摄取的刺激作用。这种降低不能用心肌细胞中GLUT-1或GLUT-4蛋白含量的变化来解释。长期暴露于β-OHB与胰岛素和过钒酸钠刺激的蛋白激酶B激活受损有关。这些结果表明，长期暴露于酮体会改变心肌细胞中的胰岛素作用，并提示这种底物可能在心脏胰岛素抵抗的发生发展中起作用。
