Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Institut du Savoir Montfort - recherche, Ottawa, Ontario, Canada.
Am J Physiol Cell Physiol. 2024 Jun 1;326(6):C1710-C1720. doi: 10.1152/ajpcell.00718.2023. Epub 2024 May 6.
Ketone bodies (acetoacetate and β-hydroxybutyrate) are oxidized in skeletal muscle mainly during fasting as an alternative source of energy to glucose. Previous studies suggest that there is a negative relationship between increased muscle ketolysis and muscle glucose metabolism in mice with obesity and/or type 2 diabetes. Therefore, we investigated the connection between increased ketone body exposure and muscle glucose metabolism by measuring the effect of a 3-h exposure to ketone bodies on glucose uptake in differentiated L6 myotubes. We showed that exposure to acetoacetate at a typical concentration (0.2 mM) resulted in increased basal glucose uptake in L6 myotubes, which was dependent on increased membrane glucose transporter type 4 (GLUT4) translocation. Basal and insulin-stimulated glucose uptake was also increased with a concentration of acetoacetate reflective of diabetic ketoacidosis or a ketogenic diet (1 mM). We found that β-hydroxybutyrate had a variable effect on basal glucose uptake: a racemic mixture of the two β-hydroxybutyrate enantiomers (d and l) appeared to decrease basal glucose uptake, while 3 mM d-β-hydroxybutyrate alone increased basal glucose uptake. However, the effects of the ketone bodies individually were not observed when acetoacetate was present in combination with β-hydroxybutyrate. These results provide insight that will help elucidate the effect of ketone bodies in the context of specific metabolic diseases and nutritional states (e.g., type 2 diabetes and ketogenic diets). A limited number of studies investigate the effect of ketone bodies at concentrations reflective of both typical fasting and ketoacidosis. We tested a mix of physiologically relevant concentrations of ketone bodies, which allowed us to highlight the differential effects of d- and l-β-hydroxybutyrate and acetoacetate on skeletal muscle cell glucose uptake. Our findings will assist in better understanding the mechanisms that contribute to muscle insulin resistance and provide guidance on recommendations regarding ketogenic diets.
酮体（乙酰乙酸和β-羟丁酸）在空腹期间主要在骨骼肌中被氧化，作为葡萄糖的替代能源。先前的研究表明，肥胖和/或 2 型糖尿病小鼠中肌肉酮分解增加与肌肉葡萄糖代谢之间存在负相关关系。因此，我们通过测量酮体暴露 3 小时对分化的 L6 肌管葡萄糖摄取的影响来研究增加的酮体暴露与肌肉葡萄糖代谢之间的联系。我们表明，在典型浓度（0.2mM）下暴露于乙酰乙酸会导致 L6 肌管中基础葡萄糖摄取增加，这依赖于增加的膜葡萄糖转运蛋白 4（GLUT4）易位。基础和胰岛素刺激的葡萄糖摄取也随着类似于糖尿病酮症酸中毒或生酮饮食的乙酰乙酸浓度（1mM）而增加。我们发现β-羟丁酸对基础葡萄糖摄取有不同的影响：两种β-羟丁酸对映体（d 和 l）的外消旋混合物似乎降低了基础葡萄糖摄取，而单独的 3mM d-β-羟丁酸增加了基础葡萄糖摄取。然而，当乙酰乙酸与β-羟丁酸结合存在时，没有观察到酮体的单独作用。这些结果提供了有助于阐明特定代谢疾病和营养状态（例如 2 型糖尿病和生酮饮食）下酮体作用的见解。少数研究调查了反映典型禁食和酮症酸中毒的酮体浓度的影响。我们测试了一组生理相关的酮体浓度，这使我们能够突出 d-和 l-β-羟丁酸和乙酰乙酸对骨骼肌细胞葡萄糖摄取的差异作用。我们的发现将有助于更好地理解导致肌肉胰岛素抵抗的机制，并为生酮饮食的建议提供指导。
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