Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Am J Physiol Endocrinol Metab. 2010 Sep;299(3):E364-73. doi: 10.1152/ajpendo.00142.2010. Epub 2010 Jun 1.
Blood ketone body levels increase during starvation and untreated diabetes. Here we tested the hypothesis that ketone bodies directly inhibit insulin action in skeletal muscle. We investigated the effect of d,l-beta-hydroxybutyrate (BOH; the major ketone body in vivo) on insulin-mediated glucose uptake (2-deoxyglucose) in isolated mouse soleus (oxidative) and extensor digitorum longus (EDL; glycolytic) muscle. BOH inhibited insulin-mediated glucose uptake in soleus (but not in EDL) muscle in a time- and concentration-dependent manner. Following 19.5 h of exposure to 5 mM BOH, insulin-mediated (20 mU/ml) glucose uptake was inhibited by approximately 90% (substantial inhibition was also observed in 3-O-methylglucose transport). The inhibitory effect of BOH was reproduced with d- but not l-BOH. BOH did not significantly affect hypoxia- or AICAR-mediated (activates AMP-dependent protein kinase) glucose uptake. The BOH effect did not require the presence/utilization of glucose since it was also seen when glucose in the medium was substituted with pyruvate. To determine whether the BOH effect was mediated by oxidative stress, an exogenous antioxidant (1 mM tempol) was used; however, tempol did not reverse the BOH effect on insulin action. BOH did not alter the levels of total tissue GLUT4 protein or insulin-mediated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 but blocked insulin-mediated phosphorylation of protein kinase B by approximately 50%. These data demonstrate that BOH inhibits insulin-mediated glucose transport in oxidative muscle by inhibiting insulin signaling. Thus ketone bodies may be potent diabetogenic agents in vivo.
在饥饿和未经治疗的糖尿病期间，血液酮体水平会升高。在这里，我们检验了这样一个假设，即酮体直接抑制骨骼肌中的胰岛素作用。我们研究了 d,l-β-羟基丁酸（BOH；体内主要的酮体）对离体小鼠比目鱼肌（氧化）和伸趾长肌（EDL；糖酵解）肌肉中胰岛素介导的葡萄糖摄取（2-脱氧葡萄糖）的影响。BOH 以时间和浓度依赖的方式抑制比目鱼肌（但不抑制 EDL 肌肉）中的胰岛素介导的葡萄糖摄取。在 5 mM BOH 暴露 19.5 小时后，胰岛素介导的（20 mU/ml）葡萄糖摄取被抑制了约 90%（在 3-O-甲基葡萄糖转运中也观察到明显的抑制）。d-BOH 再现了 BOH 的抑制作用，但 l-BOH 没有。BOH 对缺氧或 AICAR 介导的（激活 AMP 依赖性蛋白激酶）葡萄糖摄取没有显著影响。由于在培养基中用丙酮酸替代葡萄糖时也观察到了 BOH 效应，因此 BOH 效应并不需要葡萄糖的存在/利用。为了确定 BOH 效应是否是由氧化应激介导的，使用了一种外源性抗氧化剂（1 mM tempol）；然而，tempol 并没有逆转 BOH 对胰岛素作用的影响。BOH 没有改变总组织 GLUT4 蛋白水平或胰岛素介导的胰岛素受体和胰岛素受体底物-1 的酪氨酸磷酸化，但阻止了胰岛素介导的蛋白激酶 B 的磷酸化约 50%。这些数据表明，BOH 通过抑制胰岛素信号转导来抑制氧化肌肉中的胰岛素介导的葡萄糖转运。因此，酮体在体内可能是有效的致糖尿病剂。
