Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Biochem Biophys Res Commun. 2011 Nov 4;414(4):670-4. doi: 10.1016/j.bbrc.2011.09.122. Epub 2011 Oct 1.
Recently it was demonstrated that the ketone body β-hydroxybutyrate (BOH) inhibits insulin-mediated glucose transport in isolated oxidative muscle, which was associated with decreased phosphorylation of Akt/protein kinase B. The purpose of the present study was to determine if activation of AMP-dependent protein kinase by the pharmacological activator AICAR could reverse the insulin resistance induced by BOH. Isolated mouse soleus muscle was incubated in vitro in the absence or presence of 5mM BOH for ∼20 h. Following prolonged incubation, insulin increased 2-deoxyglucose glucose (2-DG) uptake 3-fold, but in the presence of BOH most of the insulin response was lost (only ∼30% remained). Addition of 2mM AICAR during the last 2h of prolonged incubation increased the insulin response in the presence of BOH to ∼80% of the normal insulin effect on 2-DG uptake. The AICAR-mediated reversal of the insulin resistance was not associated with a restoration of the insulin effect on Akt/protein kinase B phosphorylation. However, AICAR enhanced the insulin-induced phosphorylation of the Akt substrate, AS160. In conclusion, these data demonstrate that AICAR reverses the negative effect of BOH on insulin-mediated glucose uptake and this is attributed to activation of a late step in insulin signaling.
最近有研究表明，酮体β-羟丁酸（BOH）可抑制分离的氧化型肌肉中的胰岛素介导的葡萄糖转运，这与 Akt/蛋白激酶 B 的磷酸化减少有关。本研究的目的是确定 AMP 依赖的蛋白激酶是否可以通过药理学激活剂 AICAR 的激活来逆转 BOH 诱导的胰岛素抵抗。将分离的小鼠比目鱼肌在体外于不存在或存在 5mM BOH 的情况下孵育约 20 小时。经过长时间孵育后，胰岛素可使 2-脱氧葡萄糖（2-DG）摄取增加 3 倍，但在 BOH 存在下，胰岛素的大部分反应丧失（仅剩余约 30%）。在长时间孵育的最后 2 小时内添加 2mM AICAR，可使 BOH 存在时的胰岛素反应增加至正常胰岛素对 2-DG 摄取的约 80%。AICAR 介导的胰岛素抵抗逆转与胰岛素对 Akt/蛋白激酶 B 磷酸化作用的恢复无关。然而，AICAR 增强了胰岛素诱导的 Akt 底物 AS160 的磷酸化。总之，这些数据表明 AICAR 逆转了 BOH 对胰岛素介导的葡萄糖摄取的负面影响，这归因于胰岛素信号转导的晚期步骤的激活。
