Tzeng T-F, Liu I-M, Cheng J-T
Department of Internal Medicine, Pao Chien Hospital, Ping Tung City, Taiwan, Republic of China.
Diabetologia. 2005 Jul;48(7):1386-92. doi: 10.1007/s00125-005-1791-6. Epub 2005 Jun 15.
AIMS/HYPOTHESIS: This study investigated the role of opioid mu-receptor activation in the improvement of insulin resistance.
Myoblast C2C12 cells were cultured with IL-6 to induce insulin resistance. Radioactive 2-deoxyglucose (2-DG) uptake was used to evaluate the effect of loperamide on insulin-stimulated glucose utilisation. Protein expression and phosphorylation in insulin-signalling pathways were detected by immunoblotting.
The insulin-stimulated 2-DG uptake was reduced by IL-6. Loperamide reversed this uptake, and the uptake was inhibited by blockade of opioid mu-receptors. Insulin resistance induced by IL-6 was associated with impaired expression of the insulin receptor (IR), IR tyrosine autophosphorylation, IRS-1 protein content and IRS-1 tyrosine phosphorylation. Also, an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase, Akt serine phosphorylation and the protein of glucose transporter subtype 4 were observed in insulin resistance. Loperamide reversed IL-6-induced decrement of these insulin signals.
CONCLUSIONS/INTERPRETATION: Opioid mu-receptor activation may improve IL-6-induced insulin resistance through modulation of insulin signals to reverse the responsiveness of insulin. This provides a new target in the treatment of insulin resistance.
目的/假设：本研究调查了阿片类μ受体激活在改善胰岛素抵抗中的作用。
将成肌细胞C2C12细胞与白细胞介素-6（IL-6）共同培养以诱导胰岛素抵抗。采用放射性2-脱氧葡萄糖（2-DG）摄取法评估洛哌丁胺对胰岛素刺激的葡萄糖利用的影响。通过免疫印迹法检测胰岛素信号通路中的蛋白质表达和磷酸化情况。
IL-6降低了胰岛素刺激的2-DG摄取。洛哌丁胺逆转了这种摄取，且该摄取被阿片类μ受体阻断所抑制。IL-6诱导的胰岛素抵抗与胰岛素受体（IR）表达受损、IR酪氨酸自身磷酸化、胰岛素受体底物-1（IRS-1）蛋白含量及IRS-1酪氨酸磷酸化有关。此外，在胰岛素抵抗中还观察到磷脂酰肌醇3-激酶的p85调节亚基减弱、蛋白激酶B（Akt）丝氨酸磷酸化以及葡萄糖转运蛋白4亚型的蛋白质减少。洛哌丁胺逆转了IL-6诱导的这些胰岛素信号的减少。
结论/解读：阿片类μ受体激活可能通过调节胰岛素信号来逆转胰岛素的反应性，从而改善IL-6诱导的胰岛素抵抗。这为胰岛素抵抗的治疗提供了一个新靶点。
