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长期酒精暴露诱导胰岛素抵抗及视网膜微血管损伤：神经鞘磷脂的可能作用
徐高磊 王志新 赵静雅 陈文静 崔占军 王延芬 王卉 邓锦波* 高晓群
解剖学报 ›› 2013, Vol. 44 ›› Issue (4) : 441-450.
长期酒精暴露诱导胰岛素抵抗及视网膜微血管损伤：神经鞘磷脂的可能作用
Long-term alcohol exposure inducing insulin resistance and retinal microvascular damage, a possible role of sphingomyelin
目的 探讨长期酒精暴露诱导胰岛素抵抗对小鼠血视网膜屏障的损伤以及神经鞘磷脂(SM)可能的作用。 方法 选取神经鞘磷脂合成酶
2（SMS2）基因敲除(SMS2-/-)和野生型(WT)小鼠76只，酒精暴露建立动物模型。用血糖仪测定血糖浓度，酶联免疫法(ELISA)测定血胰岛素浓
度，并计算胰岛素抵抗指数(HOMA-IR)，利用免疫荧光染色、HE和电子显微镜观察血视网膜屏障的损伤。结果 长期酒精暴露引起小鼠胰岛素抵
抗 (P <0.05)，并出现血视网膜屏障的损伤，如无细胞毛细血管数增多(P <0.05)，星形胶质细胞数量减少(P <0.05)，内皮细胞和周细胞线粒
体肿胀，嵴消失，基底膜欠清晰，呈剂量依赖性。和WT小鼠相比，SMS2-/-小鼠胰岛素抵抗指数较小和血视网膜屏障损伤程度较轻(P<0.05)，
提示SMS2-/-小鼠有延缓胰岛素抵抗形成和减少血视网膜屏障损伤的作用。结论 长期酒精暴露可以诱导胰岛素抵抗，并造成血视网膜屏障损
伤，具有剂量依赖性；SMS2基因的缺失有延缓胰岛素抵抗的产生和减少血视网膜屏障损伤的作用。
Objective To investigate the mechanism of insulin resistance and retinal damages induced by long-term alcohol
exposure, especially the mechanisms which SM (sphingomyelin, SM) regulationin is involved in. Methods Sphingomyelin synthase
2 knockout (SMS2-/- ) mice and wild type (WT) mice were used to establish the long term alcohol exposure models. The total
cases were 76 in each group. Blood glucose and blood insulin were measured with ELISA assay, in both SMS2-/- mice and WT
mice. In the meantime, homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Finally, the pathologic
alterations about retinal microvasculature were investigated with immunofluorescent labeling, hematoxylin and eosin staining
and electron microscopy. Results Long-term alcohol exposure induced insulin resistance with dose dependency (P <0.05), and
blood retinal barrier (BRB) damages, such as acellular capillaries increased (P <0.05), astrocytes decreased (P <0.05) and
damages of endothelial cell in ultrastrctural level, with dose dependency. In addition, either insulin resistance index
increase or BRB damages in SMS2-/- mice were less than in WT mice (P <0.05), suggesting SMS2-/- mice might attenuate insulin
resistance and BRB damages. Conclusion The insulin resistance (IR) and BRB damages can be induced by long-term alcohol
exposure. As an oxidative stress factor, alcohol exposure may lead to the activation of PKC-NFκB-(Bcl-Xs) pathway and
produce the effects of IR and BRB damages.
胰岛素抵抗 / 酒精 / 视网膜血管 / 神经鞘磷脂 / 神经鞘磷脂合成酶2 / 免疫荧光 / 小鼠
Insulin resistance / Alcohol / Retinal capillary / Sphingomyelin / Sphingomyelin synthase 2 / Immunofluorescence / Mouse
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30670688，30771140，31070952 U1204311;国家自然科学基金重点资助项目
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