罗格列酮对糖尿病大鼠模型早期皮肤改变防护作用的机制研究

摘要/Abstract

摘要：

目的探讨罗格列酮对糖尿病大鼠早期皮肤病变的防护作用。方法用链脲佐菌素将8 ～ 10周龄雄性Wistar大鼠诱导成糖尿病大鼠模型，分为胰岛素治疗组、罗格列酮治疗组、未治疗组，并以正常大鼠作对照组。于第16周末抽取各组大鼠心脏血，测定TNF-α、IL-6、C反应蛋白、SOD、P物质水平。处死大鼠，取背正中处皮肤进行病理学观察，皮肤全层与真皮厚度测量；免疫组化染色观察皮肤中晚期糖基化终末产物（AGE）与过氧化物酶体增殖物激活受体（PPAR-γ）含量的变化。结果未治疗组IL-6（135.05 ± 43.39 ng/L）、TNF-α（1.45 ± 0.67 μg/L）、C反应蛋白（3.51 ± 0.62 mg/L）水平均明显高于正常对照组（99.92 ± 32.36 ng/L、0.86 ± 0.60 μg/L、2.54 ± 1.31 mg/L），P值均＜ 0.05，而胰岛素组和罗格列酮组与正常对照组比较差异无统计学意义；未治疗组的SOD（70.71 ± 37.52 U/mL）、P物质（22.22 ± 7.93 ng/L）与正常对照组（137.76 ± 27.6 U/mL、29.57±3.74 ng/L）相比，均明显降低（P ＜ 0.01），胰岛素组和罗格列酮组的SOD（149.96 ± 13.25 U/mL、128.50 ± 38.27 U/mL）和P物质（29.79 ± 5.21 ng/L、33.35 ± 15.0 ng/L）与未治疗组比较显著增高（P < 0.01、 < 0.05）。第16周末未治疗组大鼠皮肤全层明显变薄（0.77 ± 0.18 mm），与正常对照组（1.59 ± 0.26 mm）、胰岛素组（1.47 ± 0.50 mm）、罗格列酮组（1.22 ± 0.47 mm）比较，差异均有统计学意义（P ＜ 0.01或＜ 0.05）。第16周末未治疗组大鼠表皮细胞层次欠清晰，真皮层胶原萎缩、肿胀，退化变性，皮下脂肪进行性萎缩或消失。胰岛素组和罗格列酮组未出现明显的组织学改变。免疫组化显示：AGE蛋白、PPAR-γ蛋白均呈棕黄色颗粒状，定位于皮肤的血管基底膜、基质细胞等处；在未治疗组AGE最高，PPAR-γ最低。结论糖尿病大鼠皮肤病变AGE蓄积和炎症因子增高，罗格列酮对糖尿病大鼠早期皮肤病变具有防护作用。

关键词: 【关键词】糖尿病, 罗格列酮, 晚期糖基化终末产物（AGE）, 过氧化物酶体增殖物激活受体-γ(PPAR-γ), 皮肤, 病理

Abstract:

Objective To study the protective effects of rosiglitazone against early skin changes in experimental diabetic rats. Methods Diabetic models were established in male Wistar rats aged 8 to 10 weeks by using streptozotocin （STZ）. Then, 39 experimental diabetic rats were equally divided into insulin-treated diabetic group （DI group）, rosiglitazone-treated diabetic group （DR group）, diabetic control group （DC group）, and 13 normal rats served as the control （C group）. The rats were given subcutaneous insulin （1 - 2 U） twice daily in DI group, intragastric rosiglitazone （5 mg/kg） once daily in DR group, and intragastric sterile water in DC and C groups. Sixteen weeks later, heart blood samples were collected from all the rats for the measurement of tumor necrosis factor （TNF）-α, interleukin （IL）-6, C reactive protein （CRP）, superoxide dismutase （SOD） and P substance （SP） levels, then the rats were killed and tissue samples were obtained from the medial area of the dorsal skin and subjected to pathological observation, measurements of skin as well as dermal thickness, and immunohistochemical examinations for the expression of advanced glycation end products （AGEs） and peroxisome proliferator activated receptor-γ （PPAR-γ）. Results The levels of IL-6, TNF-α and CRP in the DC group were significantly higher than those in the C group （135.05 ± 43.39 ng/L vs. 99.92 ± 32.36 ng/L, 1.45 ± 0.67 μg/L vs. 0.86 ± 0.60 μg/L, 3.51 ± 0.62 mg/L vs. 2.54 ± 1.31 mg/L, all P ＜ 0.05）, while no significant difference was found between C group and DI group or DR group （all P > 0.05）. Decreased levels of SOD and SP were noted in the DC group （70.71 ± 37.52 U/mL, 22.22 ± 7.93 ng/L）, compared with the C group （137.76 ± 27.6 U/mL, 29.57 ± 3.74 ng/L, both P ＜ 0.01）, DI group （149.96 ± 13.25 U/mL, P < 0.01; 29.79 ± 5.21 ng/L, P < 0.05） and DR group （128.50 ± 38.27 U/mL, P < 0.01; 33.35 ± 15.0 ng/L, P < 0.05）. Micrometer measurements indicated that the skin thickness was significantly lower in the DC group than in the C group, DI group and DR group （0.77 ± 0.18 mm vs. 1.59 ± 0.26 mm, 1.47 ± 0.50 mm and 1.22 ± 0.47 mm, P ＜ 0.01, 0.01, 0.05 respectively）. Histological observation found a mild disarrangement of epidermal cells, shrinkage, swelling and degeneration of dermal collagen as well as progressive atrophy or disappearance of subcutaneous fat in the DC group. No obvious histological changes appeared in the DI or DR group. Immunohistochemistry indicated that AGEs and PPAR-γ proteins, which were stained into brown granules, were located in the vascular basement membrane, stromal cells, etc, of skin. The DC group showed the highest expression of AGEs but lowest expression of PPAR-γ. Conclusions There is an accumulation of AGEs and elevated expressions of inflammatory factors in the skin of experimental diabetic rats, and rosiglitazone shows a protective effect against the early skin changes.

张晓菲郝飞杨景. 罗格列酮对糖尿病大鼠模型早期皮肤改变防护作用的机制研究[J]. 中华皮肤科杂志, 2010, 43(11): 796-800.

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