姜黄素衍生物L6H4对2型糖尿病大鼠肝组织的保护作用

The protective effect of curcumin derivative L6H4 on the hepatic tissue from type 2 diabetic rats

目的:探讨姜黄素衍生物L6H4对2型糖尿病及高脂大鼠肝组织的保护作用及其机制。方法:40只雄性SD大鼠随机均分为5组:正常对照组、高脂组、高脂治疗组、糖尿病组及糖尿病治疗组。高脂高糖喂养诱导高脂模型,高脂高糖喂养加腹腔注射链脲佐菌素(STZ)诱导2型糖尿病模型。高脂治疗组和糖尿病治疗组用0.2mg·kg^(-1)·d^(-1)L6H4灌胃8周。生化法检测大鼠血糖、血脂水平以及血谷丙转氨酶(ALT)、谷草转氨酶(AST)、血浆白蛋白(ALB)等肝功能指标;放射免疫法测定血胰岛素(FINs)水平并计算胰岛素抵抗指数(HOMA-IR);光镜及透射电镜下观察大鼠肝组织形态改变;免疫组织化学法检测大鼠肝脏转化生长因子β1(TGF-β1)、基质金属蛋白酶抑制剂2(TIMP-2)、基质金属蛋白酶2(MMP-2)的蛋白表达水平。结果:高脂组、糖尿病组血糖,血脂及血清ALT、AST水平显著升高,ALB水平显著下降,经L6H4干预后,高脂治疗组及糖尿病治疗组的血糖,血脂及血清ALT、AST均明显下降,ALB明显增高。高脂组肝细胞脂肪变性,有少量胶原纤维形成;糖尿病组正常肝索结构破坏,肝细胞脂肪变性更为显著,局灶可见坏死,纤维增生明显,纤维间隔增厚,汇管区可见粗大胶原纤维;L6H4治疗后上述形态学改变明显改善。高脂组及糖尿病组肝脏TGF-β1、TIMP-2蛋白表达升高,MMP-2蛋白表达下降,L6H4治疗后,TGF-β1、TIMP-2蛋白表达明显降低,MMP-2蛋白表达明显升高。结论:姜黄素衍生物L6H4可改善2型糖尿病大鼠的糖脂代谢及胰岛素抵抗,对2型糖尿病及高脂大鼠肝组织具有保护作用,抑制肝脏TGF-β1及TIMP-2表达,上调MMP-2表达为其可能机制。

Objective： To investigate the protective effect and its mechanism of curcumin derivative L6H4 on hepatic tissue from type 2 diabetic and hyperlipidemic rats. Methods： Forty male Sprague-Dawley （SD） rats were randomly divided into five groups evenly, normal control group, high fat group, high fat＋L6H4 treated group, diabetes mellitus group and diabetes mellitus＋L6H4 treated group. The rats were fed with high fat and high sugar diet to induce hyperlipidemic model, and then injected with streptozotocin intraperitoneally to induce type 2 diabetic models. Rats in high fat＋L6H4 treated group and diabetes mellitus＋L6H4 treated group were given a gavage of curcumin derivative L6H4 at a dosage of 0.2 mg·kg^-1·d^-1 for 8 weeks. After the treatment, blood glucose and lipid levels as well as serum liver function indexes： alanine aminotransferase （ALT）, aspartate ami- notransferase （AST）, albumin （ALB） were measured by automatic biochemical analyzer, free blood insulin （FIN） was tested by radioimmunoassay and homeostasis model assessment of insulin resistance （HOMA-IR） were calculated. The morphology of liver was observed under light microscope and transmission electron microscope. The expression of transforming growth factor β1 （TGF-β1）, tissue inhibitor metalloprotemase 2 （TIMP-2） and matrix metalloproteinase 2 （MMP-2） were measured by immunohistochemical method. Results： Compared with normal control group, blood glucose and lipid levels, ALT as well as AST were significantly increased while ALB was significantly decreased in high fat and diabetes mellitus groups. After the treatment of L6H4, blood glucose and lipid levels as well as serum liver function indexes （ALT, AST） were markedly decreased while ALB was in- creased in high fat＋L6H4 treated group and diabetes mellitus＋L6H4 treated groups. Fatty degeneration and mild proliferation of fibrous tissue could be observed in high fat group, and the diabetes mellitus group showed further damage with focal necrosis, more pronounced fatty degeneration, and destruction of the hepatic cord, proliferation of fibrous tissue was remarkable, resulting in the thicker septa and the well observed deposition of collagen fiber in portal area, and were relived by the treatment of L6H4. The expression of TGF-β1, TIMP-2 and MMP-2 were markedly increased in high fat group and diabetes mellitus group, after the appliance of L6H4, TGF-β1 and TIMP-2 were decreased while MMP-2 was increased. Conclusion： Curcumin derivative L6H4 shows an effect in attenuating insulin resistance and regulating glucolipid metabolism, and exerts protective effect on the hepatic tis- sue from type 2 diabetic rats, down-regulation of the expression of TGF-[31, TIMP-2 and up-regulation of MMP-2 maybe involved in it.