血糖波动对2型糖尿病大鼠肾组织病理改变及IGF-1 、MMP-2表达的影响

Impacts of blood glucose fluctuation on renal pathologic changes and IGF-1, MMP-2 expression

目的 观察血糖波动对2型糖尿病大鼠肾组织病理及胰岛素样生长因子（IGF）-1、基质金属蛋白酶（MMP）-2表达的影响.方法 将45只雄性Sprague-Dawley（SD）大鼠根据随机数字表法随机分为正常对照组（N组,n=10）和糖尿病模型组（DM组,n=35）.糖尿病模型组给予高糖、高脂饲料4周后,腹腔注射链脲佐菌素（STZ）35 mg/kg诱导建立2型糖尿病大鼠模型.造模成功的糖尿病大鼠根据随机数字表法随机分为持续高血糖组（C组,n=17）和血糖波动组（F组,n=17）.F组大鼠每日皮下注射普通胰岛素并错时给予葡萄糖诱导血糖波动.N组及C组予以等量生理盐水腹腔注射,F组、C组继续喂以高糖、高脂饲料,N组给予普通饲料.12周后采集尿液标本测24 h尿白蛋白,10％水合氯醛腹腔麻醉后,腹主动脉取血测血尿素氮、血肌酐、HbA1c,取肾组织行HE、PAS染色观察肾组织形态,电镜观察超微结构,免疫组织化学检测IGF-1、MMP-2的表达.结果 F组大鼠血糖波动较大,与N组、C组相比,血糖变异系数（CV值）明显升高（P＜0.05）.与N组相比,F组、C组HbA1c水平升高,差异有统计学意义（P＜0.05）,C组与F组相比,HbA1c水平差异无统计学意义（P＞0.05）.与C组相比,F组的尿白蛋白水平、肾脏肥大指数、肾小球硬化指数、肾小球基底膜厚度明显升高,差异均有统计学意义（P均＜0.05）;与C组相比,F组大鼠肾组织IGF-1表达增多,MMP-2表达减少（P均＜0.05）.结论 血糖波动可加重糖尿病肾病进展,其机制可能与上调IGF-1及下调MMP-2表达有关.

Objective To investigate the impacts of blood glucose fluctuation on renal pathologic changes and IGF-1,MMP-2 expression.Methods Forty five male Sprague-Dawley （SD） rats were divided into two groups according to random number table method：experimental group （DM group,n =35） and normal control group（N group,n =10）.Streptozotocin （35 mg/kg） was used to induce diabetes.SD rats were fed with high sugar and high fat diet for 4 weeks,and then were divided into fluctuating blood glucose group（F group,n =17） and continuous high blood glucose group （C group,n =17）.The rats in F group were given intraperitoneal injection of insulin and glucose at different time points every day.The same volume of physiological saline was given to rats in C and N group.High sugar and high fat diets were maintained in rats in F and C group,while ordinary diet were given to the rats in N group.12 weeks later,24 hours urine protein,blood urea nitrogen,serum creatinine were determined,HE and PAS staining were used to observe the renal morphology,and electron microscopy was applied to observe the ultrastructural change of kidney.Expression of IGF-1 and MMP-2 were determined by immunohistochemistry.Results Rats of F group suffered more serious blood glucose fluctuation with CV value significantly higher than that in rats of C and N group.No significant difference of HbA1c between rats of F and C group,while both higher than rats of N group.Compared with C group,rats in F group showed higher 24 hours urinary protein,kidney hypertrophy index,glomerulosclerosis index,thicker of glomerular basement membrane,and greater elevation of IGF-1 expression,while less MMP-2 expression（all P＜0.05）.Conclusions Blood glucose fluctuation may aggravate diabetic kidney damage,the mechanism of which may be related to the upregulation of IGF-1,while downregulation of MMP-2.