糖尿病血糖波动模型致大鼠海马体的炎性损伤

目的探讨血糖波动对糖尿病大鼠海马体造成的炎性损伤。方法用链脲佐菌素（streptozotocin,STZ）和葡萄糖制备SD大鼠糖尿病模型（M组）和持续高血糖模型（MS组）,并错时腹腔注射给予葡萄糖、胰岛素制备糖尿病血糖波动大鼠模型（MF组）。血糖波动造模第6周时,测定大鼠一般生理学指标,血糖（glucose,Glu）、甘油三酯（triglyceride,TG）、低密度脂蛋白（low density lipoprotein,LDL-C）和高密度脂蛋白（high density lipoprotein,HDL-C）等血液生化指标;同时采用荧光定量PCR法检测大鼠海马体中IL-1β、IL-2、IL-6、IL-8、TNF-α等炎性因子mRNA的表达,Morris水迷宫试验检测血糖波动对糖尿病大鼠学习和空间记忆功能的影响。结果 （1）血糖波动造模第6周时,M组、MS组及MF组大鼠体质量显著低于N组（P〈0.01）,M组、MS组及MF组之间在1%极显著水平下无差异（P〉0.01）。（2）尾静脉注射STZ 1周后,M组、MS组、MF组的Glu、TG、LDL-C都有显著性的提高（P〈0.01）,HDL-C显著性下降（P〈0.01）。（3）与正常组比较,各模型组海马组织的IL-1β、IL-6、IL-8以及TNF-α均呈现显著性变化（所有P〈0.05）,组间IL-2水平则差异无显著性（P〉0.05）。其中,血糖波动模型MF组IL-1β和TNF-α水平的变化最大,达到极显著水平（P〈0.01）,并显著高于M组和MS组水平（P〈0.01）。尽管IL-2水平在各组间无统计学上的差异显著,仍可见血糖波动模型MF组中表达水平最低。（4）M组、MS组、MF组的逃避潜伏期、经过平台的次数以及在平台象限内的游泳距离与N组相比均呈极显著提高（所有P〈0.01）,其中血糖波动模型MF组的逃避潜伏期和过平台次数显著高于M组和MS组（P〈0.01）,提示MF组空间定位和记忆功能受损最严重,平台象限内的游泳距离在三种糖尿病模型组间差异无显著性（P〉0.05）。结论相较急性高血糖和慢性持续性高血糖而言,波动性高血糖对大脑海马体造成的炎性损伤以及功能影响更为严重。

Blood-glucose fluctuation induces inflammatory changes in the hippocampus in rat models of diabetes mellitus

Objective To analyze the effect of blood-glucose fluctuation on inflammatory changes in the hippocampus in rat models of diabetes mellitus. Methods Sixty male Sprague-Dawley rats in the age of 6-8 weeks and body weight of 180 -210 g were included in this study. The diabetic rat model （M） was established by injection Of streptozotocin （STZ）. The persistent high glucose diabetic rat model group （MS） was established by intraperitoneal injection of glucose, and the blood-glucose fluctuation rat model group （MF） was developed by alternative intraperitonealinjection of insulin and glucose administration. Body weight, serum glucose （Glu）, triglyceride （TG）, low density lipoprotein （ LDL-C ） and high density lipoprotein （ HDL-C ） were measured at 6 weeks after MF model establishment. mRNA expression levels of IL-1 3, IL-2, IL-6, IL-8 and TNF-a in the rat hippocampus were detected by real-time PCR. The influence of blood-glucose fluctuation on learning and memory function of hippocampus was observed by Morris water maze test. Results （ 1 ） The body weights of M, MS and MF groups were signhClcantly decreased compared to that of the normal rat group （N） （P 〈 O. 01 ）. （2） One week after intravenous injection of STZ, the levels of Glu, TG and LDL-C in the M, MS and MF groups were significantly increased （all P 〈0. 01 ） , and HDL-C was significantly decreased compared with those of the N group （P 〈 0.01 ）. （3） Compared with the N group, the expression levels of IL-I ~,IL-6, IL-8 and TNF-a mRNA in the M, MS and MF groups were all changed significantly （ all P 〈 0.05 ） , while there was no significant difference in the expression of IL-2 mRNA in all rats groups （ P 〉 0.05 ）. The expression levels of IL-11~ and TNF-a mRNA in the MF group were significantly higher than those of the M and MS groups （all P 〈 0. 01 ）. （4） The escape latency, the number of rats passing hidden platform and the swimming distance in the quadrant of hidden platform of the M, MS and MF groups were significantly higher than those of the N group （all P 〈0. 01 ）. The escape latency and number of rats passing hidden platform in the MF group were significantly higher than those of the M and MS groups. There was no significant difference in swimming distance in the quadrant of h~dden platform among M, MS and MF groups （ P 〉 0. 05 ）. Conclusions Blood glucose fluctuation induces inflammatory damage and dysfunction of the hippoeampus in diabetic rats more seriously than that induced by acute hyperglycemia and chronic persistent hyperglycemia.