小剂量胰岛素治疗对糖尿病大鼠脊髓N-甲基-D-天冬氨酸受体及其下游信使表达的影响  

Effect of low-dose insulin on spinal N-methyl-D-aspartate receptor levels and the downstream signals in streptozotocin-induced diabetic rats

作　　者：王佳超[1] 张劲松[3] 孙文佳[1] 孙杰[1] 齐若梅[1] 龚涛[2] 蒋云[2] 

机构地区：[1]卫生部北京老年医学研究所,100730 [2]北京医院神经内科 [3]北京医院病理科

出　　处：《中华老年医学杂志》2016年第4期432-436,共5页Chinese Journal of Geriatrics

基　　金：人事部回国启动基金（BJ-2008-133）

摘　　要：目的探讨小剂量胰岛素治疗对糖尿病大鼠脊髓N-甲基-D-天冬氨酸受体（NMDAR）及其下游信使，主要是丝裂原活化蛋白激酶（MAPKs）的家族成员c—Jun氨基末端激酶（JNK）及细胞外调节蛋白激酶（ERK）表达的影响及其意义。方法10周龄雄性SD大鼠随机分为三组：正常对照组、糖尿病组和糖尿病胰岛素治疗组。链脲霉素（Strepzotocin，STZ）腹腔内注射2周后，胰岛素治疗组开始皮下注射甘精胰岛素2U／d，连续8周，取腰段脊髓，采用蛋白免疫印迹法检测磷酸化胰岛素受体底物1（P-IRS1）、磷酸化NMDAR NR1亚单位（P-NR1）、P-JNK和P—p44／42MAPK的表达。实验结束前1周，测定三组动物的足底热痛觉潜伏期。结果（1）糖尿病组和糖尿病胰岛素治疗组的血糖水平均显著升高；（2）与对照组相比，糖尿病组和糖尿病胰岛素治疗组足底热痛觉潜伏期均明显缩短（P〈0．001）；与糖尿病治疗组相比，糖尿病组足底热痛觉潜伏期缩短更明显（P〈0．05）。（3）与对照组相比，糖尿病组P—IRS1、P—NR1、P—JNK及P—p44／42MAPK的表达分别增加了79．2％、35．1％、47．6％、64．3％和87．6％（均P〈0．001），糖尿病胰岛素治疗组分别增加了49．4％、19．1％、16．5％、31．8％和39．9％（均P〈0．05）；与糖尿病组相比，胰岛素治疗组的上述四个参数分别降低了29．8％、16．0％、31．2％、32．5％和47．7％（均P〈0．05）。结论NMDAR及其下游信使JNK和p44／42MAPK参与糖尿病性神经痛的发生；小剂量胰岛素治疗虽然不能控制血糖，但是可以通过抑制NMDAR通路的活化，部分抑制热痛觉过敏的发生。Objective To investigate the effect and its significance of low dose insulin on N- methyl-D-aspartate receptor （NMDAR） level and its downstream signaling of e Jun N-terminal kinase （JNK） and the extracellular signal-regulated protein kinase （ERK, p44/42MAPK） in streptozotocininduced diabetic rats. Methods Ten-week-old male SD rats were randomly divided into 3 groups： control group,diabetic group and insulin-treated diabetes group. Diabetes was induced by streptozocin （STZ,60mg/kg） injected intraperitoneaily. Two weeks after STZ injection, insulin glargine （92u/day for 8 weeks） was subcutaneously injected in the insulin-treated diabetes group. Then, the rat lumbar spinal cords were collected. The protein levels of phospho-Insulin receptor substrate 1 （P-IRS1）, phospho-NMDAR NR1 subunit （P-NR1）, P-JNK and P-p44/42MAPK were evaluated by Western blotting. One week before the terminal of the study,paw thermal response latency was measured in all groups. Results Blood glucose levels were tremendously high in both the diabetic group and insulintreated diabetes group. Compared with the control group, paw thermal response latency was markedly shortened in the diabetic group （P〈0. 001） and the insulin treated diabetes group （P〈0. 001）,and the alteration was more pronounced in the diabetic group （P〈 0.05）. Compared with the control group,the protein levels of P IRS1, P-NR1 ,P-JNK and P p44/42MAPK were increased by 79.2G, 35.1%,47.6%,64.3% and 87.6%,respectively in diabetic group and 49.4%,19.1%,16.5%,31.8% and 39.9% ,respectively in insulin treated diabetes group （all P〈0. 001 or 0.05）. In comparison with diabetic group, the increased amplitudes of above 4 parameters were decreased by 29.8%, 16.0%, 31.2%,32.5% and 47.7% respectively in the insulin-treated diabetes group （all P〈0.05）. Conclusions NMDAR and its downstream signals, such as JNK and p42/44MARK, are involved in the pathogenesis of painful diabetic neuropathy. Although it could not efficiently control th

关 键 词：糖尿病 神经痛 脊髓 受体 N-甲基-D-天冬氨酸 

分 类 号：R587.2[医药卫生—内分泌]