Zhang Yu, Wang Qingping, Zhang Jingfa, Lei Xia, Xu Guo-Tong, Ye Wen
Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, 12 Middle Wulumuqi Road, Building 3, Room 802, Shanghai, 200040, China.
Graefes Arch Clin Exp Ophthalmol. 2009 May;247(5):699-706. doi: 10.1007/s00417-008-1004-3. Epub 2008 Dec 16.
Diabetic retinopathy (DR) is one of the leading causes of blindness, affecting over 90% of diabetics. Exendin-4 (E4) is a potent and long-acting agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 is an insulinotropic gut peptide, which normalizes blood glucose level and is now being tested in clinical trials as a treatment for diabetes. The purpose of our study was to explore the protective effect of subcutaneous (sc.) exendin-4 analogue (E4a) on early DR.
Expression of GLP-1R was detected at both mRNA and protein levels and verified by immunohistochemistry. Thirty-six Sprague-Dawley (SD) rats were included in the experiment. Diabetes was induced by intraperitoneal injection (ip) of streptozotocin (STZ). The rats were divided into three groups: normal control (N), diabetic control (D) and E4a-treated diabetic (E4a) group. For the E4a group, the rats were treated with E4a (sc.0.05 microg/g BW/day); for the N and D groups, the rats were treated with normal saline (NS, sc). Blood glucose levels and body weight were measured weekly. Electroretinogram (ERG) was performed 1 and 3 months after diabetes onset. The retinal thickness and cell counts in each layer were evaluated under light microscopy after ERG examination.
GLP-1R was expressed at both mRNA and protein levels in the retina of SD rats. Immunostaining of the rat retina revealed that GLP-1R was predominantly expressed in the inner layer of the retina. E4a can reduce the blood glucose level of diabetic rats to the normal control level. B-wave amplitudes and OPs decreased with the progress of diabetes, and E4a prevents the loss of b-wave amplitude and OPs caused by diabetes. The retinal thickness was reduced in a diabetes-duration-dependent fashion. The cell counts of both ONL and INL were reduced accordingly in the diabetic rats. E4a prevented cell loss and maintained a normal thickness.
GLP-1R is expressed in rat retina. Apoptosis is an important constituent of retinal cell death in early DR. E4a administration can reverse the changes of ERG, prevent the retinal cell death and maintain normal retinal thickness in diabetic rats. Therefore, this is a potent approach for treatment of early DR.
糖尿病视网膜病变（DR）是导致失明的主要原因之一，影响超过90%的糖尿病患者。艾塞那肽-4（E4）是胰高血糖素样肽-1（GLP-1）受体的强效长效激动剂。GLP-1是一种促胰岛素分泌的肠肽，可使血糖水平正常化，目前正在临床试验中作为糖尿病的治疗方法进行测试。我们研究的目的是探讨皮下注射艾塞那肽-4类似物（E4a）对早期DR的保护作用。
在mRNA和蛋白质水平检测GLP-1R的表达，并通过免疫组织化学进行验证。36只Sprague-Dawley（SD）大鼠纳入实验。通过腹腔注射链脲佐菌素（STZ）诱导糖尿病。大鼠分为三组：正常对照组（N）、糖尿病对照组（D）和E4a治疗糖尿病组（E4a）。对于E4a组，大鼠接受E4a治疗（皮下注射0.05μg/g体重/天）；对于N组和D组，大鼠接受生理盐水（NS，皮下注射）治疗。每周测量血糖水平和体重。糖尿病发病后1个月和3个月进行视网膜电图（ERG）检查。ERG检查后，在光学显微镜下评估视网膜厚度和各层细胞计数。
GLP-1R在SD大鼠视网膜的mRNA和蛋白质水平均有表达。大鼠视网膜免疫染色显示，GLP-1R主要在内层视网膜表达。E4a可将糖尿病大鼠的血糖水平降低至正常对照水平。随着糖尿病进展，B波振幅和振荡电位降低，E4a可防止糖尿病引起的B波振幅和振荡电位丧失。视网膜厚度以糖尿病病程依赖的方式降低。糖尿病大鼠外核层（ONL）和内核层（INL）的细胞计数相应减少。E4a可防止细胞丢失并维持正常厚度。
GLP-1R在大鼠视网膜中表达。细胞凋亡是早期DR视网膜细胞死亡的重要组成部分。给予E4a可逆转ERG变化，防止糖尿病大鼠视网膜细胞死亡并维持正常视网膜厚度。因此，这是治疗早期DR的有效方法。
