Protection of exendin-4 analogue in early experimental diabetic retinopathy.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Zhang
Yu
Y
Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, 12 Middle Wulumuqi Road, Building 3, Room 802, Shanghai, 200040, China.
Wang
Qingping
Q
Zhang
Jingfa
J
Lei
Xia
X
Xu
Guo-Tong
GT
Ye
Wen
W
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002452:Cell Count; D003921:Diabetes Mellitus, Experimental / Q000175:diagnosis / Q000378:metabolism / Q000517:prevention & control*; D003930:Diabetic Retinopathy / Q000175:diagnosis / Q000378:metabolism / Q000517:prevention & control*; D004596:Electroretinography; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D007279:Injections, Subcutaneous; D008297:Male; D010455:Peptides / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D055211:Retinal Photoreceptor Cell Inner Segment / Q000473:pathology; D055214:Retinal Photoreceptor Cell Outer Segment / Q000473:pathology; D014688:Venoms / Q000627:therapeutic use*
D001786:Blood Glucose; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide