Insulin increases retinal hemorrhage in mild oxygen-induced retinopathy in the rat: inhibition by riluzole.
OBJECTIVE
Although hyperglycemia is likely the main stimulus for VEGF induction in diabetic retinopathy (DR), a switch from oral hypoglycemic therapy to parenteral insulin injection, despite producing better glucose control, sometimes paradoxically aggravates DR. The induction of VEGF by insulin, as observed in certain conditions, may be a plausible mechanism for this phenomenon. In the present study, to determine the role of insulin in proliferative diabetic retinopathy, the authors examined whether insulin treatment affected the outcome of oxygen-induced retinopathy (OIR) in rats and whether the anti-amyotrophic lateral sclerosis (ALS) drug riluzole with protein kinase C-inhibiting activity can attenuate the effects of insulin.


METHODS
To examine in vivo the effects of insulin, mild OIR was produced in 7-day-old rat pups by raising them with a nursing mother in a 55% oxygen environment for 5 days. After that, rat pups were injected daily with subcutaneous saline or insulin (4 U/d) with or without additional riluzole injection (10 mg/kg/d, intraperitoneally) for 5 days in room air.


RESULTS
Insulin treatment substantially increased VEGF levels, extraretinal vessel formation, matrix metalloproteinase activity, and the extent of retinal hemorrhage in rat pups with mild OIR compared with saline controls. Riluzole substantially reduced all these changes induced by insulin.


CONCLUSIONS
In the present study, OIR was used as a surrogate model for DR because the core pathology and the VEGF-mediated mechanism are shared by both conditions. As in human DR, in rat pups with mild OIR, insulin treatment aggravated retinal hemorrhage, which was blocked by riluzole. Riluzole is a Food and Drug Administration-approved anti-ALS drug with a favorable adverse effect profile. It may be useful as an anti-VEGF treatment in DR, especially in reducing the retinal hemorrhage that often occurs shortly after the switch from oral hypoglycemics to parenteral insulin.
Yoo
Min-Heui
MH
NRL Neural Injury Research Center, University of Ulsan College of Medicine, Songpa-Gu, Seoul, Korea.
Yoon
Young Hee
YH
Chung
Hyewon
H
Cho
Kyung Sook
KS
Koh
Jae-Young
JY
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D003911:Dextrans; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005451:Fluorescein Angiography; D005452:Fluoresceins; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D007231:Infant, Newborn; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000009:adverse effects*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010100:Oxygen / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012166:Retinal Hemorrhage / Q000139:chemically induced / Q000517:prevention & control*; D012171:Retinal Vessels / Q000187:drug effects; D012178:Retinopathy of Prematurity / Q000139:chemically induced / Q000517:prevention & control*; D019782:Riluzole / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D003911:Dextrans; D018691:Excitatory Amino Acid Antagonists; D005452:Fluoresceins; D007004:Hypoglycemic Agents; D007328:Insulin; D042461:Vascular Endothelial Growth Factor A; C052526:fluorescein-dextran; C467498:vascular endothelial growth factor A, rat; D019782:Riluzole; D020782:Matrix Metalloproteinases; D010100:Oxygen