Amelioration of diabetes-associated abnormalities in the vitreous fluid by an inhibitor of albumin glycation.
OBJECTIVE
Albumin modified by Amadori glucose adducts is a plasma-borne factor that activates cell signaling pathways, modulates the expression of growth factors and cytokines, and participates in the pathogenesis of microvascular complications of diabetes. In the present study, streptozotocin diabetic rats were treated with an orally administered compound that inhibits the nonenzymatic glycation of albumin to evaluate whether increased glycated albumin contributes to diabetes-associated abnormalities in the vitreous fluid.


METHODS
Vitreous obtained from age-matched nondiabetic and streptozotocin-diabetic rats, half of which received the test compound 2-(3-chlorophenylamino) phenylacetic acid (23CPPA) by oral gavage for 26 weeks, was analyzed by immunoassay for pigment epithelium-derived factor (PEDF), vascular endothelial growth factor (VEGF) and glycated albumin content, by measurement of thiobarbituric acid reactive substances (TBARs) for lipid peroxide products and by colorimetric assay for hyaluronan content.


RESULTS
Compared with that of nondiabetic controls, vitreous of diabetic rats contained decreased PEDF, increased VEGF, higher VEGF/ PEDF ratio, and elevated levels of TBARs, glycated albumin, and hyaluronan. These changes were significantly attenuated in rats treated with test compound despite the presence of marked hyperglycemia.


CONCLUSIONS
Results indicate that inhibiting the formation of glycated albumin, which is increased in diabetes, ameliorates vitreous changes in angiogenic and metabolic factors associated with the development of diabetic retinopathy. The observed improvement in vitreous alterations associated with reductions in glycated albumin suggests that elevated levels of glycated albumin play a retinopathogenic role in diabetes that is operative and that can be therapeutically addressed independently of glycemic status.
Cohen
Margo P
MP
Glycadia, Inc, Philadelphia, Pennsylvania 19103, USA. drmpcohen@aol.com
Hud
Elizabeth
E
Wu
Van-Yu
VY
Shearman
Clyde W
CW
D000818:Animals; D003124:Colorimetry; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005136:Eye Proteins / Q000378:metabolism; D005500:Follow-Up Studies; D017127:Glycation End Products, Advanced; D006031:Glycosylation; D006820:Hyaluronic Acid / Q000378:metabolism; D007118:Immunoassay; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015843:Serpins / Q000378:metabolism; D012709:Serum Albumin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014822:Vitreous Body / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000093423:Glycated Serum Albumin; D000099174:Pigment Epithelium-Derived Factor
D004008:Diclofenac; D005136:Eye Proteins; D017127:Glycation End Products, Advanced; D006820:Hyaluronic Acid; D009414:Nerve Growth Factors; D015843:Serpins; D012709:Serum Albumin; D017392:Thiobarbituric Acid Reactive Substances; D042461:Vascular Endothelial Growth Factor A; D000093423:Glycated Serum Albumin; D000099174:Pigment Epithelium-Derived Factor; C518289:2-(3-chlorophenylamino)phenylacetic acid