Diabetic Retinopathy

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Diabetic retinopathy occurs in three-fourths of all persons with diabetes for more than 15 years (95) and is the most common cause of blindness in the industrialized world (96). It is primarily a disease of the intraretinal blood vessels, which become dysfunctional in response to hyperglycemia with progressive loss of retinal pericytes and eventually endothelial cells leading to capillary closure and widespread retinal ischemia (97).

It has been shown that AGEs disturb retinal microvascular homeostasis by inducing pericyte apoptosis and VEGF overproduction (98). In vitro work in bovine retinal endot-helial cells showed that AGEs induced VEGF overproduction through generation of oxidative stress and downstream activation of the protein kinase C pathway (99). In vitro studies in retinal organ cultures showed increased glyoxal-induced CML formation, a dose-dependent induction of apoptotic molecules and increased cell death, events that were prevented by anti-AGE agents and antioxidants (100).

AGEs were found to retard the growth of pericytes and exert an acute toxicity to these cells (98). In vitro, rat retinal vascular cells exposed to AGE show abnormal endothelial nitric oxide synthase expression, which may account for some of the vasoregulatory abnormalities observed in the diabetic vasculature (101). In vitro studies in human donor eyes showed that vitreous collagen undergoes glycation as well as copper and iron glycoxidation, leading to structural and functional impairment and possibly retinopathy (102).

Within a few months of diabetes, AGEs are already found to accumulate in vascular basement membrane and retinal pericytes of rats (103).

When nondiabetic animals were infused with AGEs for several weeks, significant amounts of these adducts distributed around and within the pericytes, colocalized with AGE receptors and induced basement membrane thickening (104) leading to loss of retinal pericytes (105). In contrast, the inhibition of AGE formation by aminoguanidine, a well known AGE inhibitor, prevented microaneurysm formation, endothelial proliferation, and pericyte loss (97). A combination of antioxidants and AGE inhibitors has been shown to prevent AGE-induced apoptosis in primary (rat) retinal organ cultures (100), although the administration of monoclonal antibodies, which recognize Amadori-modi-fied glycated albumin, reduced the thickening of the retinal basement membrane in db/ db mice, implying that even early glycated adducts may play a role in diabetic retinopathy (104). More studies are needed to confirm these data, however.

A study comparing postmortem human retinas between diabetic subjects with diabetic retinopathy and nondiabetic subjects, found that CML and VEGF immunoreactivi-ties, which were not evident in the control subjects, were distributed around blood vessels of diabetic retinas. Both VEGF and CML expression was greater in subjects with proliferative diabetic retinopathy (106). These data suggest that CML could have a role in VEGF expression in diabetic retinopathy.

In a clinical study of type 1 diabetics (38 males and 47 females) a significant elevation of serum AGE levels was found associated with severe diabetic retinopathy. CML-AGE levels were also increased at the stage of simple diabetic retinopathy suggesting a possible role of CML in the early phases of this condition (92).

Similarly, increased pentosidine levels were found in the majority of vitreous samples from diabetic patients with diabetic retinopathy compared to controls indicating that glycation occurs and is accelerated in human diabetic vitreous (107). This was further confirmed in another clinical study which involved 72 type 2 diabetics, in which sugar-induced AGEs correlated with the severity of retinopathy (108).

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