FORMATION OF IMMUNOCHEMICAL ADVANCED GLYCOSYLATION END-PRODUCTS PRECEDES AND CORRELATES WITH EARLY MANIFESTATIONS OF RENAL AND RETINAL DISEASE IN DIABETES

Elevated levels of advanced glycosylation end products (AGEs) have bee n found in multiple tissues in association with diabetic vascular comp lications and during tile microalbuminuric phase of diabetic nephropat hy. In this study, we have used an AGE-specific enzyme-linked immunoso rbent assay (ELISA) to measure skin AGEs to determine whether elevated levels can be detected before the onset of overt microangiopathy. Sub jects with type I diabetes (n = 48) were graded for the degree of neph ropathy (normal [23], microalbuminuria [12], or. macroalbuminuria [12] ) and retinopathy (none [13], background [20], or proliferative [15]). Subgroups with a premicroalbuminuric phase of albumin excretion (less than or equal to 28 mg/24 h, n = 27) or with the earliest stages of r etinopathy (n = 27) were identified. A significant increase in tissue AGEs was found as urinary, albumin increased during the premicroalbumi nuric phase of nephropathy even when the data were adjusted for age an d duration of diabetes (P = 0.005). Immunoreactive AGEs also increased as normal renal status advanced to microalbuminuria and macroalbuminu ria (P = 0.0001 across groups). Significant elevation of AGEs was also found in association with the earliest stages of clinically evident r etinopathy (early background versus minimal grades). In addition, high er AGE levels were found in subjects with proliferative retinopathy wh en compared with those with less severe retinopathy (P < 0.004 across groups). In contrast, no significant differences were found in tissue AGE levels between groups with or without early retinopathy based on p entosidine or fluorescent AGE measurements, although fluorescent AGEs correlated with albumin excretion. In conclusion, levels of collagen-L inked AGEs, when measured by an AGE-specific ELISA, reveal a correlati on with preclinical stages of diabetic nepluropathy and early retinopa thy not indicated by other methods and may prove useful as early marke rs of microangiopathy in type I diabetes.