Formation of Immunochemical Advanced Glycosylation End Products Precedes and Correlates With Early Manifestations of Renal and Retinal Disease in Diabetes

Abstract

Elevated levels of advanced glycosylation end products (AGEs) have been found in multiple tissues in association with diabetic vascular complications and during the microalbuminuric phase of diabetic nephropathy. In this study, we have used an AGE-specific enzyme-linked immunosorbent assay (ELISA) to measure skin AGEs to determine whether elevated levels can be detected before the onset of overt microangiopathy. Subjects with type I diabetes (n = 48) were graded for the degree of nephropathy (normal [23], microalbuminuria [12], or macroalbuminuria [12]) and retinopathy (none [13], background [20], or proliferative [15]). Subgroups with a premicroalbuminuric phase of albumin excretion (< or = 28 mg/24 h, n = 27) or with the earliest stages of retinopathy (n = 27) were identified. A significant increase in tissue AGEs was found as urinary albumin increased during the premicroalbuminuric phase of nephropathy even when the data were adjusted for age and duration of diabetes (P = 0.005). Immunoreactive AGEs also increased as normal renal status advanced to microalbuminuria and macroalbuminuria (P = 0.0001 across groups). Significant elevation of AGEs was also found in association with the earliest stages of clinically evident retinopathy (early background versus minimal grades). In addition, higher AGE levels were found in subjects with proliferative retinopathy when 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 pentosidine or fluorescent AGE measurements, although fluorescent AGEs correlated with albumin excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Simple non-invasive assessment of advanced glycation endproduct accumulation

“…In our study, creatinine levels were independently related to skin autofluorescence in diabetic patients. Renal dysfunction in diabetic patients, but also in euglycaemic patients, contributes to increased tissue AGE accumulation and to the development of cardiovascular complications in these patients [3,12,13]. Smoking, which is recognised as a source of oxidative stress in vivo [32], was also correlated with increased skin autofluorescence in control subjects.…”

“…This technique is limited by the fact that not all AGE exhibit fluorescent properties. ELISA-based assays have shown that increased accumulation of specific AGE occurs prior to increased autofluorescence in diabetes [12]. Fluorescence, as expressed in our autofluorescence ratio, is a group reactivity; consequently, it cannot provide quantitative information on the concentrations of individual compounds.…”

“…In diabetes mellitus, AGE accumulation in skin collagen is correlated both with the duration and severity of hyperglycaemia, and with the presence of long-term complications [6,7,8,12,13,14,15]. In a DCCT substudy, skin AGE levels explained 19 to 36% of the variance in the incidence of long-term diabetic complications in intensively treated patients, and 14 to 51% in conventionally treated patients [8].…”

Toxic action of advanced glycation end products on cultured retinal capillary pericytes and endothelial cells: relevance to diabetic retinopathy

“…The work of Hammes et al [37] demonstrating, (i) the presence of AGE products in retinal capillaries of 26-week diabetic rats, and (ii) significant reduction in the number of diabetes-induced acellular capillaries and pericyte loss when the formation of AGE is inhibited with aminoguanidine, seems to suggest a possible link between excessive accumulation of AGE and the pathogenesis of diabetic retinopathy. There does appear to be a good correlation between the extent to which AGE accumulates on patients' dermal collagen and the degree of diabetic retinopathy [38]. More recently, Stitt et al [32] have demonstrated that AGE-modified albumin co-localizes with the p60 and p90 component of the AGE-receptors in the retinal vasculature of both diabetic rats and AGE-infused rats suggesting that progressive accumulation of AGE may well be the underlying mechanism for the loss of pericytes and endothelial cells in early diabetic retinopathy.…”

The Framework of a Mathematical Model of the Autonomic Nervous System and Physiological Systems: Using the Neuroregulation of Blood Glucose as an Example

“…In diabetes, changes of colour perception are a feature of the onset of diabetes from its earliest pre-symptomatic onset [1,122]. This research suggests that, at least in the case of diabetes, such changes of colour perception are associated with the earliest onset of diabetes [123,124], the levels of insulin and/or blood glucose, and/or the production of highly bioluminescent glycated proteins [125,126].The development of type 2 diabetes is now measured by determining the levels of glycated haemoglobin although glycated insulin would appear to have been a more logical choice. Insulin has a relatively low half-life which may have made the selection of glycated insulin more problematic.…”