Regular articleThe role of advanced glycation in the pathogenesis of diabetic retinopathy
Section snippets
Introduction to diabetic retinopathy
Diabetes mellitus is increasing at an alarming rate, especially the noninsulin dependent diabetes mellitus (NIDDM) form of the disease. Indeed, by the year 2010, the total number of people with diabetes is projected to reach 221 million worldwide [1]. Patients with both NIDDM and insulin-dependent diabetes (IDDM) are prone to the development of complications that represent a major cause of morbidity and mortality. Together, macro- and microvascular diabetic complications are an ever-increasing
Biology of advanced glycation
Reducing sugars react with free amino groups to form Schiff base adducts and Amadori products such as fructose-lysine. In biological systems these intermediates are freely reversible and therefore exist in an equilibrium that is proportional to the amount of free glucose. As a result, the levels of Amadori products in diabetic patients are usually no more than two- to threefold higher than in their nondiabetic counterparts. This is an indication of the freely reversible nature of these products
AGEs and nonretinal diabetic microvasculopathy—clues for retinopathy?
Diabetes-mediated formation and accumulation of AGEs have been widely implicated in micro- and macrovascular complications (Fig. 3). For example, these adducts accumulate in the kidney at a rapid rate in diabetes [63] occurring in glomerular BM, mesangial cells, and renal tubules (64), (65). In this tissue, AGEs can induce transforming growth factor β (TGF-β) expression and associated upregulation of various extracellular matrix (ECM) mRNAs [66]. This contributes to glomerular hypertrophy, BM
Serum AGEs and accumulation of AGEs in diabetic retina
A number of clinical studies have reported that the levels of AGEs in serum (79), (84), (85), skin [86], or cornea [87] correlate with the onset or clinical grade of diabetic retinopathy. Indeed, it is interesting that serum AGEs are significantly elevated in diabetic prepubescent children and adolescents who have background or preproliferative retinopathy compared to counterparts who are free from clinical signs of the disease [88]. Some of these clinical studies measured a range of
Summary
It is evident that AGEs play an important pathogenic role in diabetic retinopathy. However, as with other diabetic micro- and macrovascular complications, it should be appreciated that the onset and progression of retinopathy probably involves a complex interplay between a range of pathogenic mechanisms. This reflects the multifactorial nature of metabolic upset within the diabetic milieu. Long-term management of retinopathy in the ever-growing number of diabetic patients will involve precise
Acknowledgements
The support of Fight for Sight (UK), Diabetes UK, The Juvenile Diabetes Foundation International, The National Lottery Charities Board, The Iris Fund, The Wellcome Trust and the Research and Development Office (NI) are gratefully acknowledged.
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