ABSTRACT

Merlin C Thomas1, Mark E Cooper1 , George Jerums2, 1Danielle Alberti Memorial Centre for Diabetes Complications, Baker Heart Research Institute, Melbourne 8008, Victoria, AUSTRALIA; 2University of Melbourne, Director of Endocrinology, Endocrine unit, Austin and Repatriation Medical Centre (Austin Campus), West Heidelberg, Victoria, AUSTRALIA

Prolonged hyperglycemia and oxidative stress in diabetes result in the production and accumulation of advanced glycation end products (AGEs) [1]. AGEs are formed via the Maillard or ‘browning’ reaction between reducing sugars and amine residues on proteins, lipids or nucleic acids. Under normal circumstances, this reaction is slow, meaning that AGE-modification predominantly occurs in long-lived molecules such as collagen and lens proteins [1]. The degree of AGE-modification therefore represents one mechanism to judge the ‘age’ of a molecule allowing the recognition of senescent targets for excretion or catabolism [2]. In addition, as molecular turnover is reduced with increasing chronological age [3], the amount and variety of AGE-modified tissue increases, contributing to many of the changes recognised as signs of ageing (such as cataracts and stiffness). In diabetes, prolonged hyperglycemia and oxidative stress hasten the formation of AGEs [4], meaning not only that long-lived proteins become more heavily modified but also that shorter-lived molecules such as apolipoproteins become targets for de novo advanced glycation [1,2]. In addition, the intracellular formation of AGEs from reactive carbonyl intermediates may occur at a much faster rate than glucose-derived AGE formation that occurs outside the cell. These intracellular AGEs potentially represent an important source of glycation products, as AGE levels may be increased after only days of hyperglycemia, well before similar changes can be demonstrated in vitro.