Advanced glycation end products and diabetic complications

Abstract

During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasma proteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed.

Keywords: Advanced glycation end-products; Diabetic complications; Inflammation; Oxidative stress; Plasma proteins.

Fig. 1

Persistently elevated glucose levels during long standing diabetes induce structural and functional changes in different protein in the body including albumin, globulins, fibrinogen and collagens. Glycation of these proteins is associated with induction of deleterious changes in the body.

Fig. 2

Formation of advanced glycation end products in three stages i.e., early, intermediate and late stage involving (AGEs). In an early stage, sugars react with a free amino group to form Schiff base which undergoes a rearrangement to a more stable product known as amadori product. In an intermediate stage, amadori product degrades to a variety of reactive dicarbonyl compounds. In the late stage of the glycation process AGEs (irreversible compounds) are formed.

Fig. 3

Interaction of AGE with RAGE leading to oxidative stress and initiation of inflammation cascade involving activation of MAPK pathway, NF-kB, IL-6, TNF-α, expression of ICAM-1 and VCAM-2 which ultimately leads to diabetic complications.