New Approach to Preventing and Treating Diabetes Mellitus: Focus on Advanced Glycation End Products (AGE)

In this chapter, we discuss the role of advanced glycation end products (AGE) in the pathogenesis of diabetes and its complications, as well as potential AGEfocused treatment strategies. AGE are compounds that form as a result of chemical reactions from the glycation of proteins and lipids. Glycation of proteins alters their structure and function (extracellular effects), and AGE also bind to receptors which promote inflammatory pathways (intracellular effects). AGE are formed endogenously through normal metabolism and aging, and AGE formation is accelerated in certain pathologic states such as diabetes (due to hyperglycemia) and oxidative stress (via reactive oxygen species). AGE accumulation and deposition are reported in chronic inflammatory diseases such as atherosclerosis and diabetes. AGE deposits form crosslinks with matrix proteins resulting in increased stiffness of collagen, decreased elasticity of vasculature, increased muscle stiffness and reduction in function. AGE can also be formed through prolonged heating of food (such as frying and grilling). Tobacco smoke is another source of exogenous AGE. High AGE diet is associated with increasing weight gain, adiposity, and insulin resistance. Treatment approaches include inhibiting AGE formation, breaking formed cross-links, or blocking negative effects of AGE. Treatment of underlying pathologic states that accelerate AGE formation (hyperglycemia, oxidative stress and hypoxia) is also important. Reducing exogenous intake of AGE is a lifestyle modification in the treatment and prevention of diabetes and obesity that will lower the risk of developing complications, and probably also lower the risk of developing diabetes itself. The pathogenesis of type 2 diabetes is not yet fully elucidated. AGE are implicated in the development of diabetes and its complications, and anti-AGE therapies represent a novel category of therapeutic interventions against diabetes.

Keywords: Diabetes, advanced glycation end products (AGE), retinopathy, neuropathy, nephropathy, diabetes complications, receptor for AGE (RAGE), methylglyoxal.