**2.3 Orally absorbed AGEs**

92 Biomedical Science, Engineering and Technology

C-terminally truncated soluble form of RAGE has received much attention. Soluble RAGE consists of several forms including endogenous secretory RAGE (esRAGE) which is a spliced variant of RAGE 12, and a shedded form derived from cell surface RAGE 13, 14. These heterogeneous forms of soluble RAGE, carrying all of the extracellular domains but devoid of the transmembrane and intracytoplasmic domains, bind ligands including AGEs, and may antagonize RAGE signaling in vitro and in vivo. ELISA systems to measure plasma esRAGE and total soluble RAGE have been developed, and decreased plasma esRAGE is found to be associated with insulin resistance, obesity and metabolic syndrome 15. Moreover, our recent observation highlights the direct role of RAGE in adiposity; RAGE deficiency is associated with less weight gain, less abdominal fat mass, less adipocyte size, less atherosclerotic lesion

Insulin resistance is the primary mechanism underlying the development of type 2 diabetes and is a central component defining the metabolic syndrome, a constellation of abnormalities including obesity, hypertension, glucose intolerance, and dyslipidemia. Insulin resistance or metabolic syndrome has been defined to be associated with low-grade inflammation, and therefore inflammation could contribute in large part to its development 17, implicating an intriguing possibility that this pathophysiological condition is also an additional face of metabolic memory driven by RAGE axis. Although insulin resistance has been characterized by complex factors including genetic determinants, nutritional factors, and lifestyle, growing evidence suggests that mediators synthesized from inflammatory cells are critically involved in the regulation of insulin action. In brief, insulin binding to its specific receptor stimulates tyrosine phosphorylation of insulin receptor substrate (IRS) proteins, which is a crucial step for insulin signaling system. Many inflammatory signals appear to induce serine phosphorylation of IRS, which could be involved in disruption of insulin-receptor signaling 17. In this chapter, we would like to summarize the recent findings regarding pathophysiological roles of RAGE

AGEs are proteins generated by a series of reactions termed the Maillard Reaction. Classically, AGE formation has been described by a nonenzymatic reaction between proteins and glucose 18, 19. AGEs derive from the spontaneous reaction of carbohydrates with amino group of proteins, which undergo from the formation of reversible products (Schiff base adducts) to the generation of more stable products (Amadori products). Subsequently, complex reactions occur including intermolecular crosslink formation, and cleavage through oxidation, dehydration, condensation, cyclization, and other reactions follows, with generation of AGEs through a late reaction characterized by fluorescent and brown coloration and molecular crosslinkage. Recently, it was confirmed that AGEs are also formed by non-enzymatic reaction of reactive carbonyl compounds such as 3 deoxyglucosone, methylglyoxal resulting from persisting high blood glucose level, and

There is also increasing evidence that AGEs are also formed through lipid-derived intermediates, resulting in advanced lipoxidation products 20. AGEs might be formed directly by autoxidation of free glucose 21, 22. In this pathway, known as autoxidative

formation and higher plasma adiponectin than wild type control 16.

and soluble RAGE in insulin resistance and metabolic syndrome.

oxidative stress associated with the amino residues of proteins.

**2.2 AGEs formation independent of hyperglycemia** 

**2.1 AGE formation by glucose and its derivatives** 

**2. AGEs** 

In addition to the endogenously formed, AGEs are abundant in exogenous sources such as foods, especially when prepared under elevated temperatures 23. Vlassara's group has extensively examined the role of the exogenous AGEs in several pathological conditions (see review in 24). After ingestion, 10% of orally-administered AGEs are absorbed into the circulation 25-27, majorities of which are shown to be accumulated in tissues. Among them are tissue-reactive α, β-dicarbonyl-containing intermediate products, such as methylglyoxal, which has been linked to cellular oxidant stress and apoptosis 28, and terminal products, such as ε *N*-carboxymethyllysine (CML), which is formed by glycoxidation as well as by lipoxidation 29-31. Both methylglyoxal and CML have been identified in vivo and are shown to be associated with oxidant stress and tissue damage 31-33.
