**1. Introduction**

90 Biomedical Science, Engineering and Technology

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Large randomized studies in diabetes have established that early intensive glycemic control reduces the risk of diabetic microvascular complications, with less impact on macrovascular complications 1, 2. In type 2 diabetic patients, further intensive therapy to target normal glycated hemoglobin levels also failed to reduce mortality and major cardiovascular events 3, 4, while it may be rather harmful 5. However, follow-up data of these trials reveal a longterm influence of early metabolic control on longer cardiovascular outcomes, even though the influence on glycemic control has been immediately disappeared after the trials 6, 7. This phenomenon has recently been defined as "metabolic memory". In at-risk patients with type 2 diabetes, intensive intervention with multiple drug combinations and behavior modification had similar sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes 8. Similarly in patients with end-stage renal disease (ESRD), intensive interventions to the general risk factors, such as high LDL-cholesterol or C-reactive protein, have not been successful in improving their cardiovascular outcomes 9, 10, suggesting that the beneficial effect of risk reduction may be overwhelmed by accumulated "metabolic memory" by long-term exposure to oxidative stress during the progression of renal failure.

Potential mechanisms for propagating this "memory" are the non-enzymatic glycation of cellular and tissue proteins which are conceptualized as advanced glycation end-products (AGEs), the generation of which has been implicated to be deeply associated with increased oxidative stress as well as hyperglycemia. AGEs, with their receptor (receptor for AGEs, RAGE), potentially mediate molecular and cellular pathway leading to metabolic memory. Moreover, interaction of the RAGE with AGEs leads to crucial biomedical pathway generating intracellular oxidative stress and inflammatory mediators, which could result in further amplification of the pathway involved in AGE generation.

By utilizing genetically engineered mouse models, emerging evidence suggests that AGE/RAGE axis is also found to be profoundly associated with non-diabetic, non-uremic pathophysiological conditions including 1) atherogenesis, 2) angiogenic response, 3) vascular injury, and 4) inflammatory response (see review in 11), many of which are now implicated in metabolic syndrome. Numerous truncated forms of RAGE have also been described, and the 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 formation and higher plasma adiponectin than wild type control 16.

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 and soluble RAGE in insulin resistance and metabolic syndrome.
