The receptor for advanced glycation of end products (RAGE) plays a critical role in the progressionof type 2 diabetes (T2D). Soluble RAGE (sRAGE) is one of the RAGE variants, whichacts as a decoy domain receptor and competes with RAGE, thus contributing to preventionof T2D. In this study, we conducted clinical trials of (–)-epigallocatechin-3-gallate (EGCG)rich green tea extract (300–900 mg/day) to investigate the effect of EGCG on relationshipbetween S100A12 RAGE ligand and diverse sRAGE in T2D. Moreover, mechanism of sRAGEproduction also confirmed in vitro. Our data indicated that EGCG could stimulate sRAGEcirculation but inhibited RAGE ligand in T2D, and ADAM10-mediated ectodomain shedding ofextracellular RAGE was mainly involved in EGCG-stimulated sRAGE circulation. The presentevidence indicates that EGCG has a potential to block S100A12-RAGE axis by stimulatingsRAGE production through ADAM10-mediated ectodomain shedding of extracellular RAGE.Therefore, EGCG contributes to nutritional strategies for diabetes, not only because of itsefficient antioxidant activity to scavenge free radicals, but also because of its ability stimulatingsRAGE release in the circulation. Additionally, ADAM10-induced ectodomain shedding ofextracellular RAGE leading to sRAGE circulation should be a potential of passive mechanism ofsRAGE production to block S100A12-RAGE axis-related pathogenesis of proinflammation anddiabetes
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