Advanced glycation end products and RAGE signaling in diabetic cardiomyopathy: distinct mechanisms, human evidence, and translational barriers

Figure 1. Integrated framework linking diabetic metabolic and dicarbonyl stress to AGE-mediated myocardial remodeling and translational barriers. AGE, advanced glycation end product; RAGE, receptor for advanced glycation end products; DCM, diabetic cardiomyopathy; ROS, reactive oxygen species; NF-κB, nuclear factor kappa B; MAPK, mitogen-activated protein kinase; JAK/STAT, Janus kinase/signal transducer and activator of transcription; MGO, methylglyoxal; 3-DG, 3-deoxyglucosone; GLO1, glyoxalase 1. Diabetic metabolic stress expands AGE burden through chronic hyperglycemia, reactive dicarbonyl formation, oxidative imbalance, and impaired renal clearance. MGO is shown as a representative dicarbonyl; the broader category also includes glyoxal and 3-DG, while impaired GLO1-dependent detoxification may further increase dicarbonyl burden. The schematic distinguishes RAGE-independent matrix cross-linking/stiffening from RAGE-dependent ligand signaling. These mechanisms may contribute to myocardial remodeling and functional deterioration, but their pathway-specific causal contribution in human DCM remains incompletely established.

Figure 2. Structural organization of RAGE and multiligand signaling under physiological conditions and diabetic cardiometabolic stress. AGE, advanced glycation end product; RAGE, receptor for advanced glycation end products; sRAGE, soluble receptor for advanced glycation end products; HMGB1, high-mobility group box 1; DIAPH1, diaphanous-related formin 1; ROS, reactive oxygen species; NF-κB, nuclear factor kappa B; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinase 1/2; JNK, c-Jun N-terminal kinase; JAK/STAT, Janus kinase/signal transducer and activator of transcription. The right panel depicts the broader diabetic cardiometabolic environment, which may include hyperglycemia, obesity, hypertension, renal dysfunction, lipotoxicity, and systemic inflammation. Increased AGEs and non-AGE ligands may enhance RAGE engagement and DIAPH1-dependent signaling. DIAPH1 is an intracellular signaling effector rather than a ligand, and evidence for myocardial RAGE–DIAPH1 signaling in human DCM remains predominantly preclinical and indirect. sRAGE is shown as a potential extracellular decoy receptor.

Figure 3. RAGE-dependent multiligand inflammatory–oxidative signaling network in diabetic cardiomyopathy. AGE, advanced glycation end product; RAGE, receptor for advanced glycation end products; TLR4, Toll-like receptor 4; MyD88, myeloid differentiation primary response 88; DIAPH1, diaphanous-related formin 1; ROS, reactive oxygen species; NF-κB, nuclear factor kappa B; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinase 1/2; JNK, c-Jun N-terminal kinase; NLRP3, NOD-like receptor family pyrin domain containing 3; ASC, apoptosis-associated speck-like protein containing a CARD; SIRT1, sirtuin 1; PPARγ, peroxisome proliferator-activated receptor gamma; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; IL-1β, interleukin-1β; IL-18, interleukin-18; TGF-β, transforming growth factor-β; ECM, extracellular matrix; DCM, diabetic cardiomyopathy. This figure specifically summarizes receptor-dependent signaling initiated by AGEs and non-AGE DAMPs. RAGE-independent structural effects of AGEs, particularly extracellular matrix cross-linking and myocardial stiffening, are presented separately in Figure 1 and discussed in the main text. RAGE-dependent signaling…