Advanced Glycation End Products: Formation, Role in Diabetic Complications, and Potential in Clinical Applications

Abstract

Hyperglycemic conditions and disruptions to glucose-regulating pathways lead to increased formation of highly reactive aldehydes, methylglyoxal and glyoxal, which react with certain arginine and lysine residues in proteins to form advanced glycation end products (AGEs). These AGEs damage the integrity of the retinal vasculature predominantly through two mechanisms: non-receptor-mediated damage, which pertains to the interaction with extracellular matrix and its functional properties, and receptor-mediated damage through AGE interactions with their receptors (RAGE) on pericytes and Muller cells. Damage occurring between AGE and RAGE potentially generates reactive oxygen species, inflammatory cytokines, and growth factors. Both mechanisms result in increased permeability of endothelial tight junctions, and this increased permeability can lead to leaking and eventually ischemia. Once this ischemia becomes significant, neovascularization can occur, the hallmark of proliferative diabetic retinopathy. Current pharmaceutical studies have shown the potential of AGE inhibitors, such as aminoguanidine, in decreasing AGE production, thus minimizing its effects in hyperglycemic conditions. Other pharmaceutical interventions, such as Tanshinone IIA, aim to protect cells from the impacts of AGEs. Future research will not only continue to understand the properties of AGEs and their effects on diabetes and diabetic complications like diabetic retinopathy but will also explore how they impact other diseases.

Association of glycation markers with the progression of the initial stages of diabetic non-proliferative retinopathy in type 2 diabetes mellitus

“…The biggest diabetic manifestations with ETDRS 35, 43, 47, which corresponded to moderate NPDR, were determined in patients with the maximum initial content of AGE-CML and the minimum -sRAGE. Enhancement of the AGE-RAGE pathway removes the inhibitory signal for endothelial cell proliferation, activates VEGF formation and facilitates angiogenesis, leading to pericyte death, which are crucial factors in the development of vascular abnormalities in NPDR [24].…”

Prediction of the Development of the Initial Stage of Non-Proliferative Diabetic Retinopathy in Type 2 Diabetes Mellitus

“…Итак, уже начавшись, патологический процесс приобретает характер самоподдерживающегося и прогрессирующего по типу порочного круга. Усиление пути AGE-RAGE снимает запрещающий сигнал на пролиферацию эндотелиальных клеток, активирует образование VEGF и облегчает ангиогенез, приводит к гибели перицитов, что и является решающим фактором в развитии сосудистых аномалий при НПДР [27]. Накопление AGE-RAGE в перицитах индуцирует активацию фактора некроза опухоли-α (TNF-α), что приводит к перемещению NF-κB в ядро и создает условия для активации проапоптических белков [28].…”

The Insights of Microbes’ Roles in Wound Healing: A Comprehensive Review

“…Additionally, the ulcerated foot can be seen with systemic infection, extensive cellulitis (more than 2 cm distant from the ulceration), bone necrosis, or gangrene, with reduced oxygen to the limb [ 59 ]. Apart from this, high glucose content in the blood produces substances known as advanced glycation end products (AGEs), which trigger the release of TNF-α and IL-1β that interrupt the synthesis of collagen and diminishes proliferation to re-epithelialize the wound [ 60 ]. High sugar levels also cause factors like thromboxane, Von Willebrand factor, factor VIII fibrinogen, and plasminogen activator inhibitor levels to be elevated in DFU patients.…”