Advanced Glycation End Products and Diabetes Complications

Advanced glycation end products (AGEs) are a heterogeneous group of irreversible adducts formed by the non-enzymatic reaction of reducing sugars with amino groups on proteins, lipids or nucleic acids. Persistent hyperglycaemia in diabetes accelerates AGE formation both endogenously and through dietary intake, leading to accumulation in tissues with slow turnover such as vascular collagen, renal glomeruli and retinal structures. Binding of AGEs to their principal receptor, RAGE, triggers oxidative stress and pro-inflammatory signalling cascades that compromise insulin sensitivity, promote endothelial dysfunction and drive extracellular matrix remodelling. The AGE-RAGE axis contributes centrally to microvascular complications—retinopathy, neuropathy and nephropathy—as well as macrovascular disease manifested by atherosclerotic plaque formation and calcification. Cross-linking of long-lived proteins by AGEs increases arterial stiffness and impairs wound healing, while epigenetic modifications induced by glycation reactions can perpetuate metabolic memory. Recognition of the multifaceted role of AGEs in diabetes has prompted investigations into inhibitors of AGE formation, RAGE antagonists and interventions to enhance endogenous detoxification pathways, with the aim of mitigating the global burden of diabetes-associated morbidity.

Research from Nature Portfolio

Recent studies have illuminated a novel mechanism by which hyperglycaemia-induced AGEs accelerate calcification in atherosclerotic plaques. In a mouse model of diabetes, selective deletion of the RNA-binding protein NF90 in vascular smooth muscle cells attenuated AGE-driven transformation of these cells into osteoblast-like phenotypes, reduced apoptotic matrix vesicle release and markedly diminished plaque calcification. Mechanistically, AGEs upregulate NF90 activity, which stabilises mRNA encoding the E3 ubiquitin ligase FBXW7; increased FBXW7 then targets the AGE-clearance receptor AGER1 for proteasomal degradation. Loss of AGER1 exacerbates AGE accumulation, creating a feed-forward loop that promotes vascular stiffening and calcification. This work identifies VSMC NF90 as a potential therapeutic target to disrupt pathological AGE signalling in diabetic macrovascular disease.

Advanced Glycation End Products and Diabetes Complications publication trend

The graph below shows the total number of articles in advanced glycation end products and diabetes complications across all publications each year (not limited to Nature Index journals).

Technical terms

Advanced Glycation End Products (AGEs): Irreversible adducts formed by non-enzymatic reaction of reducing sugars with proteins, lipids or nucleic acids, implicated in diabetic complications.

Receptor for Advanced Glycation End Products (RAGE): A transmembrane immunoglobulin-type receptor that binds AGEs and activates pro-inflammatory and oxidative stress signalling pathways.

Hyperglycaemia: A metabolic state characterised by elevated blood glucose levels, central to AGE formation in diabetes.

Atherosclerotic Calcification: Deposition of calcium salts within atherosclerotic plaques, often exacerbated by AGE accumulation and vascular smooth muscle cell transformation.

Oxidative Stress: An imbalance between reactive oxygen species production and antioxidant defence, frequently triggered by AGE–RAGE interactions.

References

1. Smooth muscle NF90 deficiency ameliorates diabetic atherosclerotic calcification in male mice via FBXW7-AGER1-AGEs axis. Nature Communications (2024).
2. Advanced Glycation End Products and Diabetes Mellitus: Mechanisms and Perspectives. Biomolecules (2022).
3. Effect of Collagen Turnover on the Accumulation of Advanced Glycation End Products*. Journal of Biological Chemistry (2000).
4. Dietary Advanced Glycation End Products and Aging. Nutrients (2010).
5. Advanced Glycation End-Products (AGEs): Formation, Chemistry, Classification, Receptors, and Diseases Related to AGEs. Cells (2022).
6. Advanced Glycation End Products (AGEs): Biochemistry, Signaling, Analytical Methods, and Epigenetic Effects. Oxidative Medicine and Cellular Longevity (2020).