Type 2 diabetes mellitus (DM) and advanced glycation end product (AGE) pathophysiology affect the metabolism of proteins, carbohydrates, and lipids, which in turn mediate oxidative stress and inflammation in the background of chronic hyperglycemia. A newly published review provides an in-depth look at the vascular effects of AGEs in DM.
Type 2 diabetes mellitus (DM) is a prevalent chronic metabolic disorder characterized by impaired fat, protein, and carbohydrate metabolism. DM is associated with vascular complications, which can be prevented by intensive glycemic control. The well-established standard for the assessment of glycemic management is HbA1c. HbA1c is produced from non-enzymatic hemoglobin glycation. On the contrary, advanced glycation end products (AGEs) are produced by glycation-mediated glucose–lipid or glucose–protein interaction. AGEs are derived from both endogenous and exogenous sources.
Heterogenous AGEs are classified into free-form, protein-bound, and peptide-bound AGEs. The endogenous production of AGEs is mediated by the formation of Amadori products and Schiff bases via the Maillard reaction. AGEs bind to extracellular AGE transmembrane receptors, initiating signaling cascades. The receptor for AGEs (RAGE) is a central transduction receptor for AGEs. It is activated with increased levels of RAGE ligands in response to inflammation. RAGE is associated with endothelial cell dysfunction in type 2 DM.
This research study, published in the journal Nutrients, discusses the effects of AGEs on the vascular complications of type 2 DM. AGE is involved in the structural modifications in the vasculature. In uncontrolled type 2 DM, chronic hyperglycemia accelerates AGE accumulation. The AGE–RAGE axis correlates with type 2 DM complications. Microvascular complications include diabetic peripheral neuropathy, retinopathy, and nephropathy. In diabetic nephropathy (DN), there is cross-linking between AGEs and matrix proteins, manifesting as DM glomerulosclerosis. DN also involves vascular permeability to albumin, mesangial hypertrophy, and activated angiotensin II. In diabetic retinopathy (DR), the AGE–RAGE pathway causes endothelial permeability and damages the subretinal membrane and microvasculature. In diabetic peripheral neuropathy (DPN), AGE accumulation leads to vascular dysfunction in the vasa nervorum endothelium. This affects nerve blood flow and sensory and motor nerve conduction.
Clinical studies demonstrate the positive correlation between AGEs and risk of DM microvascular complications.
Concerning macrovascular complications of type 2 DM, AGEs mediate the alteration of extracellular proteins, leading to vascular stiffness and impairing arterial integrity. AGEs also cause alterations in lipids, promoting the development of atherosclerosis. In cardiomyocytes, the presence of AGEs leads to cellular dysfunction, which contributes to the development of atherosclerosis.
Reference
Lee, J., Yun, J. S., & Ko, S. H. (2022). Advanced Glycation End Products and Their Effect on Vascular Complications in Type 2 Diabetes Mellitus. Nutrients, 14(15). https://doi.org/10.3390/nu14153086
