1. Overview of advanced glycation end-products (AGEs) Part 2

2. Complications of Advanced Glycation End-products (AGEs) in Diabetic Patients

3. AGEs in Diabetes Mellitus (DM)
Cells have receptors for AGE products “RAGE”
Normally present in low levels in the body
In DM, upregulation of these receptors occurs
Contributes to microvascular and macrovascular complications
Vascular and inflammatory cells, Muller cells of the retina, podocytes of the kidney, neurons and microglial cells, epithelial cells, etc may have low levels of RAGE.

4. Retinopathy AGEs Cause pericyte cell death unprotected capillary
Stimulate VEGF hyperpermeability
Increase leukocyte adhesion inflammation
Increase platelet activation microthrombosis
Pericytes (a type of CNS cell) cover the retinal capillary and provide protection. AGEs bind to RAGE on pericytes causing production of reactive oxygen species (ROS) which leads to cell death and loss of pericyte (this leaves vessel more vulnerable to angiogenesis, thrombogenesis and endothelial cell injury)
AGEs also stimulate vascular endothelial growth factor (VEGF) which leads hyperpermeability seen in retinopathy
AGEs cause vascular inflammation by increasing leukocyte activation and adherence
AGEs also cause platelet activation and aggregation and fibrin stabilization contributing to microthrombosis

5. Nephropathy Alter ECM biology
Stimulate cytokines, adhesion molecules, chemokines, growth factors and increase oxidative stress
Interact with renin- angiotensin system
Mesangial cells (specialized cells around blood vessels in kidney) of kidney have RAGE on cell surface. AGE binds to receptors and following consequences occur:
AGEs cross-link with extracellular matrix (ECM) proteins leading to development of diabetic glomerulosclerosis. These also accumulate in the extracellular space and cause basement membrane thickening and mesangial growth
AGEs cause cell death and stimulate VEGF on mesangial cells (leads to glomelular hyperfiltration)
AGEs stimulate growth factors on podocytes and proximal tubular cells too
Growth factor stimulation part of glomerulosclerosis and tubulointerstitial fibrosis in pathogenesis of nephropathy

6. Neuropathy
AGE products accumulate on cytoskeleton proteins and myelin components
Causes axonal degeneration and demyelization
AGE product may alter ECM protein
Affects regeneration
AGE-RAGE interaction promotes oxidative stress leading to neurovascular damage
Not fully understood
Pathogensis thought to develops due to glycation of cytoskeletal proteins & myelin components which causes structural and functional changes in nerve fibers
AGE may alter extracellular matrix protein laminin damaging regeneration process

7. Neuropathy
Sugimoto K, Yasujima M, Yagihashi S. Role of advanced glycation end products in diabetic neuropathy. Curr Pharm Des. 2008;14(10):

8. Neuropathy
Sugimoto K, Yasujima M, Yagihashi S. Role of advanced glycation end products in diabetic neuropathy. Curr Pharm Des. 2008;14(10):

9. Macrovascular Disease
AGE cross-links with matrix proteins in the vascular wall
Increases vessel rigidity
Decreases nitric oxide
Traps lipoproteins in arterial wall
AGE-RAGE interaction increases oxidative stress
Also activates NF-κB in vascular wall cells, which stimulates the expression several atherosclerosis-related genes
AGE interacts with renin-angiotensin system
Enhances angiotensin II-induced smooth muscle cell proliferation and activation
Lipoproteins enable to be cleared thus increases LDL and contributes to atherosclerosis
Nitirc oxide important for vasodilation (this adverse effect on nitric oxide is seen in microvascular complications as well)
Again the increase in oxidative stress will lead to endothelial cell injury and VEGF is also stimulated on endothelial cells