Chronic complications of diabetes mellitus (molecular mechanisms, diabetic nephropathy, diabetic retinopathy, diabetic polyneuropathy
Introduction
Chronic complications develop due to long-standing hyperglycemia, affecting small vessels ( microangiopathy ) and large vessels (macroangiopathy ).
Major microvascular complications: nephropathy, retinopathy, neuropathy.
Macrovascular: atherosclerosis (e.g., coronary, cerebral, peripheral arteries).
Molecular mechanisms of chronic hyperglycemia
1 Advanced glycation end- products (AGEs)
Hyperglycemia → non-enzymatic glycation of proteins and lipids → formation of AGEs.
AGEs bind to their receptor ( RAGE) on endothelial cells, mesangial cells, macrophages.
Effects:
- Cross- linking of matrix proteins → thickening of basement membranes.
- Induce oxidative stress and pro-inflammatory cytokine release → vascular injury.
2 Polyol pathway activation
Excess glucose in cells (e.g., Schwann cells, lens, pericytes) converted to sorbitol via aldose reductase, then to fructose.
Consequences:
- Sorbitol accumulation → osmotic stress → cellular swelling and dysfunction.
- NADPH depletion → reduced glutathione → increased oxidative stress.
3 Protein kinase C (PKC) activation
Hyperglycemia increases diacylglycerol (DAG) levels → activates PKC.
PKC effects:
- Increases vascular permeability.
- Stimulates VEGF → pathological neovascularization (retinopathy).
- Enhances pro- fibrotic and pro- inflammatory gene expression.
4 Hexosamine pathway
Excess fructose-6-phosphate enters hexosamine pathway → modifies transcription factors → overexpression of transforming growth factor-beta (TGF- β) and plasminogen activator inhibitor- 1 (PAI- 1).
Leads to fibrosis and pro-thrombotic state.