Etiology and pathogenesis

The exact mechanism by which diabetes causes retinopathy remains unclear. Several theories have been proposed to explain the origin and typical course of the disease. In general, retinopathy and other microvascular complications of diabetes multifactorial, attributed to chronic hyperglycemia, vascular damage and leakage, edema, capillary basement membrane thickening, neovascularization, hemorrhage, and ischemia.

Increased levels of blood glucose are thought to damage the structural and functional integrity of the retinal capillaries. The increase in blood glucose switches the normal glucose metabolic pathway (though aldose reductase activation) leading to sugar conversion into alcohol (e.g. glucose into sorbitol). Increased levels of sorbitol damage the intramural pericytes of the retinal capillaries, causing weakness and eventual saccular outpouching of capillary walls, and loss of retinal capillaries autoregulation and primary function. The relatively selective loss of pericytes from the retinal capillaries is a characteristic lesion that occurs early in the course of DR.

Variety of hematologic abnormalities seen in diabetes (increased erythrocyte aggregation, decreased red blood cell deformability, increased platelet aggregation and adhesion) predispose to sluggish circulation, endothelial damage, and focal capillary occlusion. This leads to retinal ischemia, which contributes to the development of DR.

As the disease progresses, eventual closure of the retinal capillaries occurs leading to hypoxia. More extensive retinal hypoxia triggers compensatory mechanisms within the eye to provide enough oxygen to tissues (e.g. venous caliber abnormalities). Further increases in retinal ischemia trigger the production of vasoproliferative factors that stimulate new vessel formation.

Neovascularization is most commonly observed at the borders of perfused and nonperfused retina, and most commonly occurs along the vascular arcades and at the optic nerve head. The new vessels break through and grow along the surface of the retina and into the scaffold of the posterior hyaloid face. By themselves, these vessels rarely cause visual compromise, but they are fragile and highly permeable. They are easily disrupted by vitreous traction, which leads to hemorrhage into the vitreous cavity or the preretinal space. The new blood vessels initially are associated with a small amount of fibroglial tissue formation, which increases with the increase in the density of the neovascular frond. In later stages, the vessels may regress leaving only networks of avascular fibrous tissue adherent to both the retina and the posterior hyaloid face. As the vitreous contracts, it may exert tractional forces on the retina via these fibroglial connections. Traction may cause retinal edema, retinal heterotropia, and both tractional retinal detachments and retinal tear formation with subsequent detachment.

Increased permeability of the retinal vessels results in leakage of fluid and proteinaceous material, which clinically appears as retinal thickening and exudates. If the swelling and exudation involve the macula, a macular edema and diminution in central vision occur. Another theory to explain the development of DME deals with the increased levels of diacylglycerol from the shunting of excess glucose. This is thought to activate protein kinase C (PKC), which, in turn, affects retinal blood dynamics, especially permeability and flow, leading to fluid leakage and retinal thickening. PKC up-regulates the vascular endothelial growth factor (VEGF) and also is active in "downstream" actions of VEGF following binding of the cytokine to its cellular receptor. VEGF isoforms are specifically mitogenic for vascular endothelial cells and also increase permeability at blood-tissue barriers. VEGF expression is enhanced by hypoxia, which is a major stimulus for retinal neovascularization. Indeed, markedly increased levels of VEGF (x20) in the vitreous humor of patients undergoing vitrectomy, in the presence of active retinal or iris neovascularisation, provided initial evidence that VEGF has a role in proliferative diabetic retinopathy. VEGF and pigment-epithelium-derived factor (PEDF) appear to have a reciprocal relation in the eye. In proliferative DR, it has been shown that the levels of VEGF increase, whereas those of PEDF decrease, suggesting that abnormal production and/or secretion of VEGF and PEDF in retinal tissues may have important role in the pathogenensis of the retinal disease.

Several other biochemical mechanisms have recently been proposed to explain the development and progression of the DR. These involve reactive oxygen species, inflammation, apoptotic death of retinal capillary pericytes and endothelial cells, up-regulation of the transcription factor NF-κB. Altered expression of still unidentified critical gene(s) may also cause alteration of one or more critical cellular pathways associated with the pathogenesis of DR. Growth hormone seems also implicated in the development and progression of diabetic retinopathy. Its action is mediated primarily through stimulation of the production of the insulin-like growth factors (IGF). Indeed, blocking IGF-1 secretion appears to prevent retinal neovascularization.