The Pathophysiology of Diabetic Retinopathy

By Dana N. Koff, MSc, BSc Optometry. Former lecturer of Optometry at the Jordan University of Science & technology, Ingrid

Diabetic retinopathy is one of the major causes of visual loss in the industrial countries1, which affects about 3-6% of the population in these developed countries2, 3. All types of diabetes mellitus will eventually develop diabetic retinopathy, with type 1 diabetes mellitus and 75% of diabetes mellitus type 2, especially after the duration of 15 years4, 5.

In the early stages of diabetic retinopathy the vascular reactivity becomes impaired, which is related to the presence of a retinal edema.6 Diabetic retinopathy occurs due to complications affecting retinal pre-capillary arterioles, capillaries and venules.7, 8 the damage in the retina results from the breakdown of the inner-blood retinal barrier and microvascular occlusion.7

Diabetic retinopathy is classified in to preclinical, nonproliferative, which is the commonest type and requires no treatment9, and a proliferative type of the disease3, 10. Diabetic maculopathy with all of its types can be associated with both proliferative and non-proliferative type of the disease.3

Manifestations of diabetic retinopathy in the retina: From the manifestation of diabetic retinopathy disease in the retina is the formation of micro aneurysms, haemorrhages, hard exudates, and retinal and macular edema.7 the risk of blindness in diabetic retinopathy is mainly due to neovascularisation in type 1 diabetes mellitus and the macular disease in type 2.7

Pathophysiology of Diabetic retinopathy: there are so many theories regarding the pathophysiology of diabetic retinopathy, one theory states that an electrolytic imbalance especially with an increase in the aldose reductase levels can lead to the death of the cells, including retinal pericytes, which leads to the formation of micro aneurysm and with the loss of pericytes, it can end up with neovascularisation.2 Another theory concentrates on the capillary basement membrane and the raised amount of extracellular matrix components deposition in blood vessels, which in turn lead to an abnormal retinal blood dynamic.2

Other reasons include, changes in the inner blood retinal barrier, which increases the extracellular fluids.2 Another suggested mechanism for the disease includes capillary occlusion, non-profusion endothelial damage and vascular leakage due to increased retinal leukostasis.2 Vascular endothelial growth factors lead with the addition of retinal ischemia to retinal neovascularization, which ends up with the formation of proliferative diabetic retinopathy.2

Other factors that may lead to diabetic retinopathy include venular dilatation, which had been suggested to cause retinal hypoxia and venus stasis, reduced vascular reactivity which is accompanied with inflammatory process and endothelial dysfunction which both play a major role in the formation of glucose intolerance.11

the visual impairment that results from macular edema and proliferative diabetic retinopathy can be either due to retinal thickening or hard exudates near the macula, which are formed as a result of increased retinal permeability of retinal blood vessels leading to macular edema and retinal thickening4 in proliferative retinopathy which can be accompanied by a sudden vitreous hemorrhage, and which ends up with visual loss from the pre-retinal hemorrhage, fibrosis and traction of the macula.4

Retinal changes result from the formation of retinal capillary micro aneurysms, an increased vascular permeability, vascular occlusion and proliferation of new blood vessels and the associated fibrous tissue on the retina and the optic disc, ending up with contractions of the fibro vascular proliferations with the vitreous.4

Oxidative stress, protein alteration, and redox modifications can all lead to the diabetic microangiopathy changes seen in the early stages of diabetic retinopathy.4

In the preclinical stage of diabetic retinopathy, the blood flow is affected.3 The retinal microcirculation is changed in three ways: There are progressive capillary closure, more fragile and permeable vessel walls, break downs of the blood-retinal barrier, and growth of new blood vessels and an ancilliary fibroglial tissue12, which represents an ill angiogenic response after deprivation of oxygen by the retina .3

In the mild non-proliferative diabetic retinopathy, Capillary micro aneurysms and micro hemorrhages are present in the retina in the shape of red colored spots and blots .3

Moderate type of the non-proliferative diabetic retinopathy leads to more severe hemorrhages, abnormalities in the veins, cotton wool spots, and the formation of hard exudates. Cotton wool are those substances that are carried by oxygen deprived nerve axons and which can be associated with flame shaped hemorrhages and is seen in the moderate type, whereas leaky retinal capillaries are the blood vessels responsible for to the formation of hard exudates which are lipids and cholesterol that are seen within the nerve fibers.3 In the severe non-proliferative type of diabetic retinopathy multiple cotton wool spots, venous changes and intraretinal micro vascular changes are usually seen.3

In the proliferative diabetic retinopathy, new blood vessels are usually formed from the optic disc or the peripheral retina with thickening in the fibroglial tissue.3, 12 The new blood vessels are fragile and can burst easily leading to hemorrhages in the preretinal space and the vitreous.3 This eventually leads to the blindness seen with diabetic retinopathy.3 The formation of a fibrous tissue in the retina leads to retinal retraction and detachment.3 If neovascularisation is not treated promptly it can reach the anterior chamber angle, blocks the drainage of aqueous humour and lead to glaucoma, which eventually will lead to blindness.3

In proliferative retinopathy, pericytes drop out can be clearly seen, which is associated with endothelial dysfunction leading to capillary occlusions and ischemia, which ends up with neovascularisation as a response to this dysfunction.13 It was also discovered that heparin-binding iso-forms of the vascular endothelium growth factor play a major role in the normal vascular growth.13

The vascular disruption of diabetic retinopathy and macular edema are characterized by an abnormal vascular flow, changes in the permeability, or non-profusion of capillaries.14

The early manifestations of diabetic retinopathy include changes in the structure and the composition of the microvasculature in the retina. Damage of the endothelial cells lead to increased vascular permeability and that's what happens in the early stages of diabetic retinopathy in which damage to the inner blood-retinal barrier leads to the accumulation of extracellular fluids in the macula. Pericytes damage lead to the alteration of retinal homodynamics including changes in the auto-regulation of retinal blood flow and pericytes damage is usually accompanied by the formation of micro aneurysms. Another complication of diabetic retinopathy is the thickening of capillary basement membrane and increased extracellular matrix components.

Leukostasis was also proved to play a vital role in the pathogenesis of diabetic retinopathy. In diabetes there is an increased retinal leukostasis which affects retinal endothelial function, retinal perfusion, angiogenesis and vascular permeability. Diabetic leukostasis can be involved in capillary non-prefusion, endothelial cell damage and vascular leakage in the retinal microcirculation. A lot of occlusions by leukocytes and capillary dropout or degeneration associated with leukocytes can be clearly seen in diabetic retinopathy, in addition to leukocytes, platelets and erythrocytes in the diabetic retinopathy process. Occluded capillaries lead to ischemia, ischemia then leads to neovascularisation in the retina which is mediated by vascular endothelial growth factor which ends up with proliferative diabetic retinopathy. Hemorrhages from the new fragile blood vessels formed into the vitreous can lead to tractioinal retinal detachment.14

Polyol accumulation, formation of advanced glycation end products (AGEs), oxidative stress, and activation of protein kinase C (PKC) like hyperglycemia and micro vascular complications all contribute in the pathophysiology of diabetic retinopathy too in addition to the other factors mentioned earlier in this article15 and which will be hopefully covered in the next issue, so stay tuned for that.


1. Kristinsson J. Diabetic retinopathy. Screening and prevention of blindness. A doctoral thesis. Acta Ophthalmol Scand Suppl. 1997; 223:1-76.
2. Singh R, Ramasamy K, Abraham C, Gupta V, Gupta A. Diabetic retinopathy: An update. Indian Journal of Ophthalmology 2008; 56:179-188.
3. Porta M, Allione A. Current approaches and perspectives in the medical treatment of diabetic retinopathy. Pharmacology & Therapeutics 2004; 103:167-177.
4. Rema M, Pradeepa R. Diabetic retinopathy: An Indian perspective. Indian J Med Res. 2007; 125:297-310.
5. Wilkinson-Berka J, Miller A. Update on the treatment of diabetic retinopathy. Scientific World Journal 2008; 8:98-120.
6. Gilmore E, Hudson C, Nrusimhadevara R, et al. Retinal atreriolar diameter, blood velocity, and blood flow response to an isocapnic hyperoxic provocation in early sight-threating diabetic retinopathy. Invest Ophthalmol Vis Sci. 2007; 48:1744-1750.
7. Watkins P. ABC of diabetes retinopathy. BMJ. 2003; 326:924-926.
8. Grassi G. Diabetic retinopathy. Minerva Med. 2003;94:419-35.
9. Torpy J. Retinopathy. JAMA 2007;298:944.
10. Nguyen T, Wang J, Wong T. Retinal vascular changes in pre-diabetes and prehypertension. Diabetes Care 2007;30:2708-2715.
11. Liew G, Wang J. Retinal vascular signs in diabetes and hypertension: Review. Araq Bras Endocrinol Metab. 2007;51:352-362.
12. Gardner T, Antonetti D, Barber A, LaNoue K, Levison S. Diabetic retinopathy: More than meets the eye. Surv Ophthalmol 2002;47:S253-62.
13. Sinclair S, Delvecchio C, Malamut R, Li W. Diabetic retinopathy: Treating systemic conditions aggressively can save sight. Cleveland Clinic Journal of Medicine 2005;72:447-454.
14. Ciulla T, Amador A, Zinman B. Diabetic retinopathy and diabetic macular edema. Diabetes Care 2003;26:2653- 2664.
15. Fong D, Aiello L, Ferris F, Klein R. Diabetic retinopathy. Diabetes Care 2004;27:2540-2553.


Eyezone Institute of Opticianry and Private Training, is a comprehensive continuing education training centre established to welcome new perspectives in eye care learning. It offers internationally-accredited programs and customized courses dedicated to reinforce thousands of eye care professionals across the region.