In patients with diabetes, the leading cause of vision problems is diabetic retinopathy (DR).1 DR is a common microvascular complication of diabetes that encompasses a range of severity, from mild nonproliferative DR, characterized by retinal vessel microaneurysms, to severe nonproliferative DR, characterized by microvascular abnormalities and hemorrhages throughout the retina.2 When retinal neovascularization (new blood vessel formation) occurs, the condition is called proliferative diabetic retinopathy (PDR). DR can also progress to diabetic macular edema (DME), which is intraretinal fluid accumulation due to disruption of the blood-retinal barrier.3,4 While DR is the most common diabetic eye disease, DME is the most common cause of blindness among people with diabetes.1
The mechanisms by which DR may lead to visual disturbances are numerous, including neovascularization, vitreous hemorrhage, retinal detachment, macular edema, and neovascular glaucoma.2-5 Hyperglycemia, the hallmark of diabetes, first causes constriction and leakage of retinal vessels.6,7 The basement membrane, the thin layer directly underneath the outermost retinal layer, thickens in response. These changes cause decreased retinal blood flow and thus hypoxia (low oxygen).8 At first, when the retina is deprived of oxygen, it can compensate through vasodilation (widening of blood vessels), angiogenesis (the creation of new vessels), and erythropoiesis (the creation of more red blood cells).7 However, these protective mechanisms can only function for a few hours, so tissue damage occurs with a sustained lack of oxygen.
Inflammation is also seen in the retina when it is deprived of oxygen. Pro-inflammatory molecules can cause white blood cells, the main cell type of the immune system, to adhere abnormally to the vessel walls, blocking some smaller vessels.9 The importance of inflammation as a mechanism behind DR is supported by a standard treatment of the disease, corticosteroid injections into the eye, as corticosteroids are anti-inflammatory medications .5,10-12
New Blood Vessel Formation
The retina has a high metabolic requirement, given its composition of highly active photoreceptors, so it is very sensitive to ischemia (lack of oxygen).8 With continued ischemia caused by hyperglycemic microvascular damage, the retinal cells produce molecules that promote blood vessel formation (proangiogenic factors), which lead to the development of abnormal, leaky, fragile new vessels.13 These vessels proliferate on the inner surface of the retina, known as the vitreous surface (vitreous is the gel-like filling of the eye).14 Bleeding can occur when these vessels are broken, adding the further complication of vitreous hemorrhage. Vitreous hemorrhage is characterized by painless unilateral floaters and/or visual field deficits.
The repeated damage causes the new vessels to undergo fibrosis, forming inflexible scar tissue between the retina and the vitreous, increasing vitreoretinal traction.6,15With scar tissue contraction, the retina is distorted, increasing the risk of retinal detachment. This is another mechanism by which DR can cause sudden, possibly irreversible vision loss.
It is not completely known how DME occurs in relation to DR; DME is usually correlated with advanced DR, but in reality, can present at any stage.16 What we do know is that retinal neovascularization leads to serum leakage and retinal edema.14 As this edema is greatest around the macula, the area responsible for the sharpest vision in the center of the visual field, consequences for eyesight can be profound.
The proangiogenic molecules (signals to create blood vessels) that are produced by the retina may also travel towards the iris of the eye and cause neovascularization there.17 These vessels can grow towards the output drain of the eye, known as the trabecular meshwork, and obstruct the outflow of aqueous fluid, raising intraocular pressure and causing acute glaucoma. This complication, known as neovascular glaucoma, is relatively rare but can cause serious problems. At its most severe, it can cause extremely elevated eye pressure, eye pain, and possibly permanent vision loss.
Uncontrolled hyperglycemia increases retinal ischemia, inflammation, and ultimately angiogenesis, leading to DR and DME. Accordingly, tight glycemic control is the best supported method of prevention for DR. DR and its sequelae are typically asymptomatic until they have progressed significantly, highlighting the need to emphasize frequent eye exams in diabetic patients.
- NIH National Eye Institute. Facts About Diabetic Eye Disease. 2015; https://nei.nih.gov/health/diabetic/retinopathy. Accessed June 3, 2019.
- Heng LZ, Comyn O, Peto T, et al. Diabetic retinopathy: pathogenesis, clinical grading, management and future developments. Diabet Med 2013; 30 (6): 640-650.
- Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev 2013; 93 (1): 137-188.
- Semeraro F, Cancarini A, dell'Omo R, et al. Diabetic retinopathy: vascular and inflammatory disease. J Diabetes Res 2015; 2015: 582060.
- Abiko T, Abiko A, Clermont AC, et al. Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation. Diabetes 2003; 52 (3): 829-837.
- Ola MS, Nawaz MI, Siddiquei MM, et al. Recent advances in understanding the biochemical and molecular mechanism of diabetic retinopathy. J Diabetes Complications 2012; 26 (1): 56-64.
- Chistiakov DA. Diabetic retinopathy: pathogenic mechanisms and current treatments. Diabetes Metab Syndr 2011; 5 (3): 165-172.
- Arden GB, Sivaprasad S. The pathogenesis of early retinal changes of diabetic retinopathy. Doc Ophthalmol 2012; 124 (1): 15-26.
- Zhang W, Liu H, Rojas M, et al. Anti-inflammatory therapy for diabetic retinopathy. Immunotherapy 2011; 3 (5): 609-628.
- Felinski EA, Antonetti DA. Glucocorticoid regulation of endothelial cell tight junction gene expression: novel treatments for diabetic retinopathy. Curr Eye Res 2005; 30 (11): 949-957.
- Adamis AP. Is diabetic retinopathy an inflammatory disease? Br J Ophthalmol 2002; 86 (4): 363-365.
- Tamura H, Miyamoto K, Kiryu J, et al. Intravitreal injection of corticosteroid attenuates leukostasis and vascular leakage in experimental diabetic retina. Invest Ophthalmol Vis Sci 2005; 46 (4): 1440-1444.
- Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 2009; 78 (6): 539-552.
- Gupta N, Mansoor S, Sharma A, et al. Diabetic retinopathy and VEGF. Open Ophthalmol J 2013; 7: 4-10.
- Bandello F, Zarbin M, Fogliato G, et al. Proliferative Diabetic Retinopathy. In: Bandello F, Zarbin M, Lattanzio R, et al., eds. Clinical Strategies in the Management of Diabetic Retinopathy: A Step-by-Step Guide for Ophthalmologists. 2 ed. Cham, Switzerland: Springer Nature Switzerland; 2019:185-246.
- Cai J, Boulton M. The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye (Lond) 2002; 16 (3): 242-260.
- Hayreh SS. Neovascular glaucoma. Prog Retin Eye Res 2007; 26 (5): 470-485.