Diabetic retinopathy: Pathogenesis
- David K McCulloch, MD
David K McCulloch, MD
- Washington Permanente Medical Group
- Section Editors
- David M Nathan, MD
David M Nathan, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Diabetes Mellitus
- Professor of Medicine
- Harvard Medical School
- Jonathan Trobe, MD
Jonathan Trobe, MD
- Section Editor — Ophthalmology
- Professor of Ophthalmology and Visual Sciences
- Professor of Neurology
- University of Michigan Kellogg Eye Center
Retinopathy is a major cause of morbidity in patients with type 1 and 2 diabetes. The incidence of blindness, for example, is 25 times higher in patients with diabetes than in the general population. Furthermore, diabetic retinopathy (DR) is the most common cause of blindness in middle-aged subjects, accounting for at least 12,000 new cases in the United States each year . Visual loss from DR may be secondary to macular edema (retinal thickening and edema involving the macula), hemorrhage from new vessels, retinal detachment, or neovascular glaucoma.
The pathogenesis of DR is multifactorial but is primarily caused by the metabolic effects of chronic hyperglycemia, which result in vascular changes and subsequent retinal injury and ischemia. More advanced retinal disease, including proliferative vascular changes and neovascularization in the setting of retinal ischemia, may be mediated by other mechanisms such as the action of vasoactive substances released during the inflammatory process.
The pathogenesis of DR is reviewed here. Issues related to screening and treatment are discussed separately. (See "Diabetic retinopathy: Screening" and "Diabetic retinopathy: Classification and clinical features" and "Diabetic retinopathy: Prevention and treatment".)
Chronic hyperglycemia — Chronic hyperglycemia is thought to be the primary cause of DR . Evidence in support for this hypothesis has come from the Diabetes Control and Complications Trial (DCCT), which found that intensive insulin therapy, achieving a mean glycated hemoglobin (A1C) of 7.9 percent, reduced the incidence of new cases of retinopathy by as much as 76 percent compared with conventional therapy. The reduction was directly related to the degree of glycemic control as estimated from A1C values (mean A1C with conventional therapy was approximately 9.9 percent); progressive retinopathy was uncommon in patients with A1C values below 7 percent (figure 1). (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)
The United Kingdom Prospective Diabetes Study (UKPDS) found similar results in patients with type 2 diabetes; each 1 percent point reduction in A1C was associated with a 37 percent reduction in development of retinopathy . (See "Glycemic control and vascular complications in type 2 diabetes mellitus".)
- Centers for Disease Control and Prevention. 2003 National Diabetes Fact Sheet. http://www.cdc.gov/diabetes/pubs/estimates.htm#complications (Accessed on March 28, 2008).
- Frank RN. Diabetic retinopathy. N Engl J Med 2004; 350:48.
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837.
- Kohner EM, Patel V, Rassam SM. Role of blood flow and impaired autoregulation in the pathogenesis of diabetic retinopathy. Diabetes 1995; 44:603.
- Sheetz MJ, King GL. Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA 2002; 288:2579.
- Ruberte J, Ayuso E, Navarro M, et al. Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease. J Clin Invest 2004; 113:1149.
- Ko BC, Lam KS, Wat NM, Chung SS. An (A-C)n dinucleotide repeat polymorphic marker at the 5' end of the aldose reductase gene is associated with early-onset diabetic retinopathy in NIDDM patients. Diabetes 1995; 44:727.
- Nyengaard JR, Ido Y, Kilo C, Williamson JR. Interactions between hyperglycemia and hypoxia: implications for diabetic retinopathy. Diabetes 2004; 53:2931.
- Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes 1998; 47:859.
- Lee AY, Chung SK, Chung SS. Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens. Proc Natl Acad Sci U S A 1995; 92:2780.
- Brownlee M. Lilly Lecture 1993. Glycation and diabetic complications. Diabetes 1994; 43:836.
- Yeh PT, Yang CM, Huang JS, et al. Vitreous levels of reactive oxygen species in proliferative diabetic retinopathy. Ophthalmology 2008; 115:734.
- Yamagishi S, Matsui T, Nakamura K, et al. Olmesartan blocks inflammatory reactions in endothelial cells evoked by advanced glycation end products by suppressing generation of reactive oxygen species. Ophthalmic Res 2008; 40:10.
- Boeri D, Maiello M, Lorenzi M. Increased prevalence of microthromboses in retinal capillaries of diabetic individuals. Diabetes 2001; 50:1432.
- Smith LE, Shen W, Perruzzi C, et al. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med 1999; 5:1390.
- Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977.
- Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1998; 116:874.
- Sharp PS, Fallon TJ, Brazier OJ, et al. Long-term follow-up of patients who underwent yttrium-90 pituitary implantation for treatment of proliferative diabetic retinopathy. Diabetologia 1987; 30:199.
- Boulton M, Foreman D, Williams G, McLeod D. VEGF localisation in diabetic retinopathy. Br J Ophthalmol 1998; 82:561.
- Katsura Y, Okano T, Noritake M, et al. Hepatocyte growth factor in vitreous fluid of patients with proliferative diabetic retinopathy and other retinal disorders. Diabetes Care 1998; 21:1759.
- Watanabe D, Suzuma K, Matsui S, et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med 2005; 353:782.
- Aiello LP. Angiogenic pathways in diabetic retinopathy. N Engl J Med 2005; 353:839.
- Katsura Y, Okano T, Matsuno K, et al. Erythropoietin is highly elevated in vitreous fluid of patients with proliferative diabetic retinopathy. Diabetes Care 2005; 28:2252.
- Hernández C, Fonollosa A, García-Ramírez M, et al. Erythropoietin is expressed in the human retina and it is highly elevated in the vitreous fluid of patients with diabetic macular edema. Diabetes Care 2006; 29:2028.
- Sivalingam A, Kenney J, Brown GC, et al. Basic fibroblast growth factor levels in the vitreous of patients with proliferative diabetic retinopathy. Arch Ophthalmol 1990; 108:869.
- Gao BB, Clermont A, Rook S, et al. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat Med 2007; 13:181.
- Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Diabetes 1997; 46:1829.
- Matsubara Y, Murata M, Maruyama T, et al. Association between diabetic retinopathy and genetic variations in alpha2beta1 integrin, a platelet receptor for collagen. Blood 2000; 95:1560.
- Harris EL, Sherman SH, Georgopoulos A. Black-white differences in risk of developing retinopathy among individuals with type 2 diabetes. Diabetes Care 1999; 22:779.
- Emanuele N, Sacks J, Klein R, et al. Ethnicity, race, and baseline retinopathy correlates in the veterans affairs diabetes trial. Diabetes Care 2005; 28:1954.
- Wong TY, Klein R, Islam FM, et al. Diabetic retinopathy in a multi-ethnic cohort in the United States. Am J Ophthalmol 2006; 141:446.
- Kendall C, Wooltorton E. Rosiglitazone (Avandia) and macular edema. CMAJ 2006; 174:623.
- Colucciello M. Vision loss due to macular edema induced by rosiglitazone treatment of diabetes mellitus. Arch Ophthalmol 2005; 123:1273.
- Estacio RO, McFarling E, Biggerstaff S, et al. Overt albuminuria predicts diabetic retinopathy in Hispanics with NIDDM. Am J Kidney Dis 1998; 31:947.