Treatment of neovascular age-related macular degeneration in patients with diabetes ketoacidosis, coma and death. Type 1A diabetes is thought to arise from a chronic autoimmune destruction of the pancreatic beta cells, usually initiated by exposure of genetically suscep- tible individuals to environmental agents. This event is usually a cell-mediated immune process and is characterized by the presence of islet cell, insulin or glutamic acid decarboxylase (GAD) autoantibodies. Genetic inﬂuences include the pres- ence of susceptibility genes, such as in the human leukocyte antigen (HLA) region on chromosome 6p21, which accounts for nearly half of familial clustering. Potential environmental factors have implicated viruses (eg, herpes virus, mumps, rubella, and retroviruses), perinatal factors, dietary factors, and exposure to toxins (Steck and Rewers 2004). Type 1B diabetes refers to a heterogeneous group of individuals who show no evidence of autoimmune destruc- tion of pancreatic beta cells; they account for up to 40% of patients with type 1 diabetes (Urakami et al 2002). Type 2 process The process underling type 2 diabetes is insulin resistance and defective insulin secretion, either of which predominates. Type 2 diabetes is heterogeneous and has many distinct causes. However, most patients are obese with concomitant insulin resistance and fulﬁll the classiﬁcation of the metabolic syndrome (see Table 3) (Alberti et al 1998). Diabetic complications Macrovascular The major abnormality present in diabetes is atherosclerosis (Kannel et al 1979), usually preceded by endothelial dysfunction. Much debate surrounds whether this is an exaggeration of the process seen in non-diabetic subjects, or whether there are specific features pathognomonic of diabetes. Overall, diabetes seems to be associated with an increase in amount, extent, and distribution of atherosclerosis leading to susceptibility to ischemic heart Table 3 The metabolic syndrome (modiﬁed WHO deﬁnition) (Alberti et al 1998) • Fasting plasma glucose 6.1 mmol/L or hyperinsulinemia (upper quartile of the non-diabetic range), and At least 2 of the following: • Abdominal obesity: BMI 30 kg/m2, waist-hip ratio 0.90 or waist circum- ference 94 cm • Dyslipidemia: serum triglycerides 1.7 mmol/L or HDL cholesterol 0.4 mmol/L • Hypertension: blood pressure 140/90 mmHg or medication Abbreviations: BMI, body mass index; HDL, high density lipoprotein. Clinical Ophthalmology 2008:2(2) disease, cerebrovascular and peripheral vascular disease and erectile dysfunction. The association between glycemic control and macrovascular disease is less pronounced compared with other vascular risk markers such as smoking, hypertension and dyslipidemia. Microvascular Microvascular complications consist of pathological changes that mainly affect the function of the retina, kidney and neurological system, and a much more established link to the duration and severity of hyperglycemia (DCCT 1996; UKPDS 2000). The role of hyperglycemia plays in induc- ing these complications at a cellular level is now better understood. Within the retina itself, the classical ﬁnding is that of basement membrane thickening, which is associated with leakage and a loss of negative charge. Altered pericyte function, increased blood viscosity and altered ﬁbrinolytic activity may lead to capillary occlusion with tissue hypoxia and, ultimately, new vessel formation. In addition to hyper- glycemia, a number of other risk factors are associated with development or worsening of retinopathy, including hypertension, nephropathy, pregnancy, alcohol, smoking and ethnic origin (Shotliff et al 2005). The classiﬁcation of different forms of diabetic retinopathy is now well established (see Table 4). Distinction between diabetic retinopathy and wet AMD Diabetic retinopathy Diabetic retinopathy is a characteristic group of lesions found in the retina of individuals who have had diabetes for a number of years. Successful management of glycemia reduces the risk of developing, and slows the progression of, retinopathy. However, in many cases, diabetic retinopa- thy can result in progressive visual loss in well-controlled patients. It is important to realize that the natural history of diabetic retinopathy does not follow a standard timetable of progression; contrastingly, it has a rather variable course. Factors that most inﬂuence the evolution of the disease are the type and duration of diabetes, increased blood pressure and pregnancy. In the pre-clinical stage, alterations preced- ing ophthalmoscopic changes have been demonstrated by a variety of more sensitive methods of examination and by his- tological examination (Cunha-Vaz and Bernardes 2005). Diabetic retinopathy is essentially a microangiopathy: its initial pathologic processes include endothelial prolif- eration in the capillaries and venules, as well as endothelial swelling and apoptosis in the smallest arteriolar branchings. 371