Diabetes mellitus (DM) is a silent killer disease which slowly damages all the systems of the body including heart, brain, kidneys, eyes etc. There are two main types of diabetes as type 1 and type 2. type 1 is known as insulin dependent diabetes mellitus (IDDM) and type 2 is known as non insulin dependent diabetes mellitus (NIDDM). The pathological manifestations of DM occurs in response to hyperglycemia and are time related. When these manifestations occurs in eye and retina they are called as diabetic retinopathy.

Diabetic retinopathy often has no early warning signs. Even macular edema, which may cause vision loss more rapidly, may not have any warning signs for some time. In general, however, a person with macular edema is likely to have blurred vision, making it hard to do things like read or drive. In some cases, the vision will get better or worse during the day.

On the first stage which is called Non-proliferative diabetic retinopathy (NPDR) there are no symptoms, are not visible to the naked eye and have 6/6 vision, but can be detected by fundus photography. While reading the fundus photograph, we can see microaneurysms (microscopic blood-filled bulges in the artery walls). Macular oedema may occur in which blood vessels leak contents into the macular region can happen at all stages of NPDR. The macular oedema symptoms are blurring, darkening or distorted images which are not the same between two eyes.

On the other hand, as abnormal new blood vessels (neovascularization) form at the back of the eye as a part of proliferative diabetic retinopathy(PDR), new blood vessel walls  are weak and can bleed easily causing blurred vision. When for first time this happens, it may not be very severe. In most cases, it will leave just a few specks of blood, or spots, floaters in visual field, though the spots often go away after a few hours.

Risk factors for the development and progression of diabetic retinopathy

• Age
• If diabetes occurs before the age of 30 yrs development of retinopathy after 10 yrs is 50%.
• If diabetes occurs after 30 yrs of age, chances of development of retinopathy after 10 yrs is 90%.
• Type of diabetes
• It is common in type 1 of diabetes and is 40%
• It is less common in type 2 of diabetes and is 20%

Duration of diabetes

• Duration of onset is a strong prediction
• IDDM patients do not have retinopathy for first five years of their diabetes.
• Years of diabetes before puberty does not count for formation of diabetic retinopathy.

Blood glucose control

• Tight control of blood glucose delays onset of retinopathy
• Tight control also slow down the progression of established retinopathy
• Raised HbA1C is associated with an increased risk of proliferative disease.

Renal involvement

• Proteinuria, elevated blood urea nitrogen and elevated blood creatinine are excellent predictors of the presence of retinopathy
• Microalbuminuria indicates a high risk of soon developing retinopathy

Systemic hypertension

• It is a very common risk factor for type 2 diabetes
• It should be controlled below 140/80

Pregnancy

• Women with diabetes mellitus beginning a pregnancy without retinopathy have a 10% risk of developing background retinopathy
• Women with background retinopathy at the onset of pregnancy may show progression, fortunately, there is usually some regression after delivery.
• About 4% of pregnant women with background retinopathy will progress to proliferative retinopathy
• Those with untreated proliferative retinopathy at the onset frequently do poorly unless they are treated with pan retinal photocoagulation.
• Women with previously treated proliferative retinopathy usually do not worsen during the pregnancy.

Obesity

• Risk of development of DR increases with increase in body mass
• It is directly proportional to waist to hip ratio

Pathogenesis of retinopathy

Effective and appropriate management of NPDR is dependent on a clear understanding of the disease course. Chronic hyperglycemia in poorly controlled diabetes results in biochemical alterations and altered hemodynamic condition of the retinal vasculature, which leads to chronic hypoxia. Since the retina is a highly metabolic tissue dependent on optimal oxygenation, compensatory pathways, such as up regulation of vascular endothelial growth factor (VEGF) protein, are targeted against this retinal hypoxia. These efforts are futile, however, and ultimately result in the pathologic processes of NPDR (retinal capillary microaneurysms, vascular permeability, and eventual vascular occlusion, or capillary closure).

Although the exact pathogenesis of diabetic retinopathy is not fully understood, several hypothesis have been proposed. It is likely that many or all of these factors act simultaneously in the pathogenesis of this condition.

1) Hyperglycemia

Hyperglycemia plays a major role in the pathogenesis of diabetic retinopathy, since it leads to increased cell uptake of glucose with deleterious effects. Hyperglycemia include extracellular nonenzymatic glycation process, sorbitol accumulation through aberrant aldose-reductase enzyme activation and alterations of various signal pathways like diacylglycerol (DAG) – protein kinase C (PKC) pathway

A) Non-enzymatic Glycation (Advanced Glycation End products) proteins:

• The ability of high levels of blood glucose to glycate hemoglobin and albumin is now widely appreciated. Similar glycation of several other proteins has also been recognized.
• Nonenzymatic glycation typically begins with the attachment of glucose to an epsilon amino group of a proteins lysine residue. After further reactions and molecular rearrangement, accumulation of a stable sugar-protein bond takes place. This process is largely irreversible.
• These proteins have the capacity to the thickening of basement membranes, as well as a number of other abnormalities in tissues, especially the endothelium.
• The rate of formation of advanced glycation end products can differ in diabetic patients with similar levels of chronic hyperglycemia.
• A higher rate of formation has been reported in diabetic patients with retinopathy than in those without retinopathy. This may help to explain why retinopathy develops at a faster rate in some patients than in others, despite the same levels of diabetic control.
• AGEs may participate in the pathogenesis diabetic retinopathy through their ability to increase retinal VEGF gene expression.
• It has been found that AGEs increase VEF mRNA levels in the ganglion, inner nuclear and retinal pigment epithelial (RPE) cell layers of the rat retina.
• In vitro, AGEs increased VEGF mRNA and secreted protein in human RPE and bovine vascular smooth muscle cells.
• The AGE-induced increase in VEGF expression were dose and time dependent, inhibited by antioxidants and additive with hypoxia. Use of an anti-VEGF antibody blocked the capillary endothelial cell proliferation

B) Sorbitol Accumulation:

• When the blood glucose level is high, the sorbitol pathway becomes operative. Sorbitol is then produced and accumulates intracellularly in possibly toxic concentrations.
• Aldose reductase is the rate-limiting enzyme in this pathway.
• Accumulation of sorbitol in tissue may be a factor in the pathogenesis of diabetic complications such as neuropathy.
• The sorbitol pathway is also operative in the pericytes of retinal capillaries.

C) Protein Kinase C (PKC)

• Endothelial cells line the insides of tiny blood vessels in the retina, and regulate the movement of molecules across the walls of the blood vessels.
• During diabetes the endothelial cells are thought to divide (giving rise to more blood vessels), and become leaky (allowing potentially toxic material near the nerve cells).
• Recent discoveries have shown that division and permeability of endothelial cells is controlled in part by a cellular protein called Protein Kinase C (PKC).br /> It also< prolonges retinal circulation time.
• Inhibition of PKC may therefore slow or stop the growth of unwanted blood vessels and make them less leaky.
• In addition to vessel permeability changes, PKC-beta is associated with other classic pathological changes seen in diabetes, such as basement membrane thickening and Retinal edema resulting from increased vascular permeability is particularly significant if it occurs in the macula.

2) Haemodynamic Alteration

• Endothelial cell stress is increased in patients with diabetes because of an increase in blood viscosity.
• This is mediated through changes in red cell deformability and may result in thrombosis within vessels.
• Vascular endothelial cells become deformed and elongated and lose their elasticity. This may lead to increased perfusion pressure, resulting in exudation.
• Chronic hypoxia may stimulate Neovascularisation by causing vessel dilatation and endothelial cell proliferation. Chronic vessel dilation causes increased vessel stress, resulting in leakage of fluid.
• In addition, ischemia may lead to local synthesis and secretion of growth factors as described.

3) Histamine in the Pathogenesis of Diabetic Retinopathy

• Leakage of retinal blood vessels is a major feature of diabetic retinopathy. Histamine, which is well known as a factor that causes blood vessels to leak, is produced in increased amounts in the retinas of rats with experimental diabetes.
• The enzyme that produces it is found in the nerve cells of the retina of diabetic patient. This finding suggests that nerve cells in the retina secrete molecules that act on the blood vessels, causing them to leak.
• Adjacent endothelial cells in the capillary wall are bound together by a tight junction complex to regulate the passage of molecules out of the blood and into the tissue of the retina.
• Tight junction protein zonlula occludens-1 (ZO-1) is decreased when retinal endothelial cells are cultured in the presence of high physiological levels of histamine. Histamine likely acts via the tight junction proteins between endothelial cells of the blood vessels.

4) Vascular endothelial growth factor (VEGF) 

• VEGF is protein that is released from cells within tissues and acts on blood vessels to increase their permeability.
• This protein comes from cells in the retina. Its elevation in diabetes may lead to loss in endothelial cells.
• VEGF can increase endothelial permeability by decreasing occluding.
• Advanced Glycation End Products Increase Retinal Vascular Endothelial Growth Factor Expression

5) Lupus anticoagulant positivity in insulin dependent diabetic patients 

• Lupus anticoagulant positivity could represent an additional risk factor for diabetic retinopathy, acting as a link between the immunological and haemostatic systems.
• The clinical association between LA positivity and thrombotic events in other disease is thought to be due to a LA induced endothelial cell dysfunction.
• In IDDM, a similar dysfunction of the coagulant and anticoagulant pathways, as a result of endothelial cell damage, has been described.
• Altered coagulation is manifested by enhanced prothrombin conversion to thrombin as demonstrated by increased prothrombin degradation fragments (F1+2) plasma concentrations and down regulation of the anticoagulant pathway, caused by reduced antithrombin III activity and thrombomodulin’s endothelial receptors.

6) Hepatocyte Growth Factor and Proliferative Diabetic Retinopathy

• Investigators from Spain have added hepatocyte growth factor (HGF) to the list of substances that may be involved in the pathogenesis of diabetic retinopathy.
• Dr Canton and colleagues from Barcelona reported that HGF levels were three times higher in patients with proliferative diabetic retinopathy compared with non diabetic patients (17.04 ng/mL vs 5.87 ng/mL) and that HGF levels in the vitreous fluid were many times higher than in serum of the same patients.
• Thus, local production of HGF in the eye may contribute to the pathogenesis of new vessel formation in diabetic retinopathy.
• These findings support the idea that targeting a single growth factor may not be sufficient to prevent proliferative diabetic retinopathy, something that should be considered when developing new pharmacologic treatments.

7) ACE Inhibitors and the Progression Diabetic Retinopathy

• Recently, investigators presented results from a clinical study of normotensive-normoalbuminuric type 1 diabetic patients.
• They reported that angiotensin-converting enzyme (ACE) inhibitors slowed the progression of diabetic retinopathy from milder to more severe nonproliferative levels.