Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia secondary to insulin resistance or defects in insulin secretion leading to long-term multi-organ complications including complications in the eyes, kidneys, nerves, blood vessels and heart.
Types of Diabetes
According to the World Health Organization there are two types of diabetes mellitus
Type 1 Diabetes Mellitus
(T1DM) is primarily due to an autoimmune-mediated destruction of the insulin-producing pancreatic β-islet cells(1). These patients have an absolute insulin deficiency, and require exogenous insulin for survival. T1DM can be an isolated deficiency or be part of the polyglandular autoimmune deficiency syndrome.
Type 2 Diabetes Mellitus
(T2DM) is characterized by relative insulin deficiency due to insulin resistance and/or impaired insulin secretion(1). People with T2DM are not dependent on exogenous insulin and can be treated with diet, oral agents and/or insulin, and newer agents such as incretins.
These two types of diabetes have some overlap in age at onset. T2DM can progress to an insulin requiring state the so called “type 1 1/2 diabetes” (starts as type 2 DM and progresses to insulin deficiency). Other types of diabetes are relatively uncommon and include: diabetes secondary to pancreatic diseases, endocrinopathies (Cushings’ disease, pheocromocytoma, acromegaly and glucagonoma), or drug related (i.e. steroid therapy).
The natural history of T2DM, is shown in Figure 1. Several metabolic abnormalities precede the appearance of T2DM. Insulin resistance, hyperinsulinemia, and lipid abnormalities (main components of metabolic syndrome) are already present when impaired glucose tolerance (IGT) the most common form of pre diabetes is detected.
Overall DM is a chronic progressive disorder with acute metabolic and chronic vascular complications. The acute metabolic complications include diabetic ketoacidosis, hyperosmolar coma and hypoglycemia. The chronic vascular complications involve the macrovascular circulation with clinical manifestations of cerebrovascular disease, coronary artery disease and peripheral arterial disease. The microvascular diseases can present as neuropathy, nephropathy and retinopathy.
Epidemiology of Diabetes Mellitus and Diabetic Retinopathy
The global prevalence of diabetes mellitus was estimated to be around 171 million (2.8% of the world wide population) and is expected to increase to 366 million (4.4% of the world wide population) by the year 2030(1). Diabetes mellitus affects approximately 20 million persons in the United States. Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes, affecting approximately 25-44%of patients with diabetes at any point in time(1). DR is the leading cause of preventable blindness in the adult working population(2) being responsible for more than 24, 000 cases of blindness each year in the United States(3).
Diabetic retinopathy was reported to occur during the pre-diabetic state. According to the Diabetes Prevention Program (DPP) data, DR was present in nearly 8 % of pre-diabetic participants and in 12% of participants who developed diabetes during the DPP trial. This suggests that DR can be seen within an average of 3 years after diagnosis of DM.(4)
The prevalence of DR is influenced by several factors such as age of onset, duration and treatment of DM. For example after 20 years duration of DM , diabetic retinopathy is present in nearly 100% of patients with T1 DM and 50-80% of patients with T2 DM, and is more common among patients who are on insulin. Other factors which influence the prevalence of DR are blood glucose control, presence of neuropathy, nephropathy and obesity (body mass index > 30 kg/m2). Among the various risk factors the duration of DM is the most important predictor of macular edema and proliferative retinopathy in both T1DM and T2DM (Figure 2a-b).
Development of DR is influenced by several risk factors, which are summarized in Table 1.
1) Duration and type of treatment influences the development of DR. The risk of DR increases with the duration of DM. After five years from diagnosis, 25% of T1DM patient have retinopathy. The prevalence of DR among T2DM of less than 20 years duration is 84% in patients treated with insulin vs. 53% in patients treated with oral agents(9).
2) The contribution of glycemic control in the development of DR was reported in several studies, such as DCCT, UKPDS, WESDR and Hoorn studies. (58,11,12) The DCCT and UKPDS, landmark studies of diabetic complications showed the exponential relation between HbA1C level and progression of diabetic retinopathy. (58) In T1DM the DCCT found that each 1.0% decrease in HbA1C was associated with a 39% decrease risk of retinopathy progression. (1314) Similar data was reported in T2DM by the UKPDS study, which showed that a 1.1% reduction of HbA1C was associated with 25% risk reduction of microvascular disease and 29% reduction in the need for laser treatment. (8) Overall the development of DR was strongly influenced by both baseline blood glucose levels as well as by the level of chronic glycemic exposure (15).
Figure 3: Relationships of LDL cholesterol with DR end points. Shown are the rate ratio (RRs) of CSME (blue), retinal hard exudates (red), three-step progression of DR (green), and PDR (yellow) per one-fifth of the distribution of serum LDL cholesterol in the DCCT. RRs >1, with a significant P value for linear trend, indicate an increased risk with higher serum LDL levels (18).
3) The risk of developing retinopathy, after 10 years, is more than 2 times higher in diabetics with hypertension versus those who are normotensives(12). Similar data was shown in UKPDS study, which reported that for each 10 mmHg reduction in systolic BP, there was a 10% reduction in the risk of DR(8).
4) LDL cholesterol is an established risk factor for DR(16), particularly for macular edema(17) (Figure 3).
5) The Hoorn study also showed that the high waist hip ratio (WHR), not BMI, is an independent risk factor developing after 10 years. This was independent of age, sex, HbA1C and HTN(12). However, a positive association between BMI and DR was found during DCCT among patient with type 1 DM(14). The combination of HbA1C, HTN and WHR may have a role as risk factors for DR.Insulin resistance may be implicated in pathogenesis of DR(12).
6) The presence of diabetic nephropathy predicts the development and progression of DR(19). Conversely, diabetic retinopathy predicts the presence of diabetic nephropathy (renal-retinal syndrome).The WESDR study showed that both microalbuminuria or gross proteinuria is a marker for proliferative diabetic retinopathy (PDR).(20)
7) Pregnancy was reported to double the risk of DR (21). Among pregnant females with nonproliferative diabetic retinopathy (NPDR), the disease progressed in 47% of patients. Among those with PDR, the disease progression occurred in 46% of patients (1). The progression of DR during pregnancy was greater in those with DM more than 15 year, hypertension and an elevated HbA1C (22).
8) Genetic factors (e.g. TGF-β1, VEGF, IGF-1, aldose reductase, etc.) were also reported to regulate the severity and onset of DR (23).
Pathogenesis of Diabetic Retinopathy
Subclinical / Preclinical Changes in Diabetic Retinopathy
Preceding the recognizable clinical manifestations of DR, there are preclinical changes at the molecular and cellular levels that are coincident with hyperglycemia.
The retina (Latin = network) is a neurovascular tissue, whose function is to receive light and to transmit electrical signals (Figure 4) to the brain (24). The retina is composed of 5% blood vessels and 95% of neurons and glial (structural) cells.
The retina has high levels of polyunsaturated fatty acids, and has high levels of glucose oxidation and O2 uptake, which increases the susceptibility of the retina to oxidative stress(25). Retinal oxidative stress was reported to negatively affect the interaction between the blood cell elements and endothelial cells, and to alter the complex cellular structures which support the retinal vessels.
Figure 4: About half of the photoreceptor cells capture the light information; the other half are secondary cells that integrate and recode the photoreceptor outputs before sending them on to the brain. The retina is also woven throughout with tiny blood vessels that nourish the continuously active retinal tissue and give it the characteristic red color. The foveal pit is created by thinning and spreading apart the synaptic bodies, secondary cells and retinal support cells (nerves and blood vessels) that form a blanket of tissue over the photoreceptors. This enhances image clarity and partly shields the fovea from light scattered inside the eye.
The preclinical stages of DR are related to abnormalities in blood rheology, hyperglycemia induced biochemical abnormalities and glial cells changes. Glial cells are known to directly participate in information processing in the central nervous system(26) and to support the interaction between the neurons, the blood vessels (e.g. astrocytes) and regulate blood vessel function. This network of cell communication becomes disrupted in diabetic patients, and may occur early in the preclinical stages of DR.
a) Blood rheology: Hyperglycemia is reported to alter the normal blood rheology. Alteration of normal blood rheology contributes to the development of diabetic retinopathy (27). Blood rheology is also influenced by the FFA, Il-6 and leptin, known markers of insulin resistance. This suggests that insulin resistance (IR) is a risk factor for abnormal blood rheology(28). Other factors which influence the blood rheology are increases in PAI-1 and plasma fibrinogen levels (29).
b) Hyperglycemia driven biochemical alterations: Several biochemical pathways (Figure 5andTable 2) have been proposed to explain the pathogenesis of diabetic retinopathy(25).
Figure 5: Hyperglycemia-driven biochemical alterations precipitated by mitochondria-driven oxidative stress leading to diabetic complications(25) 1)polyol pathway; 2) hexosamine pathway flux, 3) advanced glycation end-products (AGE) formation; and 4) activation of protein kinase C (PKC).
Increased Polyol Pathway
The polyol pathway consists of two steps:1) reduction of glucose to sorbitol by aldose reductase and NADPH, followed by 2) oxidation of sorbitol to fructose. Since the retina does not use insulin for intracellular transport of glucose, hyperglycemia results in increase in aldose reductase activity, and accumulation of sorbitol. Accumulation of sorbitol results in: osmotic stress, decreased Na/K ATPase activity, and depletion of other oxidative defenses (25’ 29). These metabolic changes culminate in tissue damage and structural changes in the retinal vasculature(25).
During normal physiology, approximately 3% of glucose is channeled into the hexosamine pathway. However, during hyperglycemia there is an increased flux of glucose through the hexosamine pathway, which via increased glucosamines contributes to IR. Insulin resistance results in increase synthesis of vascular growth factors(25). IR was reported to influence retinal neuronal apoptosis by alteration of protein glycosylation (25).
Increased AGE Formation
Another consequence of hyperglycemia is the accumulation of AGEs, a result of interaction between glucose oxidative products and amino groups of intra and extra cellular proteins. Accumulation of AGEs is reported to induce structural tissue changes (29), have a growth inhibitory effect on cells such as pericytes(25) and thereby indirectly affect proliferation of the endothelium. Involvement of AGEs in early diabetic retinopathy is shown in Figure 6a(29).
Increased PKC Activation
Hyperglycemia was also reported to activate PKC activity, a group of enzymes involved in multiple cellular functions. These enzymes are referred to as the “microchips” of cellular signaling machinery (25). The PKC b- isoforms, indirectly through both ligation of AGE receptors and increased activity of the polyol pathways have been shown to mediate retinal [and renal] blood flow abnormalities. In experimental diabetes, the inhibitors of PKC were shown to slow the retinal blood flow, induce regression of neovascularization, and inhibit vascular leakage associated with increase of VEGF (25).
The normal retina has a 1:1 ratio of pericytes to endothelial cells. In contrast, in patients with diabetes, this ratio changes to 1:4 after several years (25) and eventually to 1:10 after longer diabetic exposure (29). “Depletion” of pericytes is related to hyperglycemia induced proapoptosis(25) and to the growth inhibitory effect of AGEs. It has been postulated that loss of pericytes provides a ‘permissive’ environment for proliferation of endothelial cells, thus being responsible for vasculopathic neovascularization. Pericytes have been shown to preserve endothelial cell prostacyclin- producing ability, which serve as protective mechanism against oxidative stress (25). Therefore, loss of pericytes may have a major role in the vasculopathic changes in the retinal circulation(29).
c) Glial tissue changes: The glial cells support and interact with the vascular supply of the retina. These cells regulate the blood flow and control the microenvironment and the electrolyte homeostasis in the retina. The glial cells are affected very early in the course of DM. Animal studies showed that glial cell changes occur as early as 2 to 4 weeks of experimental diabetes and clearly before the onset of micro aneurysms. During this early period of DM, inner retinal cells like ganglion cells and astrocytes may suffer premature apoptosis with subsequent impairment of the retinal capillary circulation. These cells are also responsible for secretion of VEGF (vascular endothelial growth factor) and histamine which have important roles in the development of neovascularization and increased vascular permeability and macular edema (24, 32). The production of VEGF occurs before the onset of ischemia (32). The involvement of AGEs and VEGF in development of proliferative retinopathy is shown in Figure 6b(29).
Overall the abnormality in the glial cells changes the relationship of cell to cell communication, suggesting that retinopathy is a neurovascular disease which starts at a preclinical level. The loss of ganglion cells and inner nuclear cell in the retina, may interfere with the proper function of the retina by decreasing the transmission of the electrical signals from the eye to the brain. The glial and neural changes in the retina support the fact that DR is not only a vascular but a neurovascular disorder (2429).
Clinical Stages in Diabetic Retinopathy
The clinical stages of DR are nonproliferative diabetic retinopathy and proliferative diabetic retinopathy. The first clinically visible features of DR are related to two major processes: 1) vessel closure and 2) abnormal vessel permeability.
NONPROLIFERATIVE DIABETIC RETINOPATHY
1) Vessel Closure
The source of capillary closure is not completely understood. Several theories have been proposed:
- Clumping of blood cells or other blood elements.
- Abnormality of or damage to the endothelium
- Swelling of an abnormally permeable vessel wall.
- Compression of the capillary by surrounding retinal swelling.
Regardless of the exact mechanism, diabetic patients have an increased risk of capillary closure causing patches of hypoxemia.
As a response to a decrease in oxygen supply, there is dilation of the adjacent capillaries, which result in small focal dilations of the retinal capillaries called microaneurysms(24). These microaneurysms are small sacs budding off from the vessel (Figure 7) often visible as tiny red dots, and may be present in only one eye.
The other eye will become involved over the course of 1 to 4 years(33). After the development of the first microaneurysm there is a tendency for more to develop even if the initial ones are no longer visible(33). Their presence may be transient, but when seen in large numbers, may suggest more severe retinopathy(33). It is reported that the change of microanerysm number is influenced by the duration of diabetes, not the age or sex of the patient. Fluorescein angiography can detect microaneurysms as small as 20 μm in diameter. Leakage from these the small retinal arteries may be transient (vide infra) and appears as fluffy white patches, called “cotton-wool spots.”
Retinal hemorrhages can be “blot-shaped” (deep within the retina) or “flamed-shaped” more superficial, and may be transient in appearance.
Soft exudates are localized infarctions of the nerve fiber layer with secondary coagulative necrosis of retina. They can be transient due to natural regeneration of the retina. The duration of the soft exudates from onset to complete resolution, varies from 2 to (18) months (approximately 50% can disappear within 8 months) (33). Presence of soft exudates is the hallmark for the onset of progressive change in diabetic retinopathy and is associated with extensive subclinical retinal microvascular disease.
Intra-retinal microvascular abnormalities (IRMA) are microvascular loops originating in the distended preexisting capillaries, which act as vascular shunts(33). Some consider IRMA as the harbinger of neovascular growth.
Venous beading is a sign of retinal ischemia and occurs adjacent to an area of decreased perfusion. It is considered to be the most significant predictor of progression to PDR(34).
2) Abnormal Vessel Permeability
The blood-retinal barrier maintains the retina in a relatively dehydrated state. The normal flow of water and other blood molecules between the endothelial cells is regulated and limited by tight junction proteins (i.e. occludins and claudins)(24). In DR there is a breakdown in the blood-retinal barrier, resulting in abnormal leakage. This is mediated by hyperglycemia and an increase in the VEGF levels, which opens the tight junctions of the endothelial cells (Figure 8) (24). The increased vascular permeability results in extravasation of water, blood cells, proteins, fats, and other large molecules into the surrounding retinal tissue with formation of hard exudates and diabetic maculopathy.
Hard exudates are the result of an increase in vascular permeability and the leakage of fluid and lipoprotein in the surrounding tissue. Reabsorption of the edema results in precipitation of the residue within the outer plexiform layer of the retina (Henle's layer). If there is involvement of the macula, various degrees of decreased vision occur.
Maculopathy is the result of functional damage and necrosis of the retinal capillaries(34).
PROLIFERATIVE DIABETIC RETINOPATHY
Neovascularization is the hallmark of proliferative retinopathy. The growth of new vessels and remodeling of the existing vessels provide shunts to nonperfused areas. Neovascularization is the result of increased release of neurogenic factors (e.g. AGEs, VEGF, etc), postulated to induce oxidative stress and cytokine mediated vascular inflammation(35). In animal models, leptin, a pro-inflammatory cytokine, was reported to upregulate the endothelial production of VEGF (Figure 9), a potent stimulus for retinal neovascularization (3036).
The action of these vascular factors is normally counteracted by the pigment epithelium-derived factor (PEDF), which has been reported to be decreased in diabetics with PDR(35).
Neovascularization is common at the borders of perfused and nonperfused retina(34), along the vascular arcades and optic nerve head. Frequently, the new vessel formation can occur near the disc (neovascularization of the disc (NVD) or within 3 disc diameters, known as new vessels elsewhere (NVE). The new vessels are fragile and highly permeable(34), and their rupture results in preretinal or vitreous hemorrhage. The distinction between PDR with or without vitreous hemorrhage can be determined by measurement of PEDF. The PEDF levels have been shown to be lower in patients without vitreous hemorrhages compared to those with vitreous hemorrhages(35).
These new blood vessels are associated with fibroglial tissue formation, which following the regression of the vessels may leave a residual area of avascular fibrotic tissue(34). These fibroglial connections play an important role in initiating vitreous contraction resulting in retinal tear and subsequent retinal detachments(34).
Early PDR is defined as neovascularization which does not meet the criteria for high risk PDR.
High-risk PDR is defined as 1) NVD greater than or equal one-third disc area, 2) any amount of NVD with vitreous or preretinal hemorrhage, 3) NVE greater or equal to one-half disk area with preretinal or vitreous hemorrhages(34).
Complications of Proliferative Diabetic Retinopathy
The abnormal growth of new blood vessels in proliferative diabetic retinopathy may produce several complications (1, 9) such as:
- Vitreous hemorrhage - small bleeding may result in few dark spots or floaters, while severe bleeding may be associated with total visual loss. The visual loss may not be permanent as blood resorption can occur within a few weeks or months.
- Traction retinal detachment - is the result of scar tissue formation, and can result in complete visual loss.
- Neovascular glaucoma - The proliferation of blood vessels in the retina and vitreous may be accompanied by the growth of abnormal new blood vessels on the iris, which will interfere with the normal flow of vitreous fluid and secondary glaucoma. The wide spread use of laser therapy has greatly reduced this complication.
Classification of Diabetic Retinopathy
The basic clinical pathological processes involved in development of DR are manifested in 4 clinical stages described by the International Clinical Classification for Diabetic Retinopathy.” in 2003 (Tables 3and4)(37).
Possible Complications of Laser Treatment
Laser treatment remains the main therapy to prevent/delay progression to visual loss. Complications of laser therapy include impaired blue-yellow color vision, suggesting damage to rods and cones cells(41). Our group reported that bilateral laser therapy, via presumably destruction of ganglion cells, can disturb the normal circadian pattern of cortisol levels and cause nocturnal hypercortisolemia(42). Nocturnal increase of cortisol secretion is known to play a role in the development of insulin resistance, sleep fragmentation, early awakening, and night eating syndrome. These conditions can worsen diabetes control (42–44).
- DR remains the leading cause of preventable blindness in the working adult population. DR is a neurovascular disease, and can develop in the “pre-diabetic” state.
- Blood pressure, metabolic control and life style modification are needed to prevent progression of DR.
- Early detection, timely and appropriate treatment (Table 5) are the standard of care(30). The indications, efficacy and safety of newer medical therapies (e.g. aldose reductase inhibitors, AGE inhibitors, PKC inhibitors, VEGF antagonists, octreotide, leptin antagonists, etc) and surgical treatments (intravitreal anti - VEGF) require further evaluation(30).
- Addressing risk factors early in the course of the diabetic state as well as post laser follow up requires a multidisciplinary approach. This combined approach was recently reported to have a sustained beneficial effect with respect to vascular complications in diabetic patients(45). The team should include internist (or primary care MD), diabetologist/endocrinologist, ophthalmologist and other appropriate personnel, to manage the complex problems of the patient with diabetes mellitus.
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