Carlo J. Pelino, OD, FAAO
Diabetes has become an epidemic in the United States and worldwide, with its prevalence increasing parallel with rising obesity rates.1 Globally, diabetes affected 382 million persons in 2013, which is projected to undergo a 55% increase to 592 million by 2035.2 In 2012, 29.1 million Americans were diabetic, representing 9.3% of the population, and reflecting a 13% increase in 2 years.3 In the United States, diabetes is the seventh leading cause of death, with 75,578 deaths annually attributed to the disease.4 Diabetes is characterized by numerous complications and comorbidities including eye disease, which contribute to its morbidity and mortality.3
Diabetes is characterized by chronic hyperglycemia resulting from defects in insulin production.5 Classification among its main types considers age at onset, abruptness of hyperglycemia, degree of obesity, presence of ketosis at presentation, and need for insulin at diagnosis.6
Type 1 Diabetes
Type 1 diabetes accounts for 5% to 10% of persons with diabetes, and is the result of autoimmune destruction of pancreatic β-cells, which usually leads to absolute insulin deficiency.5,7 Although most patients require exogenous insulin treatment, uncharacteristic presentations can confuse the diagnosis.
Type 2 Diabetes
Most persons with diabetes (90% to 95%) have type 2 diabetes, which is characterized by insulin resistance and relative, but not absolute, insulin deficiency.5 These patients often do not require insulin treatment for survival.
Gestational Diabetes Mellitus
Gestational diabetes mellitus (GDM), which occurs in approximately 9.2% of all pregnancies, is glucose intolerance that emerges during pregnancy and typically resolves with delivery.5 Most patients who are diagnosed with GDM are at risk for the development of type 2 diabetes later in life. The American Diabetes Association (ADA) recommends that high-risk women who meet the criteria for diabetes at their first prenatal visit should be given a diagnosis of overt, not gestational, diabetes.
Ocular Complications of Diabetes
Both type 1 and type 2 diabetes are associated with an increased risk of macrovascular and microvascular complications.8 Macrovascular complications, including coronary heart disease, stroke, and peripheral vascular disease, are the primary causes of morbidity and mortality in persons with diabetes. The most common microvascular complications include retinopathy, nephropathy, and peripheral neuropathy.
Diabetic retinopathy (DR) is the most frequently occurring ocular complication of diabetes. Worldwide, approximately one-third of persons with diabetes have DR, of which a third may have threatened vision.9 Diabetic retinopathy is a leading cause of blindness in the United States. The number of cases increased from 4 million to 8 million between 2000 and 2010.10 The prevalence of DR increases with age, particularly in Hispanic Americans. The importance of early detection and management is exemplified by the growing prevalence of DR with increasing hemoglobin A1C (HbA1C) levels and longer duration of diabetes.11
The Pathophysiology of Diabetic Retinopathy
The historical viewpoint that diabetic retinopathy is a microvascular disease is now considered too simplistic, as several linked mechanisms and metabolic pathways are responsible for the cellular damage and adaptive changes that occur in the retina.12 Diabetic retinopathy has considerable neurovascular and inflammatory involvement as well, with interrelationships among all pathogenic factors.
Diabetic retinopathy occurs as a consequence of the tissue-damaging effects of hyperglycemia.13 Initially, these are mediated by biochemical alterations of susceptible cell types, which includes, among others, capillary endothelial cells in the retina; that is, cells that cannot efficiently reduce glucose transport across their cell membranes when exposed to hyperglycemia. This process can be influenced by genetically determined susceptibility and accelerating factors, such as hypertension and hyperlipidemia.
The intracellular effects of hyperglycemia on cellular metabolism, signaling, and growth factors produce an environment that is conducive to the development of complications.9 Relevant effects include increased polyol pathway flux (leading to accumulation of sorbitol and resultant osmotic damage and microvascular dysfunction), increased formation of advanced glycation end products (AGEs; proteins or lipids that are nonenzymatically glycated and oxidized after exposure to aldose sugars), protein kinase C (PKC) activation, hexosamine pathway activation (with subsequent oxidative stress, production of pro-inflammatory cytokines, and overmodification of proteins by N-acetylglucosamine and possible influence on retinal neuron apoptosis), and upregulation of the renin-angiotensin-aldosterone system (RAAS) (Figure 1).9,13–15
Advanced Glycation End Products
In addition to the buildup of sorbitol, the metabolism of fructose produced by the polyol pathway can contribute to the production of AGEs. This heterogeneous group of molecules can facilitate the formation of molecular cross-links between its receptor for advanced glycation endproducts (RAGE) and the basement membrane of the extracellular matrix.14 Subsequent increases in procoagulant activity, vascular permeability, adhesion molecule expression, and monocyte influx can contribute to vascular injury. The presence of AGEs leads to activation of the PKC pathway and poly (ADP-ribose) polymerase production that may be involved in inflammation and growth factor imbalances. The levels of AGE in the retinal vessels of persons with diabetes have been shown to correlate with retinopathy severity, and AGE formation may be the inciting event for diabetic retinopathy.16,17
Protein Kinase C
Protein kinase C activation occurs indirectly through ligation of AGE receptors, and as a consequence of increased polyol pathway activity. The pleiotropic effects of PKC relate to its cascade-like influence on several pathways that produce changes in endothelial permeability, retinal hemodynamics, increased activation, and adhesion of leukocytes increased neuronal apoptosis and expression of VEGF.17
Vascular Endothelial Growth Factor
Upregulated vascular endothelial growth factor (VEGF) secretion is a key factor in the development of diabetic retinopathy and its complications. VEGF is expressed by retinal endothelial cells, pericytes, and pigment epithelial cells in response to hyperglycemia-induced hypoxia.9 Intraocular VEGF is associated with retinopathy severity, neovascularization, and macular edema. Angiogenesis is mediated by VEGF promotion of endothelial cell migration, proliferation, and survival.18
Increased expression of renin-angiotensin-aldosterone system (RAAS) receptors and signaling molecules in the retina has been shown to occur independent of systemic blood pressure. 17 The mechanism by which the RAAS system contributes to the development of diabetic retinopathy is not known; however, in vitro studies have reported it is involved with PKC activation and VEGF signaling.
Oxidative stress, an imbalance between reactive oxygen species (ROS) and antioxidant defenses, has been theorized to provide a unifying mechanism among these damaging biochemical pathways.13,19 Decreased blood flow and choroidal oxygen partial pressure produce an hypoxic state in the retina, contribute to the breakdown of the blood-retinal barrier (BRB), and disrupt cellular homeostasis.12 In addition to its role in the development of DR, oxidative stress has been suggested as a possible cause of failed retinopathy reversal that may occur after restoring glycemic control.17
Numerous studies support the role of inflammation in the pathogenesis of diabetic retinopathy and its complications. Hyperglycemia and other stresses cause upregulation of a variety of inflammatory mediators that can lead to abnormal leucocyte-endothelial interactions, with a resulting maladaptive chronic inflammatory response.9 Several characteristics of chronic inflammation are evident in diabetic retinopathy, including edema, inflammatory cell infiltration, cytokine and chemokine expression, tissue destruction, and aberrant compensatory attempts at repair.20 Consequences include increased vascular permeability, capillary nonperfusion, neurodegeneration (apoptosis of neural cells), and neovascularization.9
Alterations to the neurosensory retina include impairment of glutamate metabolism that can contribute to a loss in synaptic activity.12 Adverse neuroretinal changes, including PKC-induced accelerated neuronal apoptosis and altered metabolism in neuroretinal supporting cells, may develop before the onset of microvascular changes.9,15 The concept of a neurovascular unit is recognized; however, the extent of the relationship between neural and vascular tissues remains to be elucidated.
Progression to Diabetic Macular Edema
Diabetic macular edema (DME), is the leading cause of blindness of all the diabetic related complications diagnosed by retinal thickening and characterized by discrete (focal) or generalized (diffuse) microaneurysm leakage, is the most common cause of visual impairment in persons with diabetes.16 As with diabetic retinopathy, the prevalence of DME also increases with increasing HbA1C levels and duration of diabetes.11
The blood retinal barrier (BRB) is an essential structure comprising extensive junctional complexes between retinal pigment epithelial and vascular endothelial cells.15 The complex pathogenesis of DME is not completely understood; however, progressive events starting early in diabetes eventually lead to BRB breakdown, allowing accumulation of extracellular proteins that result in interstitial edema. Maintenance of the BRB is facilitated by glial cells, which in the diabetic setting are induced to undergo phenotypic alterations by AGEs, including VEGF induction and increased vasopermeability. 16 Occludin and claudin are 2 transmembrane proteins that play important roles in tight junction integrity. A low level of occludin and structural changes in claudin may be involved in DME pathogenesis; however, more research is needed.
Pericytes are microvascular mural cells that undergo morphological changes in early diabetes, developing impaired adhesion to the underlying matrix, with apoptosis beginning early during diabetic retinopathy. Retinal vascular endothelial cell death precedes the formation of acellular capillaries, which lead to irreversible retinal ischemia through an unknown mechanism. Leukocyte adhesion to the capillary endothelium is also observed early in the diabetic state, mediated by intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-alpha, and interleukin-6.18 In the retinal vessel wall, leukostasis is associated with apoptosis of pericytes and endothelial cells, vascular obstruction and subsequent nonperfusion, and release of cytokines that increase vascular permeability.16 Studies have shown antibodies to ICAM-1 successfully inhibit leukostasis, and may prevent pericyte and endothelial cell loss and maintain BRB integrity. Inhibition of the AGE RAGE receptor was shown to inhibit expression of ICAM-1 and leukostasis.
Therefore, although BRB breakdown is the common pathway that results in DME, it occurs secondary to these predisposing changes in the tight junctions, pericyte loss, endothelial cell loss, retinal vessel leukostasis, upregulation of vesicular transport, and increased permeability of the surface membranes of retinal vessels and retinal pigment epithelium cells.21 VEGF, induced by upstream inflammatory cytokines, is a main causal factor in the disruption of the BRB, producing conformational changes in the tight junctions of retinal vascular endothelial cells.15,16 The role of AGEs in the activation of these processes has been demonstrated in animal studies. In addition to microvascular changes, an altered vitreomacular interface may also have a role in DME pathogenesis. 16 Microvascular abnormalities may facilitate exudation in the presence of macular traction.
Other Ocular Complications of Diabetes
In addition to retinopathy and its complications including DME, diabetes is associated with retinal detachment, early cataract, blurred vision, diabetic papillopathy, glaucoma, optic neuropathies and cranial nerve palsies, ocular ischemic syndrome, and retinal vein occlusion. The association between diabetes and open-angle glaucoma and angle-closure glaucoma is controversial; however, diabetes is a common cause of neovascular glaucoma. 22 Persons with diabetes have a 2- to 5-fold increased risk of cataract that often develops at an early age. Proposed pathogenic mechanisms include increased osmotic or oxidative stress and lens AGE. Diabetic papillopathy is a rare, self-limiting condition characterized by disk swelling, with minimal or no optic nerve dysfunction.
Diabetes is a serious systemic disease that is associated with several complications that include eye disease in many patients. The effects of hyperglycemia are primarily expressed as diabetic retinopathy, with progression to vision-threatening DME a common sequela. The complicated metabolic interactions that cause the ocular complications of diabetes are not completely understood; however, many pathways are known to be involved. Some of these may offer opportunities for intervention similar to the introduction of agents targeting VEGF, which have gained widespread use in the treatment of DME in the last decade. This is of particular interest considering that, despite treatment successes, responses are not robust and resolution is not complete for all patients. Accordingly, new therapies targeting molecules other than VEGF that have a role in the pathogenesis of diabetic eye complications may allow improved outcomes in this complex disease.
Defining Diabetic Retinopathy
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