Diabetes Mellitus

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15

Diabetes Mellitus

Natural History

I. Diabetes mellitus (DM) is a heterogeneous group of disorders characterized by elevated blood glucose and other metabolic abnormalities.

The HbA1c (glycated hemoglobin) level is important in making the diagnosis of diabetes and is used as a measure of the quality of diabetic care. It is also predictive of mortality and associated with significant variations in single nucleotide polymorphisms (SNPs) based on racial and ethnic differences in populations. New susceptibility loci for diabetes type 2 are also being discovered. The presence of prediabetes varies considerably on a racial basis.

A. The disorder may result from decreased circulating insulin or from ineffective insulin action in target cells.

B. DM, which affects approximately 5% of the U.S. population and 29% of the population 65 years or older, is classified as either type 1 (previously called insulin-dependent) or type 2 (previously called noninsulin-dependent) DM.

Traditionally, type 2 diabetes has been a disease of adults. As the prevalence of obesity among adolescents has risen, there has been an emergence of type 2 diabetes in that segment of the population.

C. Type 1 diabetes, which is an autoimmune disorder probably related to infections, early childhood diet, and insulin resistance, represents a worldwide epidemic.

D. Worldwide, there are approximately 93 million people with diabetic retinopathy, 17 million with proliferative diabetic retinopathy, 21 million with diabetic macular edema, and 28 million with vision-threatening diabetic retinopathy. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with diabetic retinopathy (DR).

In 2010, worldwide there were twice as many deaths attributed to diabetes as in 1990. By 2025, 380 million people worldwide are expected to have diabetes.

E. Intensive lifestyle interventions can prevent the onset of diabetes in high-risk individuals. Control of blood sugar levels, blood pressure, and blood lipids can prevent or delay the onset of diabetes-related complications. Type 2 DM accounts for approximately 90% of diabetic patients. Target cell resistance occurs in both types, but it is a central feature in type 2. Genetic defects in the cellular insulin receptor may account for the insulin resistance.

II. DR is a leading cause of blindness in the United States.

A. More than three-fourths of the blind are women.

B. There is a significantly higher prevalence of DR in individuals of black or Latino descent compared to whites or Chinese.

C. The most important factor in the occurrence of DR is how long the patient has been diabetic.

1. Although approximately 60% of patients develop retinopathy after 15 years of diabetes, and almost 100% after 30 years, the risk of legal blindness in a given diabetic person is only 7–9% even after 20–30 years of DM.

a. When the onset of type 1 DM is before 30 years of age and no DR is present at onset, approximately 59% of patients have developed DR four years later, and almost 100% 20 years later. In this group, the incidence of proliferative DR (PDR) stabilizes after 13 or 14 years of diabetes at between 14% and 17%.

b. When the onset of type 1 DM is after 30 years of age and no DR is present at onset, approximately 47% of patients have developed DR four years later. Among patients older than 30 years of age who develop type 2 DM, 34% develop DR four years later. In this group of patients with type 1 DM, 7% who were free of PDR at onset of DM developed PDR four years later; 2% of the patients with type 2 DM developed PDR four years later.

c. The prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy is particularly high among non-Latino black individuals.

2. Overall, there has been a decline in the cumulative incidence of severe DR in patients with type 1 diabetes. Similarly, the rate of nonproliferative DR is declining in the United States.

3. Over a 25-year follow-up period, the mortality in diabetic blind individuals is 61% compared to 41% for those who are not blind. Moreover, there is significant racial difference in the quality-adjusted life-years for individuals with diabetes and visual impairment, with whites having a higher quality-adjusted life expectancy compared to black individuals.

Factors associated with mortality are glycemic regulation, dyslipidemia, and creatinine level.

4. Baseline factors associated with progression to blindness include the presence of maculopathy and glycemic control (HbA1 level).

5. Ocular symptoms occur in approximately 20–40% of diabetic patients at the clinical onset of the disease, but these symptoms are mainly caused by refractive changes rather than by DR.

6. The low frequency of retinopathy in secondary diabetes (e.g., chronic pancreatitis, pancreatectomy, hemochromatosis, Cushing’s syndrome, and acromegaly) may be due to the decreased survival among patients with secondary diabetes.

A positive correlation exists between the presence of DR and nephropathy (Kimmelstiel–Wilson disease).

7. It appears that the risk for developing DR in type 1 DM is reduced if glycemic control is achieved from the time of diagnosis; conversely, if DR is already present, early intensive insulin treatment can initially worsen the DR in approximately 10% of those individuals. The worsening may be related to increased vascular endothelial growth factor (VEGF) production. Control of accompanying hypertension can facilitate the regression of diabetic retinopathy.

8. Among diabetic individuals, plasma lipid levels are associated with the presence of hard retinal exudates. Carotid artery intima–media wall thickness is associated with retinopathy; however, other manifestations of atherosclerosis and most of its risk factors are not associated with the severity of DR.

9. Diabetic retinopathy is independently associated with coronary artery calcification suggesting that common pathophysiologic processes may underlie both micro- and macrovascular disease.

III. In juvenile DM, PDR is uncommon in patients younger than 20 years of age and almost unheard of in patients younger than 16 years of age.

A. Background DR (BDR; especially microaneurysms), however, can be demonstrated on fluorescein angiography in juvenile diabetic patients as young as three years of age, and it is present in most patients older than 10 years of age.

The autoimmune process leading to type 1 diabetes involves a T-cell response with the pancreatic β cell as the target. Enteroviruses, especially coxsackievirus B4 virus, have been suggested as potential inducers or aggravating factors of type 1 diabetes in genetically predisposed individuals. Others question the virus’s causative role. It also must be noted that viruses not only may contribute to the pathogenesis of type 1 diabetes by accelerating the progression of the disease but also may provide protection from autoimmunity. In addition, viruses can infect pancreatic β cells, with results ranging from functional damage to cell death.

IV. Most diabetic patients never acquire PDR, and in those who do, it develops only after at least 15 years of DM.
Rarely, a patient presents with BDR, or even with PDR, before any systemic evidence of DM (e.g., hyperglycemia) is discovered.

V. Other associations

A. Primary open- and closed-angle glaucoma occurs more often in diabetic patients than in nondiabetic individuals.

The presence of type 2 diabetes and longer duration of type 2 diabetes are associated with an increased risk of open-angle glaucoma in individuals of Latino descent.

B. DR is approximately 6% more frequent in diabetic patients who have a diagonal earlobe crease than in those individuals who do not have a diagonal earlobe crease. A positive association also exists between a diagonal earlobe crease and coronary artery disease in diabetic patients.

C. A positive association exists between DR and the presence of elevated blood pressure (especially increased diastolic blood pressure), glycosylated hemoglobin, and smoking.

Poor control in DM adversely impacts nerve fiber layer thickness as measured by the scanning laser polarimeter. This finding does not appear to be acute because it is not reversed by short-term blood glucose regulation.

D. Other risk factors for the development of DR include hypertension and abdominal obesity.

VI. Diabetic peripheral neuropathy affects approximately 50% of diabetic patients.

Conjunctiva and Cornea

I. Conjunctiva

A. Conjunctival microaneurysms may be found in diabetic individuals, but they are of questionable diagnostic significance because they also occur in nondiabetic subjects.

B. Transmural lipid imbibition may occur in conjunctival capillaries in diabetic lipemia retinalis (Fig. 15.2). Histologically, lipid-laden cells, either endothelial cells or subintimal macrophages, are present projecting into and encroaching on conjunctival capillary lumens.

C. The conjunctiva may show decreased vascularity in the capillary bed, increased capillary resistance, and decreased area occupied by the microvessels.

Microvascular abnormalities have even been detected in the conjunctiva of pediatric diabetic patients. The severity of these findings correlates with hemoglobin A1c levels but not with the duration of the disease. Such conjunctival microvascular changes correlate significantly with disease severity in type 2 diabetes but not with disease duration since diagnosis.

D. The prevalence and grade of pinguecula are more significant in diabetics than in nondiabetic individuals.

E. Conjunctival vasculopathy in type 2 diabetes may precede retinal changes, thereby possibly providing a window of opportunity for earlier intervention in these individuals.

F. Inflammatory markers such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are upregulated in the conjunctiva of type 2 diabetic individuals with or without retinopathy. ICAM-1, VEGF, and p53 are strongly expressed in the conjunctival of patients with PDR compared to nondiabetic controls, and they are expressed to some degree even in diabetic individuals lacking PDR.

The presence of upregulation for these mediators in the conjunctiva, often before the presence of clinical retinopathy, suggests a possible role for these mediators in the pathogenesis of diabetic microangiopathy.

II. Cornea

A. Epithelium

1. Corneal epithelium and its basement membrane may be abnormal in diabetes; epithelial erosions are common; corneal sensation may be reduced; and the stroma may be thickened. Tear production is more frequently reduced in diabetic patients than in nondiabetics.

Decreased penetration of “anchoring” fibrils from the corneal epithelial basement membrane into the corneal stroma may be responsible for the loose adhesion between the corneal epithelium and the stroma. The corneal epithelium in diabetic patients is much easier to wipe off, often in a single sheet (e.g., during vitrectomy procedures), than is the epithelium of nondiabetic patients. Approximately 50% of diabetic patients undergoing vitrectomy surgery have corneal complications following the procedure, with 44.6% having an epithelial disturbance and 23.8% exhibiting corneal edema. These complications are significantly correlated with the degree of surgical invasion during the procedure.

2. Diabetic ocular surface disease following cataract surgery is ameliorated with oral aldose reductase inhibitor treatment by improving ocular surface sensitivity.

Keratoepitheliopathy, conjunctival squamous metaplasia, and abnormal corneal sensitivity, tear breakup time, Schirmer test, and tear secretion level are all related to the status of metabolic control, diabetic neuropathy, and stage of DR. The prevalence of keratoepithelialiopathy is 22.8% in diabetic individuals, but 8.5% in nondiabetics, and it is associated with tear film abnormalities, particularly nonuniformity of the tear lipid layer, in diabetic patients.

B. Endothelium

1. Specular microscopic studies show corneal endothelial structural abnormalities reflected in an increased coefficient of variation of cell area, a decreased percentage of hexagonal cells, an increased corneal autofluorescence, polymegathism and pleomorphism, and an increased intraocular pressure. The changes in corneal endothelium resemble those that occur with aging.

2. In the Ocular Hypertension Treatment Trial, increased central corneal thickness was associated with younger age, female gender, and diabetes.

3. Contact lens studies in patients who have type 2 DM have demonstrated that the diabetic corneal endothelium shows significantly lower function than the nondiabetic corneal endothelium, even though the morphometry of corneal endothelial cells and central corneal thickness in diabetic patients who wear soft contact lenses are not appreciably different from the values found in contact lens-wearing control individuals.

4. Corneal endothelial cell density is reduced in subjects with type 2 diabetes. Endothelial cell density is inversely correlated with HbA1c levels, which are correlated with mean endothelial cell area. These corneas also are thicker than those of healthy control subjects.

Corneal endothelial cells of diabetic individuals are more susceptible to damage during cataract surgery than are those of nondiabetics. Such patients may exhibit a delay in recovering from postoperative corneal edema. Diabetes is also a significant risk factor for unsuccessful initial corneal transplant grafts because of endothelial failure.

C. Corneal nerves

1. The evaluation of corneal nerve morphology with confocal microscopy and histopathology demonstrates significant changes in the diabetic corneal nerve paralleling other forms of diabetic polyneuropathy.

2. The abnormalities are more pronounced in patients with PDR. Sub-basal nerve abnormalities correlate with reduced corneal epithelial basal cell density.

a. Corneal nerve tortuosity may relate to the severity of the neuropathy in diabetic patients.

b. Corneal confocal microscopy demonstrates that corneal nerve fiber density and branch density are reduced in diabetic patients compared to control individuals, and these measures tend to be worse in individuals with more severe neuropathy.

c. Corneal nerve morphology as evaluated by confocal microscopy improves with improvement in risk factors for diabetic neuropathy.

d. Morphologic changes in corneal nerve fibers can be detected earlier in diabetes than abnormalities in corneal sensation testing and vibration assessment.

e. Corneal Langerhans’ cell density is increased in diabetic patients, particularly in the earlier phases of corneal nerve damage, suggesting a possible immune-mediated mechanism for corneal nerve damage.

Lens

I. “Snowflake” cataract of juvenile diabetic patient

A. The cataract consists of subcapsular opacities with vacuoles and chalky-white flake deposits.

B. The whole lens may become a milky-white cataract (occasionally the process is reversible), and even may be bilateral.

C. The histopathology has not been defined.

II. Adult-onset diabetic cataract (Fig. 15.3)

A. The cataract (cortical and nuclear) is indistinguishable clinically and histopathologically from the “usual” age-related cataracts. Diabetic patients, however, are at an increased risk for cataracts compared with nondiabetic subjects. Nevertheless, diabetes is not universally accepted as a risk factor for nuclear cataracts.

1. Diabetes is a strong risk factor for the development of posterior subcapsular cataract.

Decreased antioxidant protection may contribute to diabetic cataracts. Other factors that may contribute to diabetic cataracts are zinc deficiency, socioeconomic issues in various cultures, and abnormalities related to the advanced glycation process. Improved diabetic control and smoking prevention may reduce the risk of developing cataracts in diabetes.

2. Apoptosis plays an important role in the development of cataracts in DR compared to senile cataract.

3. Nuclear fiber compaction analysis demonstrates no difference in compaction between diabetic and nondiabetic cataracts, although diabetes does appear to accelerate the formation of cataracts that are similar to age-related nuclear cataracts.

Decreased proliferation of lens epithelial cells and increased expression of ICAM-1 may play a role in the progression of cataract in type 2 diabetes. Similarly, the density of lens epithelial cells is decreased in type 2 diabetes and correlates with the level of erythrocyte aldose reductase and the level of HbA1c or diabetic retinopathy. Thus, the polyol pathway mediated by aldose reductase may be associated with the reduction in lens epithelial cells in diabetes.

B. Patients with diabetes may have transient lens opacities and induced myopia during hyperglycemia.

Aldose reductase probably plays an important role in initiating the formation of lens opacities in diabetic patients, as it does in galactosemia. Calpains may be responsible for the unregulated proteolysis of lens crystallins, thereby contributing to diabetic cataract development.

C. Cataract surgery and progression of DR

1. Compared to individuals without diabetes, cataract surgery takes place approximately 20 years earlier in type 1 diabetic patients. Moreover, age and maculopathy at baseline are both predictive of cataract surgery.

2. The visual prognosis for patients who have pre-existing DR, both nonproliferative and proliferative, and who undergo cataract extraction and posterior chamber lens implantation is less favorable than that for patients who have no retinopathy.

3. The poorer prognosis results from increased frequency of cystoid macular edema (CME) and progression of DR, both background and proliferative, after cataract extraction, which may result, in part, from changes in concentrations of angiogenic, antiangiogenic, and anti-inflammatory factors after cataract surgery.

4. Posterior capsule opacification is greater in diabetic individuals following cataract surgery than in nondiabetic control patients; however, among diabetic individuals, neither the stage of DR nor the systemic status of the diabetes correlates with the degree of posterior capsule opacification.

5. There are significant internal structural changes in the type 1 diabetic lens compared to that of type 2 diabetics or normal controls. Specifically, there is an increase in thickness of the lens nucleus and different cortical layers in type 1 diabetes.

6. Higher postoperative levels of cytokine activities and accompanying lens epithelial cell morphologic changes may indicate increased proliferative activity and contribute to strong anterior lens capsule contraction.

Iris

I. Vacuolation of iris pigment epithelium (Fig. 15.4)

A. Vacuolation of the iris pigment epithelium is present in 40% of enucleated diabetic eyes. The vacuoles contain glycogen.

Rupture of the vacuoles when the intraocular pressure is suddenly reduced, as in entering the anterior chamber during cataract surgery, results in release of pigment into the posterior chamber. The pigment is visible clinically as a cloud moving through the pupil into the anterior chamber. Lacy vacuolation and “damage” to the overlying dilator muscle may be the cause of delayed dilatation of the iris after instillation of mydriatics.

B. Pinpoint “holes” may be seen clinically with the slit lamp when transpupillary retroillumination is used. The holes may be seen in at least 25% of known diabetic patients who have blue irises.

In autopsy eyes from diabetic patients, vacuolation of the iris pigment epithelium may be related to increased blood glucose levels before death. The vacuolation is also seen histologically in neonates and in patients who have systemic mucopolysaccharidoses (the vacuoles contain acid mucopolysaccharides), Menkes’ syndrome, and multiple myeloma.

II. Neovascularization of iris (rubeosis iridis; Fig. 15.5; see also Figs. 9.13 and 9.14)

A. Rubeosis iridis is the clinical descriptive term for iris neovascularization.

1. It is present in fewer than 5% of diabetic patients without PDR, but it is present in approximately 50% of patients who have PDR.

2. The new iris vessels arise from venules.

Ischemic retina resulting in proliferative DR increases the intraocular level of VEGF, resulting in the proliferation of new, abnormal blood vessels on the iris surface. Access of VEGF to the anterior chamber inducing the development of iris neovascularization is facilitated by lensectomy and vitrectomy, both of which remove these barriers leading to the development of iris neovascularization in approximately 50% of cases.

B. Neovascularization of the iris may arise from the anterior chamber angle, the pupillary border, midway between, or all three.

Infrequently, the anterior iris stroma, between the pupil and the collarette, may show a very fine neovascularization that can remain stationary for years without the development of angle neovascularization.

C. Early, anterior chamber angle neovascularization causes a secondary, open-angle glaucoma that progresses rapidly to a closed-angle glaucoma, caused by peripheral anterior synechiae.

As the fibrovascular tissue on the anterior iris surface contracts, ectropion uveae may develop. The term ectropion uveae refers to traction by a contracting membrane resulting in drawing the pigment epithelium from the region of the posterior pupillary border onto the anterior iris surface. This result can be caused by other membranes on the iris surface, such as an endothelial membrane, and is not specific for a neovascular membrane. The new blood vessels often give a reddish hue to the iris surface. This finding is commonly called rubeosis irides. These newly formed blood vessels tend to bleed easily, hence the misused and poor term hemorrhagic glaucoma; neovascular glaucoma is the preferred term so as not to confuse the entity with glaucoma secondary to traumatic hemorrhage. Even without the development of iris neovascularization, an increased incidence of both primary open- and closed-angle glaucoma exists in diabetes.

Ciliary Body and Choroid

I. Basement membrane of ciliary pigment epithelium (external basement membrane of ciliary epithelium; Fig. 15.6)

A. The multilaminar basement membrane of the pigment epithelium is diffusely thickened in the region of the pars plicata.

B. The diffuse thickening of the external basement membrane of ciliary pigment epithelium in diabetic patients is different from the “spotty” or “patchy” thickening that may be seen in nondiabetic subjects.

II. The multilaminar basement membrane of ciliary nonpigmented epithelium (internal basement membrane of ciliary epithelium) is not affected.

III. Fibrovascular core of ciliary processes (see Fig. 15.6)

A. Fibrosis results in obliteration of capillaries in the “core” of the ciliary processes.

B. The capillary basement membrane is often significantly thickened.

IV. Choriocapillaris, Bruch’s membrane, and retinal pigment epithelium (Figs. 15.7 and 15.8)

A. Periodic acid–Schiff-positive material thickens and may partially obliterate the lumen of the choriocapillaris in the macula.

B. The cuticular portion of Bruch’s membrane (basement membrane of the retinal pigment epithelium; basal laminar-like deposits) may become thickened, and the lumen of the choriocapillaris may become narrowed by endothelial cell proliferation and basement membrane elaboration.

The incidence of choriocapillaris degeneration is approximately fourfold greater in diabetic patients than in nondiabetic individuals.

C. Drusen are common.

D. Scanning electron microscopy of choroidal vascular casts shows increased tortuosity, dilatation and narrowing, hypercellularity, vascular loop and microaneurysm formation, “dropout” of choriocapillaris, and formation of sinus-like structures between choroidal lobules.

V. Arteries and arterioles of choroid (see Figs. 15.7 and 15.8)

Arteriosclerosis occurs at a younger age in diabetic patients than in the general population.

A. The incidence increases sharply beyond the 15th year of the disease.

B. The change is reflected in atherosclerosis and arteriolosclerosis of the choroidal vessels.

Neural Retina

I. The cause(s) of DR (Table 15.1; see also discussion of PDR later in this section)

A. Although DR is usually discussed relative to the characteristic and clinically apparent vascular changes, recent evidence suggests that DR involves alterations in all of the retinal cellular elements, including vascular endothelial cells and pericytes; glial cells, including macroglia (Müller cells and astrocytes) and microglia; and neurons, including photoreceptors, bipolar cells, amacrine cells, and ganglion cells (Table 15.2). Each of these elements makes unique contri­butions to visual function and participates in multiple homeostatic relationships to the other cellular elements.

Retinal neuronal damage, as diagnosed by spectral-domain optical coherence tomography, may precede clinical evidence of diabetic neuropathy.

B. Damage to multiple retinal neuronal elements through apoptosis, and accompanying glial cell reactivity and microglial activation, suggest that DR might be classified as a neurodegenerative disorder and not simply as a vasculopathy.

Support for the concept of a neurodegenerative proces in diabetes is found in the fact that neurovisual tests are abnormal in type 1 diabetic individuals prior to the onset of clinically apparent retinopathy. Viewed from this perspective, it is doubtful that the entity that we call “diabetic retinopathy” is the manifestation of a single pathophysiologic disturbance or of the malfunction of one cell type. Rather, as can be seen in Table 15.2, multiple pathophysiologic mechanisms come into play in DR, including structural alterations, cell death, inflammation, cellular proliferation, and atrophy. These apparent alterations must require the participation of numerous biologically active mediators. For example, in DR, advanced glycation end products (AGEPs) and/or lipoxidation end products form on the amino groups of proteins, lipids, and DNA and may impact the retina by modifying the structure and function of proteins and/or cause intramolecular and intermolecular cross-link formation. AGEPs not only alter structure and function of molecules but also increase oxidative stress. AGEPs with polyol pathway activation may mediate the direct impairment of retinal endothelial cell barrier function caused by high glucose levels.

C. Apoptosis probably contributes to retinal ganglion cell death in DR, and glial cells may modify the expression of such apoptosis.

D. Inflammation appears to play a significant role in the pathogenesis of diabetic retinopathy.

1. VCAM-1, ICAM-1, and proinflammatory cytokines [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP)] are inflammatory mediators that are upregulated in diabetes with the development and progression of diabetic microvascular complications.

2. Mueller cells exhibit a proinflammatory response in diabetes that may be regulated, in part, by the receptor for advanced glycation and end products (RAGE) and its ligands.

Upregulation of anti-inflammatory mediators and their receptors, such as the retinal pigment epithelial receptor GPR109A and its ligand β-HB, appears to be an attempt by ocular tissue to suppress this inflammatory response. Activated microglia and microglial vasculitis has been implicated in the pathogenesis of diabetic vasculopathy, neuropathy, and retinopathy. Declining retinal microvascular blood flow correlates with the progression of insulin resistance in diabetes.

TABLE 15.1

Proposed Pathogenic Mechanisms for Diabetic Retinopathy

Proposed Mechanism* Putative Mode of Action Proposed Therapy
Aldose reductase Increases production of sorbitol (sugar alcohol produced by reduction of glucose) and may cause osmotic or other cellular damage Aldose reductase inhibitors (clinical trials in retinopathy and neuropathy thus far have been unsuccessful)
Inflammation Increases adherence of leukocytes to capillary endothelium, which may decrease flow and increase hypoxia; may also increase breakdown of blood–retinal barrier and enhance macular edema Aspirin (ineffective in the Early Treatment Diabetic Retinopathy Study but did not increase vitreous hemorrhage; therefore not contraindicated in patients with diabetes who require it for other reasons); corticosteroids (intravitreal injection or slow-release implants for macular edema now being tested)
Protein kinase C Protein kinase C upregulates VEGF and is also active in “downstream” actions of VEGF following binding of the cytokine to its cellular receptor. Protein kinase C activity is increased by diacylglycerol, which is accelerated by hyperglycemia. Clinical trials of a protein kinase Cβ isoform inhibitor in retinopathy have thus far been unsuccessful.
Reactive oxygen species Oxidative damage to enzymes and to other key cellular components Antioxidants (limited evaluation in clinical trials)
Nonenzymatic glycation of proteins; advanced glycation end products Inactivation of critical enzymes; alteration of key structural proteins Aminoguanidine (clinical trial for nephropathy halted by sponsor)
Inducible form of nitric oxide synthase Enhances free radical production; may upregulate VEGF Aminoguanidine
Altered expression of critical gene or genes May be caused by hyperglycemia in several poorly understood ways; may cause long-lived alteration of one or more critical cellular pathways None at present
Apoptotic death of retinal capillary pericytes, endothelial cells Reduces blood flow to retina, which reduces function and increases hypoxia None at present
VEGF Increased by retinal hypoxia and possibly other mechanisms; induces breakdown of blood–retinal barrier, leading to macular edema; induces proliferation of retinal capillary cells and neovascularization Reduction of VEGF by extensive (panretinal) laser photocoagulation; several experimental medical therapies being tested (specific VEGF inhibitors are used to treat neovascularization and macular edema)
PEDF Protein normally released in retina inhibits neovascularization; reduction in diabetes may eliminate this infection. PEDF gene in nonreplicating adenovirus introduced into eye to induce PEDF formation in retina (phase I clinical trial ongoing)
Growth hormone and IGF-1 Permissive role allows pathologic actions of VEGF; reduction in growth hormone or IGF-1 prevents neovascularization. Hypophysectomy (now abandoned); pegvisomant (growth hormone receptor blocker; brief clinical trial failed); octreotide (somatostatin analogue, clinical trial now in progress)

* For all the proposed mechanisms, hyperglycemia accelerates the progression to diabetic retinopathy.

VEGF, vascular endothelial growth factor; PEDF, pigment epithelium-derived factor; IGF-1, insulin-like growth factor-1.

(Modified from Frank RN: Diabetic retinopathy. N Engl J Med 350:48, 2004.)

II. The diagnosis of DR—the best way to diagnose DR is by means of a thorough fundus examination through a dilated pupil.

Ancillary studies, such as spectral-domain optical coherence tomography (OCT), can be very helpful in demonstrating the scope of retinal involvement. For example, retinal thickness has been found to be abnormal diffusely (but not uniformly) in the retina and not just in the areas exhibiting clinically apparent retinopathy. Microaneurysms, acellular capillaries, and pericyte ghosts are more numerous in the temporal retina than in the nasal retina; however, retinal capillary basement membrane thickness does not exhibit such regional variation.

III. Specific constellation of vascular findings—clinical BDR

A. Loss of capillary pericytes (see Fig. 15.1)

Capillary pericytes probably contribute to the mechanical stability of the capillary wall.

1. In the normal retinal capillary, the pericyte-to-endothelial cell ratio is 1 : 1.

2. In the diabetic retinal capillary, the pericyte-to-endothelial cell ratio is less than 1 : 1 because of a selective loss of pericytes.

3. Pericyte death is accompanied by morphologic nuclear changes and lack of inflammation characteristic of apoptosis (see Chapter 1). Activation of nuclear factor-κB, induced by high glucose in diabetes, may regulate a proapoptotic program in retinal pericytes.

4. Multiple anatomic and anatomic/functional abnormalities contribute to retinal vascular changes and loss of the blood–retinal barrier in diabetes and include changes in tight junctions, pericyte loss, endothelial cell loss, retinal vessel leukostasis, upregulation of vesicular transport, increased permeability of the surface membranes of retinal vascular endothelium and retinal pigment epithelial cells, activation of advanced glycation end product receptors, downregulation of glial cell-derived neurotropic factors, retinal vessel dilation, and vitreoretinal traction.

B. Capillary microaneurysms (Figs. 15.9 and 15.10)

1. Many more retinal capillary microaneurysms (RCMs) are detected microscopically and by fluorescein angiography than are seen clinically with the ophthalmoscope.

OCT provides a noninvasive tool for the detection of early diabetic retinal changes. Mean macular thickness, as measured by OCT, correlates with visual acuity in DR. Retinal thickness is increased in diabetic individuals without clinically apparent retinopathy compared to nondiabetic control subjects. In individuals with type 2 diabetes and mild nonproliferative DR, areas of increased retinal thickness are associated with retinal vascular leakage at those sites. Similarly, perimetry can provide more useful information than visual acuity testing relative to functional loss in diabetes.

2. An increase in the number of RCMs can be directly correlated with the loss of pericytes.

3. RCMs are formed in response to a hypoxic environment in which abortive attempts at neovascularization or regressed changes or both have been made in a previously proliferating vessel.

a. RCMs, which are randomly distributed across the arteriolar and venular sides of the capillary network, start as thin outpouchings (saccular) from the wall of a capillary.

b. The retinal capillary endothelial cells proliferate and lay down increased amounts of basement membrane (Figs. 15.10 and 15.11).

c. Ultimately, all of the endothelial cells may disappear; ghost retinal capillaries result.

d. The lumen of the RCM may remain patent or may become occluded by the accumulated basement membrane material.

image
Fig. 15.9 Background diabetic retinopathy. A, Background diabetic retinopathy consists of retinal capillary microaneurysms (RCMs), hemorrhages, edema, and exudates (here in a circinate pattern). B, The RCMs are seen more easily with fluorescein. The areas of circinate retinopathy show leakage (see also Figs. 15.12 and 15.13). C, Trypsin digest preparation shows that an RCM consists of a proliferation of endothelial cells (n, nonviable capillaries; m, microaneurysm). D, A histologic section shows a large blood-filled space lined by endothelium (m, microaneurysm). The caliber is approximately that of a venule. Venules, however, do not occur in this location (in the inner nuclear layer) but, rather, are mainly found in the nerve fiber layer. By a process of elimination, the “vessel” is therefore identified as a cross-section of an RCM. (A and B, Courtesy of Dr. GE Lang.)