C H A P T E R
Diabetes Mellitus and Glaucoma Jay Siak, Gavin S. Tan, Tin Aung Singapore National Eye Centre, Singapore
INTRODUCTION Glaucoma refers to a spectrum of diseases (Figure 11.1) associated with progressive optic disc cupping and irreversible loss of ganglion cell neurons, with corresponding functional visual loss. Although an elevated intraocular pressure (IOP) is the primary risk factor linked with disease onset and progression, its pathogenic mechanisms are multifactorial, and vascular factors such as optic nerve head ischemia, nocturnal hypotension, and systemic hypoxia from obstructive sleep apnea are also contributory factors. As diabetes mellitus is a major systemic cause of microvasculopathy, and the world population is facing an increasing epidemic of the condition, it is important to understand whether diabetic patients are facing an increased risk of blindness from glaucoma (besides diabetic retinopathy).
EPIDEMIOLOGY: DIABETES MELLITUS AND PRIMARY OPEN-ANGLE GLAUCOMA As primary open-angle glaucoma (POAG) is the most common type of glaucoma worldwide, most reported epidemiologic studies have examined the relationship of POAG with diabetes mellitus. In general, many studies revealed diabetes mellitus to be associated with an increased IOP,1–7 but its association with POAG remains unclear. The major population-based epidemiologic studies are summarized in Table 11.1 and Figure 11.2. A statistically significant association between diabetes and POAG was reported in the Beaver Dam study, the Rotterdam study, the Blue Mountains Eye study, the Los Angeles Latino Eye study, and the Nurse Health Study,1,8–11 but several other studies did not concur with this finding.3,6,12–18 In 2004, Bonovas et al. reported a meta-analysis of studies that evaluated diabetes mellitus as a risk factor for POAG.19 This included seven cross-sectional and
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five case-control studies, and the authors concluded that there was a statistically significant relationship between diabetes mellitus and POAG (odds ratio (OR) 1.50; 95% confidence interval (CI) 1.16 to 1.93) with the assumption of a random-effects model. However, the results of the studies were not homogeneous (P = 0.023), and the association was not significant among the case-control studies (OR 1.45; 95% CI 0.85 to 2.45). There are a number of reasons for the conflicting findings of these studies. Many of the epidemiologic studies used different diagnostic criteria to define their diabetic cohort, such as the use of self-reported diabetes history, random or fasting serum glucose, random glycated hemoglobin A1c level, and nonfasting glucose tolerance testing. The definition of POAG was also heterogeneous, although the majority of the population-based studies did define glaucoma subjects using glaucomatous optic disc changes with some form of corresponding visual field defects. Unfortunately, many of the studies were not specifically planned to examine the link between the two conditions. The studies were also performed among different ethnic groups, and there might be a difference in the relationship between diabetes and glaucoma among people of various ethnicity. Further large population studies using similar diabetes and glaucoma definitions are needed in order to arrive at a more conclusive understanding of the relationship between diabetes and POAG.
EPIDEMIOLOGY: DIABETES MELLITUS AND OTHER TYPES OF GLAUCOMA In normal-tension glaucoma (NTG), compared with POAG, vascular risk factors such as migraine,20 Raynaud phenomenon,21 and nocturnal hypotension22 are considered to be more important in its pathogenesis due to impaired autoregulation of optic nerve head vascular supply. There was only one study that specifically examined diabetes and NTG; Kim observed that
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11. DIABETES MELLITUS AND GLAUCOMA
FIGURE 11.1 (A) Open-angle glaucoma; (B) angle-closure glaucoma.
diabetes mellitus increased the likelihood of bilateral involvement in NTG by 2.31 times (P = 0.004) compared with unilateral NTG.23 Microvascular angiopathy and impaired vascular autoregulation due to autonomic neuropathy may potentiate the glaucomatous damage caused by nocturnal hypotension or large diurnal IOP fluctuations. Pseudoexfoliation (PXF) syndrome is the most common identifiable cause of secondary open-angle glaucoma,24 and it is an age-related disease of the extracellular
TABLE 11.1 Summary of Epidemiologic Studies on the Association between Diabetes Mellitus and Primary Open-Angle Glaucoma Study
No. of Subjects
Beaver Dam, USA
VF, CDR, IOP DM history, HbA1c > 1.84 ≥ 22, hx 2 SD, random serum glucose > 11.1 mmol/L
1.09 to 3.11 Yes
VF with CDR Random serum glucose 3.11 or IOP > 21 or nonfasting glucose tolerance test > 11.1 mmol/L
1.12 to 8.66 Yes
Blue Mountains, Australia
DM history, fasting serum glucose ≥ 7.8 mmol/L
1.18 to 3.79 Yes
DM history, HbA1c ≥ 7%, random serum glucose ≥ 200 mg/dL
1.03 to 1.8
Nurse Health Study, USA
Cohort study of registered nurses
Glaucoma hx, Self-reported DM VF, CDR history
1.06 to 2.22 Yes
0.85 to 1.25 No
Arizona, USA Population cross-sectional
DM history, HbA1c ≥ 7%
0.79 to 1.94 No
DM history, random serum glucose > 200 mg/dL
0.8 to 1.3
DM history, random serum glucose ≥ 200 mg/dL
0.58 to 1.79 No
Beijing, China Population cross-sectional
DM history, fasting serum glucose ≥ 7.0 mmol/L
0.61 to 2.56 No
Historical cohort population study
6631 Glaucoma diabetic, treatment, 166,144 CDR, VF nondiabetic
0.99 to 2.48 No
De Voogd 200612
Population cohort study
DM history, random serum glucose or nonfasting glucose tolerance test ≥ 11.1 mmol/L
0.25 to 1.64 No
Odds Ratio 95% CI
CI: confidence interval; DM: diabetes mellitus; DR: cup to disc ratio; FDP: frequency doubled perimetry; HbA1c: glycated hemoglobin; hx: history; IOP: intraocular pressure; POAG: primary open-angle glaucoma; RR: risk ratio; SD: standard deviation; VF: visual field.
Pathophysiologic Link Between Diabetes Mellitus and Glaucoma
FIGURE 11.2 Analysis of eight population crosssectional studies that examined the association between primary open-angle glaucoma and diabetes mellitus. Studies with insufficient data for analysis were excluded. The odds ratio and 95% confidence interval for each study as denoted by the first author and publication year are displayed on a logarithmic scale. The fixed effect model is appropriate as the test of heterogeneity is insignificant (P-value = 0.09).
matrix that was proposed to be associated with systemic vascular diseases such as aortic aneurysms.25 However, in several large studies, PXF and PXF glaucoma were not found to be significantly associated with diabetes in multivariate analyses.26–28 Primary angle-closure glaucoma (PACG) is a disease that is particularly important in Asia, with a greater morbidity of blindness compared with open-angle glaucoma.29 Previous studies have shown that the lens plays a role in the pathogenesis of primary angle closure (PAC), with increased lens thickness, lens vault,30 and shallow anterior chamber depth31 being significant risks. It was found that diabetic Chinese people have shallower mean anterior chamber depth (2.78 mm vs. 2.91 mm; P = 0.004) and thicker lenses (4.88 mm vs. 4.75 mm; P = 0.003) than non-diabetic Chinese people (Figure 11.3).32 One population-based study conducted in India also observed an association between PACG and PAC with diabetes mellitus (OR 3.181; 95% CI 1.34 to 7.58; P = 0.001) in their multivariate analysis.33 Sihota found that diabetes was more common among patients with asymptomatic chronic PACG than in patients with symptomatic chronic PACG (P < 0.01) (Table 11.2).34 More studies are necessary to understand if the relationship between angle-closure glaucoma and diabetes is similar among the other populations. Neovascular glaucoma can also develop with proliferative diabetic retinopathy or result from ocular ischemic syndrome, retinal vein occlusions, or diabetic complications such as tractional retinal detachment. Vitreous hemorrhage may also result in ghost cell glaucoma, and secondary glaucoma may develop after vitrectomy performed for the various complications of proliferative diabetic retinopathy.
FIGURE 11.3 Diabetic subjects had shallower anterior chamber depth and thicker lenses, leading to increased risk of angle-closure disease.
PATHOPHYSIOLOGIC LINK BETWEEN DIABETES MELLITUS AND GLAUCOMA How may glaucoma be related to diabetes mellitus? Although we still do not have a definitive explanation for this relationship, there is indirect evidence of similar ocular anatomical and physiologic changes that are common in diabetes and glaucoma (Table 11.3). One of the key histologic features in glaucoma is the irreversible loss of ganglion cell neurons. It has been observed in streptozotocin (STZ)-induced diabetic rats that the ganglion cell layers are significantly thinner, whereas the outer retina layers are preserved.35 Ganglion cell axon atrophy was also seen in type 1 diabetic BB/W-rats.36 A significant reduction in retinal nerve fiber thickness was also observed in human diabetic eyes with no retinopathy using high-resolution optical
11. DIABETES MELLITUS AND GLAUCOMA
TABLE 11.2 Summary of Epidemiologic Studies on the Association between Diabetes Mellitus and Primary Angle-Closure Glaucoma Study Saw
No. of Subjects Association
Diabetic Chinese people had shallower mean anterior chamber depth (2.78 mm vs. 2.91 mm; P = 0.004) and thicker lenses (4.88 mm vs. 4.75 mm; P = 0.003), which were associated with increased risk of angle-closure disease
Diabetes mellitus was significantly associated with angle-closure disease (PACG and PAC) (OR 3.181; 95% CI 1.34 to 7.58)
Sihota 200034 India
Clinic case-control 160
Diabetes was more common among patients with asymptomatic chronic PACG than those with symptomatic chronic PACG (P < 0.01)
CI: confidence interval; OR: odds ratio; PAC: primary angle closure; PACG: primary angle-closure glaucoma.
TABLE 11.3 Pathophysiologic Links between Diabetes Mellitus and Glaucoma Changes in Diabetes
Changes in Glaucoma
• Ganglion cell axon atrophy • Reduction in retinal nerve fiber thickness
• Irreversible loss of ganglion cell neurons
• Altered vascular • Altered vascular autoregulation autoregulation • Abnormalities in retrobulbar • Abnormalities in retrobulbar blood flow and retinal blood flow microcirculation • Increased neuronal and • Increased nitric oxide levels inducible nitric oxide synthase • Increased nitric oxide synthase activity in the astrocytes at activity lamina cribrosa • Higher levels of endothelin-1
• Increased levels of endothelin-1 detected in POAG and NTG compared to normal controls
• Reduced retrograde axonal transport in retinal ganglion cells
• Inhibition of retrograde brainderived neurotrophic factor transport in retinal ganglion cells
• Increased connective tissue • Overexpression of connective growth factor mRNA expression tissue growth factor leads to • Higher connective tissue modification of the trabecular growth factor levels induced by meshwork actin cytoskeleton, advanced glycation end products, causing increased IOP with high glucose levels, and vascular optic nerve damage endothelial growth factor mRNA: messenger ribonucleic acid; NTG: normal-tension glaucoma; POAG: primary open-angle glaucoma.
coherence tomography (OCT).37 Retina studies on type 1 diabetic patients using OCT also confirmed a significant reduction in ganglion cell and retinal nerve fiber layer thickness.38,39 In STZ-induced diabetic rats, there was an increase in apoptosis in the inner retina after the induction of chronic ocular hypertension (OHT) over 4 weeks by cauterization of episcleral veins, compared with control eyes.40 The larger cell body changes were found to be at the level of the ganglion cell layer.
Pattern electroretinogram (PERG) is a well-established surrogate measure of retinal ganglion cell (RGC) function, and studies reported physiologic changes in the PERG in eyes with both glaucoma and diabetes. Over a period of up to 4 years, PERG waveforms were reduced significantly in patients with diabetes and OHT compared with normal control subjects with normal vision.41 OHT subjects without diabetes did not have similar changes. The mean PERG amplitude of diabetic glaucoma subjects without retinopathy was significantly smaller (P < 0.05) than that of nondiabetic glaucoma subjects after adjustment for individual differences in age, visual acuity, visual field defect, and IOP.42 There are several ways in which diabetes may contribute toward neuronal damage in glaucoma. First, vascular autoregulation is altered in both diabetes43 and glaucoma,44 possibly related to autonomic dysfunction or local vasoactive agents such as nitric oxide. This may contribute toward ocular ischemia and reperfusion damage. Increased basal serum nitric oxide levels were found in diabetic subjects compared with nondiabetic controls (P = 0.0001).45 Retina from postmortem eyes of subjects with diabetes and nonproliferative retinopathy revealed immunoreactivity for inducible nitric oxide synthase (iNOS) in retinal Müller glial cells compared with those of subjects without diabetes and ocular disease.46 At high levels, nitric oxide has been shown to reduce blood flow at the optic nerve head,47 possibly contributing to glaucomatous optic neuropathy. Increased neuronal and iNOS activity was also observed in supporting astrocyte cells at the lamina cribrosa of patients with glaucoma.48 Endothelin-1 (ET-1) is another vasoactive agent that mediates vasoconstriction, and increased levels have been reported in the aqueous humor of POAG patients compared with normal controls who underwent cataract surgery.49 Plasma ET-1 levels were also significantly higher for 52 patients with NTG compared with normal controls.50 Intravenous administration of
ET-1 also induced a reduction in the blood flow of the optic nerve head of rabbits. Higher levels of ET-1 were also observed in blood serum samples and the vitreous humor of patients with proliferative diabetic retinopathy compared with control patients,51 and a higher ET-1 level was correlated with a higher glycated hemoglobin A1c level. Therefore, a higher ET-1 level in diabetic individuals may contribute to increased risk of optic nerve head ischemia and glaucomatous optic neuropathy. RGCs require neurotrophic factors such as brainderived neurotrophic factor (BDNF), and a substantial inhibition of retrograde transport of BDNF in RGC has been observed in rats after IOP elevation.52 Diabetes has also been shown to reduce retrograde axonal transport progressively in RGCs in STZ-induced diabetic rat models.53 Diabetes may accelerate the atrophy of ganglion cells in the presence of chronic OHT. The trabecular meshwork aqueous humor outflow is influenced by transforming growth factor-β and its downstream mediator, connective tissue growth factor (CTFG). Overexpression of CTFG has been shown to increase IOP in mice with resultant optic nerve damage due to modification of the trabecular meshwork actin cytoskeleton.54 CTFG messenger ribonucleic acid (mRNA) expression has been reported to be increased in diabetic eyes55 and can be induced by advanced glycation end products,56 high glucose levels57 and vascular endothelial growth factor.58
CONCLUSIONS Clinical and laboratory evidence suggest possible links between diabetes mellitus and various mechanisms of glaucomatous optic neuropathy. However, further studies are necessary to conclude its association with POAG, NTG, and angle-closure glaucoma.
TAKE-HOME MESSAGES • D iabetes is associated with a higher IOP, but the evidence is conflicting regarding its association with POAG. • Diabetes may be associated with bilateral NTG. • Diabetes is not associated with PXF syndrome glaucoma. • Diabetes is associated with angle-closure disease in Asian people. • Diabetes and glaucoma share many ocular anatomical and electrophysiologic similarities. • Mechanistic links may include impaired vascular autoregulation, increased RGC death from neurotrophic factor deficiency, and trabecular meshwork remodeling from increased CTFG levels.
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