Clinical background
Diabetes mellitus (DM) is an expanding major health problem. By the year 2030, it is anticipated that the worldwide incidence of DM will roughly double to 366 million, with 75% of all diabetics residing in developing countries. Diabetic adults 18 years of age and older have a 21% increased prevalence of visual impairment while those 50 years or older have a higher prevalence of vision loss from retinopathy, cataracts, and glaucoma. Cataracts develop earlier and more rapidly in diabetics. According to the Wisconsin Beaver Dam Study, the Australian Blue Mountains Eye Study, the Barbados Eye Study, the French Pathologies Oculaires Liées à l’Age (POLA) Study, and the West African Countries (Ghana and Nigeria) Study, diabetics have up to a fivefold increase in the prevalence of cataracts with cortical and/or posterior subcapsular opacities, with women developing cataracts slightly more than men.
It is anticipated that the worldwide increase in DM will lead to an upsurge of cataracts and need for cataract surgery. While cataract surgery generally results in a favorable visual outcome, the visual potential in diabetics is often less and the surgical management more complex because of pre-existent retinopathy, macular edema, or prior laser surgery. Hyperglycemia along with the duration of DM are important risk factors for cataract development ( Box 32.1 ). The risk for cataracts is reduced fivefold when children and adolescents with type 1 DM are treated with intensive insulin therapy while tight control of hyperglycemia in adults with type 2 DM lowers the need for cataract extraction.
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Diabetics have a fivefold increase in the prevalence of cataracts with cortical and/or posterior subcapsular opacities
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The anticipated worldwide doubling of patients with diabetes by 2030 will lead to an upsurge of cataracts and need for cataract surgery
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Hyperglycemia is the primary risk factor for diabetic cataracts and its tight control reduces the risks of cataract development and progression
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Transient refractive changes can occur with hyperglycemia, primarily associated with myopia, and a reduction of hyperglycemia associated with hyperopia
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Sorbitol may serve as an osmolyte in protecting lens epithelia against dehydrational effects of hyperglycemia-increased aqueous osmolarity
Pathology
Precataractous changes
Clear lenses in diabetics are often larger in size with a widened subcapsular clear zone ( Box 32.2 ). The cortex and nucleus of these lenses are also more fluorescent due to protein glycation that is proportional to glycemic control. This fluorescence is reduced with tight control. Transient refractive changes are also linked to glycemic control, with hyperglycemia primarily associated with myopia and hyperopia associated with a reduction in hyperglycemia. These changes may be linked to the lenticular accumulation of sorbitol, a sugar alcohol metabolite of glucose. Sorbitol plays an osmoregulatory role in the kidney by helping cells adjust to intraluminal hyperosmolality during urinary concentration. In the lens, sorbitol may similarly diminish the dehydrational effects of increased aqueous osmolarity due to hyperglycemia. Sorbitol, however, is not rapidly removed from lens cells. As a result, an osmotic gradient favoring lens hydration is formed when hyperglycemia is reduced. The osmotic differences between the lens and aqueous are accentuated by rapid decreases in blood and aqueous glucose levels and this can lead to an additional accumulation of water and hyperopia. If severe enough, these changes can result in lens opacification.
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Appearance of diabetic cataracts depends on age, hyperglycemia, and species
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Children and adolescents with type 1 diabetes demonstrate “snowstorm” cortical opacities or “true” osmotic cataracts where posterior subcapsular opacities with radial striae and eventually vacuoles and clefts develop
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Adults with type 2 diabetes demonstrate cortical and/or posterior subcapsular opacities, often with nuclear sclerosis, that are similar to typical senile cataracts of nondiabetics. Although morphologically similar, epithelial cell densities in cataractous lenses from diabetics are lower than those from nondiabetics
Appearance of diabetic cataracts
While hyperglycemia is the common factor in cataract development in both type 1 and 2 diabetics, the appearance of cataracts in these patients differs depending on the individual’s age and the severity of the hyperglycemia ( Figure 32.1 ). Experimental studies indicate that the appearance of diabetic cataracts is also affected by species differences, as discussed below ( Figure 32.2 ). Clinically, the most common diabetic cataracts contain cortical and/or posterior subcapsular opacities. In children and adolescents with type 1 DM, the lenses contain numerous flaky white cortical deposits which give the appearance of a snowstorm. Alternatively, posterior subcapsular opacities with radial striae extending from the equatorial zone are present. As the opacities progress to the more advanced stages, the lens fibers become distinct with the formation of vacuoles and clefts. These opacities are often referred to as “true” diabetic cataracts because they rapidly evolve bilaterally over a period of days or weeks and are osmotic in nature. Cataract development in type 1 diabetics appears primarily dependent on the severity and prolonged poor control of the hyperglycemia rather than on the duration of DM.
In adults, cataracts from diabetics are often difficult to differentiate from those from nondiabetics. In addition to cortical and/or posterior subcapsular opacities, adult-onset diabetic cataracts often contain nuclear sclerosis which closely resembles the typical senile cataracts of nondiabetics. Comparison of posterior cortical subcapsular cataracts from elderly individuals with type 2 DM and nondiabetics shows similar morphological changes. Moreover, the cataractous regions in both the diabetic and nondiabetic lenses contain similar spherical globules, which are estimated to account for most light scatter, with the remainder from fiber degeneration. Similar morphological changes have also been observed in comparisons of the inner nuclear fiber cells from diabetic and nondiabetic lenses with nuclear sclerosis. However, the epithelial cell densities are lower in cataractous lenses from diabetics compared to nondiabetics.
Pathophysiology
The specific mechanism(s) of how hyperglycemia initiates human cataracts has not been established ( Box 32.3 ). To date, sorbitol pathway hyperactivity, oxidative stress and the generation of reactive oxygen species (ROS), and nonenzymatic glycation/glycooxidation have been implicated in diabetic cataract development. These pathways are summarized in Figure 32.3 .
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The specific mechanism(s) of how hyperglycemia initiates human cataracts has not been established
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Animal studies demonstrate that sorbitol formation associated with aldose reductase (AR) activity occurs in the epithelium and superficial cortical fibers. This can initiate localized osmotic changes that trigger biochemical cascades, leading to cataract formation. Sorbitol is also produced in human epithelial cells and biochemical similarities and clinical observations have linked both AR activity and sorbitol formation with the development of diabetic cataracts
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Oxidative stress and the generation of reactive oxygen species can result from hyperglycemia-associated mitochondrial dysfunction and sorbitol accumulation-initiated endoplasmic reticular stress, both of which are localized to the lens epithelium and bow region where the endothelial cells are differentiating into lens fibers
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Protein glycation and the formation of advanced glycation end products occur in both human and animal lenses and are directly linked to the levels of hyperglycemia present. However, animal studies with aldose reductase inhibitors and the observed absence of cataracts in some diabetic animals, such as hyperglycemic mice or diabetic cats, fail to support a central role for glycation in cataract development
Aldose reductase and sorbitol pathway activity
The sorbitol pathway converts glucose to fructose. In the first step, aldose reductase (AR) utilizes NADPH to reduce glucose to sorbitol. Then sorbitol dehydrogenase (SDH) using NAD + oxidizes sorbitol to fructose. In the lens glucose is rapidly phosphorylated by hexokinase and undergoes glycolysis. Hyperglycemia results in rapidly increased lens glucose levels because glucose uptake is insulin-independent. As a result, hexokinase becomes saturated while AR is activated through gene expression by hypertonicity changes associated with excess glucose; however, SDH is not activated. Since glucose is reduced faster than sorbitol is oxidized, the net effect is the intracellular accumulation of the osmolyte sorbitol. Excess formation of sorbitol has been directly linked to the onset and progression of diabetic complications, and the clinical development of select diabetic complications has been linked to the presence of AR alleles that are associated with increased enzyme activity.
The importance of AR in initiating diabetic complications such as cataracts has been experimentally established by taking advantage of the broad substrate specificity of this enzyme. In addition to glucose, AR reduces galactose to its sugar alcohol galactitol. Galactose-induced tissue changes occur faster and are more severe than glucose-induced changes. This is because AR reduces galactose more rapidly than glucose and because higher intracellular levels of this osmolyte are achieved because galactitol is not further metabolized by SDH. Combining observations that similar cataracts develop in diabetic and galactosemic rats and that AR is present in the lens, Kinoshita et al established that these “sugar” cataracts are initiated by the intracellular accumulation of sorbitol or galactitol. Moreover, these authors demonstrated that the accumulation of sorbitol or galactitol results in localized lens swelling, membrane permeation, vacuole and cleft formation, intracellular biochemical changes, protein aggregation/modification, and light scatter. This is known as the osmotic hypothesis, aldose reductase hypothesis, or sorbitol hypothesis.
This hypothesis is supported by extensive studies utilizing AR inhibitors (ARIs), animal models, and in vitro lens culture studies. Prevention studies utilizing a broad range of structurally diverse ARIs demonstrate that sugar cataracts can be dose-dependently delayed or inhibited. Animal studies show that the onset and severity of sugar cataract formation are directly linked to the levels of lens AR activity, which decreases with age. Cataracts develop faster and are more severe in young animals and they develop faster and under milder hyperglycemic conditions in animals possessing high lens AR levels. In contrast, cataracts do not clinically appear in hyperglycemic mice where AR levels are low. However, when AR is introduced into the lenses of transgenic mice, sugar cataracts rapidly form under both diabetic and galactosemic conditions. In vitro lens culture studies indicate that lens opacification is not only prevented by reducing lens polyol formation with ARIs, but also by preventing the formation of osmotic gradients between the lens and medium in iso-osmotic experiments. This suggests that lens opacification does not directly result from AR activity.
The specific mechanism(s) of how sorbitol (or galactitol) formation and increased AR activity initiate cataract formation remains unclear. While sorbitol or galactitol as osmolytes can initiate localized osmotic stress, increased flux through AR, SDH or both have also been proposed to initiate oxidative stress and generate ROS. Reduced NADPH levels are associated with reduced levels of the antioxidant glutathione, the synthesis of nitric oxide (NO), and the activation of protein kinases. Since SDH only metabolizes sorbitol and not galactitol, it has also been suggested that alternate mechanisms of sugar cataract formation may occur with galactosemia linked to osmotic stress and diabetes linked to oxidative stress-associated ROS. This premise is not supported by animal studies, which show that sorbitol pathway activity is not altered by the administration of antioxidants and potent superoxide scavengers.
It has been proposed that sorbitol is formed through a free radical auto-oxidation of glucose rather than through the enzymatic reduction of glucose by AR; however, glucose auto-oxidation does not occur in the lens at physiological pH and sorbitol (or galactitol) is only enzymatically formed by AR. Sorbitol and galactitol formation has also been linked to oxidative stress and oxidative damage attributed to free radical scavenger formation has been observed in sugar cataracts . Both osmotic and oxidative stress in the lens is reduced by ARIs. Recent studies indicate that ROS is not directly generated by glucose metabolism but by the induction of endoplasmic reticular stress (ER stress) resulting from osmotic stress associated with sorbitol or galactitol formation. By reducing osmotic stress, ARIs also reduce ER stress and the subsequent formation of ROS. Findings that compounds suppressing the induction of ER stress also delay sugar cataract formation support this premise.
Aldose reductase and human cataracts
It is argued that sorbitol formation in the human lens is biochemically insignificant. AR levels and SDH activity in the adult human lens are lower than in the adult rat lens; however, similarities between the human lens and animal models combined with recent clinical observations suggest that a role for AR cannot be ruled out. The sorbitol pathway is functional in human lens and sorbitol and galactitol accumulate in in vitro cultured human lenses and are inhibited by the addition of ARIs. Sorbitol and fructose levels in lenses extracted from diabetics are also proportional to blood glucose levels at the time of extraction. Moreover, cataractous lenses extracted from patients with DM accumulate higher amounts of sorbitol than cataractous lenses from nondiabetics when incubated in vitro. This suggests that AR is activated in diabetic lenses. Immunohistochemical staining for AR is also increased in lenses from diabetic versus nondiabetic patients, suggesting that AR protein levels are increased. Similar increases in both immunohistochemical staining and AR activity have been observed in lenses from diabetic and galactosemic animals.
The prevalence of posterior subcapsular cataracts in patients under 60 years of age with a duration of DM of 10 years has also been correlated with erythrocyte AR levels. Erythrocyte AR levels have also been correlated with decreased lens epithelial cell densities in diabetics with hemoglobin A1c levels above 6.5% or with diabetic retinopathy. The AR gene along with age has been reported to be an important determinant for cataract formation in type 2 diabetics. Similar correlations between erythrocyte AR levels and diabetic retinopathy in type 2 diabetics and diabetic retinopathy development and increased AR activity associated with polymorphisms in the promoter region of the AR gene have been reported.
Are localized osmotic changes possible in human lens?
Classical osmotic cataracts commonly develop in infants with uncontrolled galactosemia and they have been documented in cases of acute hyperglycemia in adolescent and adult diabetics. However, in older human lens sorbitol accumulation is not adequate for initiating osmotic stress over the entire lens; nevertheless, the possibility of localized osmotic stress should not be ignored. AR is localized in the epithelial cell layer and superficial fiber cells in the human, dog, and rat ( Figure 32.4 ). Specific activity of AR in the rat lens is 14-fold higher than in the dog or human lens, which are similar. In vitro cultured dog lenses primarily accumulate sorbitol in the epithelial cells and superficial cortical fibers. Raman spectroscopy of diabetic rat lenses indicates that hydration is localized in primarily the lens epithelium and the bow and superficial cortical regions, but not in the nucleus. Similar localized osmotic changes in the rat lens have been observed by histology. Localized osmotic changes have also been demonstrated by magnetic transfer contrast magnetic resonance imaging (MTC-MRI) in galactose-fed dog lenses.
