Pathogenesis of Diabetic Cataract

Assalamu'alaikum.Wr.Wb

The enzyme aldose reductase (AR) catalyzes the reduction of glucose to sorbitol through the polyol pathway, a process linked to the development of diabetic cataract. Extensive research has focused on the central role of the AR pathway as the initiating factor in diabetic cataract formation.

It has been shown that the intracellular accumulation of sorbitol leads to osmotic changes resulting in hydropic lens fibers that degenerate and form sugar cataracts. In the lens, sorbitol is produced faster than it is converted to fructose by the enzyme sorbitol dehydrogenase. In addition, the polar character of sorbitol prevents its intracellular removal through diffusion. The increased accumulation of sorbitol creates a hyperosmotic effect that results in an infusion of fluid to countervail the osmotic gradient. Animal studies have shown that the intracellular accumulation of polyols leads to a collapse and liquefaction of lens fibers, which ultimately results in the formation of lens opacities. These findings have led to the “Osmotic Hypothesis” of sugar cataract formation, emphasizing that the intracellular increase of fluid in response to AR-mediated accumulation of polyols results in lens swelling associated with complex biochemical changes ultimately leading to cataract formation.

Furthermore, studies have shown that osmotic stress in the lens caused by sorbitol accumulation induces apoptosis in lens epithelial cells (LEC)  leading to the development of cataract. Transgenic hyperglycemic mice overexpressing AR and phospholipase D (PLD) genes became susceptible to develop diabetic cataract in contrast to diabetic mice overexpressing PLD alone, an enzyme with key functions in the osmoregulation of the lens. These findings show that impairments in the osmoregulation may render the lens susceptible to even small increases of AR-mediated osmotic stress, potentially leading to progressive cataract formation.

 The role of osmotic stress is particularly important for the rapid cataract formation in young patients with type 1 diabetes mellitus due to the extensive swelling of cortical lens fibers. A study performed by Oishi et al. investigated whether AR is linked to the development of adult diabetic cataracts. Levels of AR in red blood cells of patients under 60 years of age with a short duration of diabetes were positively correlated with the prevalence of posterior subcapsular cataracts. A negative correlation has been shown in diabetic patients between the amount of AR in erythrocytes and the density of lens epithelial cells, which are known to be decreased in diabetics compared to nondiabetics suggesting a potential role of AR in this pathomechanism.

 The polyol pathway has been described as the primary mediator of diabetes-induced oxidative stress in the lens. Osmotic stress caused by the accumulation of sorbitol induces stress in the endoplasmic reticulum (ER), the principal site of protein synthesis, ultimately leading to the generation of free radicals. ER stress may also result from fluctuations of glucose levels initiating an unfolded protein response (UPR) that generates reactive oxygen species (ROS) and causes oxidative stress damage to lens fibers. There are numerous recent publications that describe oxidative stress damage to lens fibers by free radical scavengers in diabetics. However, there is no evidence that these free radicals initiate the process of cataract formation but rather accelerate and aggravate its development. Hydrogen peroxide (H2O2) is elevated in the aqueous humor of diabetics and induces the generation of hydroxyl radicals (OH–) after entering the lens through processes described as Fenton reactions. The free radical nitric oxide (NO), another factor elevated in the diabetic lens [24] and in the aqueous humor, may lead to an increased peroxynitrite formation, which in turn induces cell damage due to its oxidizing properties.

Furthermore, increased glucose levels in the aqueous humor may induce glycation of lens proteins, a process resulting in the generation of superoxide radicals and in the formation of advanced glycation endproducts (AGE). By interaction of AGE with cell surface receptors such as receptor for advanced glycation endproducts in the epithelium of the lens further  and H2O2 are generated.
 
In addition to increased levels of free radicals, diabetic lenses show an impaired antioxidant capacity, increasing their susceptibility to oxidative stress. The loss of antioxidants is exacerbated by glycation and inactivation of lens antioxidant enzymes like superoxide dismutases. Copper-zink superoxide dismutase 1 (SOD1) is the most dominant superoxide dismutase isoenzyme in the lens, which is important for the degradation of superoxide radicals () into hydrogen peroxide (H2O2) and oxygen. The importance of SOD1 in the protection against cataract development in the presence of diabetes mellitus has been shown in various in vitro and in vivo animal studies.

In conclusion, a variety of publications support the hypothesis that the initiating mechanism in diabetic cataract formation is the generation of polyols from glucose by AR, which results in increased osmotic stress in the lens fibers leading to their swelling and rupture.

 

Buat teman2 yg sedang merantau untuk mencari ilmu ataupun untuk bekerja...

Assalamu'alaikum.Wr.Wb

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