Much research on lens carbohydrate metabolism has been stimulated by interest in sugar cataracts, which are associated with diabetes mellitus and galactosemia. True diabetic cataract is a rapidly developing bilateral snowflake cataract (see Fig 5-19 in BCSC Section 11, Lens and Cataract) that appears in the lens cortex of persons with poorly controlled type 1 diabetes mellitus. Individuals with type 2 diabetes mellitus do not typically develop this type of cataract but do have a higher prevalence of age-related cataract with a slightly earlier onset. It is likely that for these patients, the diabetes is simply an additional factor contributing to the development of age-related cataracts.
Defects in galactose metabolism also cause cataracts. Classic galactosemia is caused by a deficiency of galactose-1-phosphate uridyltransferase. Infants with this inborn error of metabolism develop bilateral cataracts within a few weeks of birth unless milk (lactose) is removed from the diet. Cataracts are also associated with a deficiency of galactokinase. Under certain conditions in which sugar levels are elevated significantly, some glucose (or galactose) is metabolized through the polyol pathway, also known as the sorbitol pathway (see Fig 10-5). Aldose reductase is the key enzyme for the pathway, and it converts the sugars into the corresponding sugar alcohols. Because aldose reductase has a very high Km (apparent affinity constant) value—that is, low affinity—for glucose (or galactose), under normal conditions little or no activity occurs through this pathway. Under hyper-glycemic conditions, however, aldose reductase competes with hexokinase for glucose (or galactose).
Figure 10-5 Glucose metabolism in the lens. Energy (ATP) from glucose is derived primarily through glycolysis. Alternatively, glucose can participate in the hexose monophosphate shunt (also called pentose phosphate pathway ), generating nicotinamide adenine dinucleotide phosphate (NADPH) for oxidation-reduction (redox) reactions. In cases of hyperglycemia or galactosemia, the polyol pathway (also called sorbitol pathway ) has been implicated in the formation of cataract.
(Adapted with permission from Hart WM Jr, ed. Adler’s Physiology of the Eye: Clinical Application. 9th ed. St Louis: Mosby; 1992:362.)
Studies using animal models have established the importance of the polyol pathway in experimental sugar cataracts. Animals with diabetes mellitus (either natural or induced) develop cataracts that are associated with the presence of sorbitol in the lens and with the influx of water. The osmotic hypothesis may account for these findings. According to this hypothesis, the activity of aldose reductase is central to the pathology by serving to increase the sorbitol content of the lens. Sorbitol is largely unable to penetrate cell membranes and thus is trapped inside the cells. Because its further conversion to fructose by polyol dehydrogenase is slow, sorbitol builds up in lens cells under conditions of hyperglycemia such that it creates an osmotic pressure that draws water into the lens, swelling the cells, damaging membranes, and causing cataract.
Hejtmancik JF, Riazuddin SA, McGreal R, Liu W, Cvekl A, Shiels A. Lens biology and biochemistry. Prog Mol Biol Transl Sci. 2015;134:169–201.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.