The glucose that is not phosphorylated to G6P enters the sorbitol pathway, which is yet another pathway for lens glucose metabolism, or it is converted into gluconic acid. The key enzyme in the sorbitol pathway is aldose reductase; this enzyme has been found to play a pivotal role in the development of “sugar” cataracts. In comparison with hexokinase, aldose reductase has a very low affinity for glucose. Less than 4% of lens glucose is normally converted to sorbitol.
As noted in the previous section, the hexokinase reaction is rate-limited in phosphorylating glucose in the lens and is inhibited by the feedback mechanisms of the products of glycolysis. When the amount of glucose increases in the lens (as occurs in individuals in hyperglycemic states), the sorbitol pathway is activated relatively more than the glycolytic pathway, and sorbitol accumulates (Fig 3-3).
Sorbitol is metabolized to fructose by the enzyme polyol dehydrogenase. Unfortunately, this enzyme has a relatively low affinity (high Km [Michaelis constant; the apparent affinity constant]), meaning that considerable sorbitol will accumulate before being further metabolized. This characteristic, combined with the poor permeability of the lens to sorbitol, results in retention of sorbitol in the lens.
A high ratio of NADPH/NADH drives the reaction in the direction of sorbitol accumulation. The accumulation of NADP that occurs as a consequence of activation of the sorbitol pathway may cause the HMP shunt stimulation that is observed in the presence of an elevated lens glucose level. In addition to sorbitol, fructose levels increase in a lens incubated in a high-glucose environment. Together, the 2 sugars increase the osmotic pressure within the lens, drawing in water. At first, the energy-dependent pumps of the lens are able to compensate, but ultimately, they are overwhelmed, resulting in swelling of the fibers, disruption of the normal cytoskeletal architecture, and opacification of the lens.
Figure 3-3 Sorbitol pathway in hyperglycemic state.
(Courtesy of Charles Cole, MD.)
Studies of cataract development in various hyperglycemic animal species demonstrate the pivotal role of aldose reductase in cataractogenesis in animals. Those species that have high aldose reductase activities develop lens opacities, whereas those lacking aldose reductase do not. In addition, specific inhibitors of this enzymatic activity, applied either systemically or topically to 1 eye, decrease the rate of onset and the severity of glucose cataracts in experimental studies.
Excerpted from BCSC 2020-2021 series: Section 11 - Lens and Cataract. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.