2.2.3 Diabetic cataract

Yes, diabetes mellitus causes cataracts, among other things. It is a unique biochemical issue.

Now, open your biochemistry textbook to Glucose Metabolism. You'll see that in addition to glycolysis and hexose monophosphate shunt (HMPS), there is a little known "sorbitol pathway". It has only two steps/enzymes, aldose reductase (AR) and polyol dehydrogenase (PD). AR requires the cofactor NADPH to turn glucose into its alcohol, sorbitol. NADPH is generated by HMPS and is also needed by glutathione peroxidase. PD with the cofactor NAD converts sorbitol to fructose. And NAD is called for elsewhere in glycolysis. It is under the interaction of these pathways that diabetic cataractogenesis initiates. Here is the scenario:

AR has very high Km for glucose, so it'll become active when glucose level is high as in diabetes. Glucose is then converted to sorbitol which cannot leave the lens cell. It is also not metabolized by PD fast enough because of low PD levels in the lens. Sorbitol therefore accumulates and becomes an osmogen causing water to enter the cell. In fact, during the early stages, water vacuoles or small water-filled "bubbles" are seen in the lens cortex. At the same time, AR activation will have taken away NADPH also needed by glutathione peroxidase to detoxify lipid peroxides. Excess peroxides results in extra oxidative stress mentioned in the previous post. So we now have a double whammy situation. Clinically, diabetic patients do seem to develop age-related cataracts earlier than the non-diabetics.

An obvious strategy for treating diabetic cataract is to inhibit AR. And indeed several AR inhibitors have been developed; although none has become clinically practical. The main reason is the sperm utilizes the sorbitol pathway to produce fructose, its main energy substrate. A systemic use of AR inhibitors will have unintended consequences. Perhaps the topical route, as eyedrops, can achieve the same therapeutic purpose. Another way is to control blood glucose tightly. The advantage is protein glycosylation also can be avoided. This glycation is indexed by hemoglobin A1c. In fact, glycosylation also has been proposed to be a diabetic cataractogenic factor as a direct challenge to the sorbitol pathway theory. And in addition to glucose, fructose, fructose-3-phosphate and others also have been implicated. By monitoring both A1c and blood glucose levels, perhaps diabetic cataract can be prevented. At least in theory.

The glycation scenario, however, does not agree with the vision change in the diabetics, unless one argues that lens protein glycation is reversible. It also should be noted that the lens cell fibers do not turn over as the erythrocytes. Each new generation of the latter of course will have an A1c level representing the present not the past. In fact, there is currently no evidence of reversible lens protein glycation.

Cortical cataracts are unique in that they appear like spokes on a bicycle wheel, i.e., there are clear zones inbetween that behave as pinholes. Sometimes, with the pinhole effect, the patient's vision in each eye becomes quite good. However, with both eyes together in binocular coordination, the visual axis no longer passes through the pinholes, and the patient's vision is now blocked by the opacities, i.e., lost. Yet another possibility is the patient can see through two or more adjacent clear zones resulting in double or multiple vision but only with one eye, which is to be distinguished from the true binocular double vision (diplopia), usually the result of a neurological deficit.

There are other situations where a diabetic's vision can change. Chief among them is the fluctuating glucose level. High glucose causes increasing myopia because of glucose/sorbitol/water accumulation. Once controlled, the patient's refractive error will now become less myopic. This is when the patient declares, "I can see better with my old glasses." In a way, a shift towards more hyperopia (or less myopia) is an indication of a well-regulated and stable blood glucose level. A good sign in fact.