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An Eye to the Future

May 2004

By Dean S. Cunningham, MD, PhD

LE Magazine May 2004
An Eye to the Future
By Dean S. Cunningham, MD, PhD

Diabetic Retinopathy
Diabetic retinopathy is the third leading cause of blindness in people over the age of 20, and eventually adversely affects at least two of three diabetics.8

The progressive degeneration of capillary walls characteristic of diabetic retinopathy results in diffuse and focal weakness (microaneurysms) with leakage (hemorrhage and exudates), thereby culminating in vascular occlusion. As the condition advances, retinal ischemia occurs with compensatory new blood vessel growth (angiogenesis or neovascularization), complicated by further hemorrhage, inflammation, scarring, and eventually retinal detachment. Diabetic retinopathy is classified as background or proliferative. Background diabetic retinopathy is further classified as simple or pre-proliferative. The onset of diabetic retinopathy is characterized by diminished visual acuity, color discrimination, and contrast sensitivity.

The diagnostic hallmark of diabetic retinopathy is a defect at the level of the retinal capillaries and is the pathological manifestation of the toxic effects of chronic hyperglycemia. Generally, risk for diabetic retinopathy is strongly correlated with the duration of uncontrolled hyperglycemia, but can be accelerated or slowed by genetic constitution. Hispanics, African-Americans, and Native Americans with diabetes have an increased prevalence of diabetic retinopathy for just such reasons.

The microvascular complications accompanying diabetes have a biochemical basis that involves four metabolic pathways: polyol, hexosamine, protein kinase C, and glycation end-products. Under-standing these pathways’ role in the pathological changes that accompany diabetes may assist in diabetes prevention and treatment. For example, glucose gives rise to oxidative stress and an alteration in the redux potential of cells vis-à-vis oxidative phosphorylation. Know-ing that makes it intuitive that antioxidants play a pivotal role in modulating the generation of oxygen free radicals,9 as has been demonstrated repeatedly with different supplements.

If you are diabetic, you should check your hemoglobin A1c every three months and strive to maintain it below 7.0. Checking daily blood sugar levels is simply not enough. Furthermore, you should also undergo an ophthalmologic examination yearly.

If you are at risk for diabetes or diagnosed as prediabetic, you should maintain your fasting insulin level in the low normal range through a diet with a reduced glycemic load and the judicious use of supplements that augment the activity of insulin (for example, magnesium,10,11 zinc,12 niacin,13 and biotin14), one’s sensitivity to insulin (for example, chromium polynicotinate,15 alpha lipoic acid,16 vitamin E,17 taurine,18 vitamin C,19 DHEA,20 and hydroxycitric acid13), or glucose homeostasis (for example, gymnema sylvestre,21 quercetin,22 biotin,14,23 bitter melon,24 conjugated linoleic acid and alpha lipoic acid in combination,25 selenium,26 vitamin E,17 pyridoxine,27 and vanadyl sulfate28,29).

Maintaining normal insulin levels is essential to longevity.30 N-acetylcysteine, a precursor of glutathione, is protective against pancreatic beta cell damage through inhibition of nuclear factor-kappa beta activation31 and maintenance of a euglycemic state.9 Aside from strict control of blood glucose levels, keys to slowing the progression of diabetic retinopathy include normalization of blood pressure, treatment of hypercholesterolemia, smoking cessation, regular exercise, and maintaining a body mass index (BMI) of less than 25.

Glaucoma is the second leading cause of blindness in the US. An increase in intraocular pressure leads to irreversible damage of the optic nerve and concomitant visual field loss. Glaucoma is classified as open-angle, angle-closure, congenital, and secondary. Unfortunately, glaucoma is painless and often is not diagnosed until in its advanced stages when the damage is irreparable.

In most cases, intraocular pressure increases when the vitreous humor reabsorption is reduced or its outflow is blocked. In addition to those with a family history, African-Americans are at increased risk. Glaucoma also can occur secondary to eye injury, as a complication of an ocular surgical procedure, as a co-morbid condition of diabetes, or following the chronic use of steroids or overuse of ocular anti-inflammatories. Those with severe nearsightedness also are at greater risk for glaucoma. Glaucoma is thought to represent one of the many age-related neurodegenerative disorders.

An annual ophthalmologic examination with tonometry is recommended for all adults over the age of 40 years. Preventive measures are aimed at maintaining normal intraocular pressures. A topical nitric oxide synthase inhibitor reduces intraocular pressure,32 as does a diluted solution of forskolin applied topically.33 Forskolin is thought to decrease intraocular pressure by activating adenylate cyclase, the enzyme which increases cyclic adenosine monophosphate in cells. The topical application of carnosine also has been shown to reduce intraocular pressure by increasing the vitreous humor outflow.34

Macular Degeneration
Macular degeneration affects one-third of adults over the age of 75, and is the principal cause of visual disability in people over 65 years of age. Because the macula alone is affected, central vision is lost (though total blindness is avoided).

The “dry” form of macular degeneration occurs as the vascular and support cells of the retina atrophy, whereas the “wet” form of macular degeneration occurs as a result of leakage and scarring of the new growth of blood vessels beneath the macula. Aside from aging and the accumulating effect of oxidative stress with concomitant alteration in protein conformation,35 a positive family history of macular degeneration, cigarette smoking, uncontrolled high blood pressure, hypercholesterolemia,36 high-fat diets, and Caucasian des-cent are relative risk factors for macular degeneration.

Antioxidants (vitamins C and E), beta-carotene, and zinc have no effect on the development of macular degeneration but are thought to slow its progression.37-39 Lutein and zeaxanthin, however, may actually prevent macular degeneration.40-44 Ginkgo biloba has a possible protective effect. Ginkgo biloba increases blood flow, antagonizes platelet activating factor, and scavenges oxygen free radicals, all of which may play a role in the development of macular degeneration.45 Glutathione and N-acetylcysteine protect against the atrophy of retinal support cells that occurs in dry macular degeneration.6

Diets rich in monounsaturated fats and omega-3 fatty acids, and low in saturated and polyunsaturated fats, retard the progression of established macular degeneration.46 Routine annual eye examinations are important. According to recent studies, measurement of C-reactive protein, a nonspecific marker for cardiac disease, is predictive for macular degeneration as well.43 Normalization of weight and regular physical exercise also have been shown to offset the risk of macular degeneration.

Interpreting the Science
The conventional gold standard for human research is the randomized, prospective, double-blind, placebo-controlled study. Not surprisingly, such studies are costly and require considerable time to design, execute, and analyze. Furthermore, although human studies control for gender, age, and a limited number of germane exclusion criteria, can one be sure that the outcome reported is not influenced by some unsuspected factor? Of course not—it is impossible to control for all variables in humans.

Conducting such controlled experiments requires syngeneic (genetically identical) animals in a controlled environment. Even then, one must extrapolate the animal model to the human condition under study. While considered clumsy by academic scientists, descriptive studies—such as those that are often the source of information about dietary supplements—can be useful, especially if scientific knowledge forms the rationale for the application. For example, since degenerative diseases in general result from increasing oxidative stress, it follows that an antioxidant like vitamin C reduces oxidative stress and decelerates or stops the degenerative process.

Of course, one must determine the difference between a dose that prevents disease and one that optimizes health. In the case of anecdotal studies, observations can be useful, too. The British Royal Air Force pilots attributed their improved night vision to eating bread with bilberry jam before flying missions. This “common knowledge” led to the science and later delineation of the role anthocyansides play in improving the microcirculation and enzymatic activity of the retina.47