Dietary Supplements for DR Patients

By Glenn L. Stoller, MD, FACS

Evidenced-based medicine, most notably the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study, has demonstrated the importance of tight glycemic control in reducing the incidence and progression of diabetic retinopathy (DR).^1,2 Similar observations have been demonstrated with tight blood pressure control in hypertensive diabetic patients.³ However, there seems to be a limit to the risk reduction for DR that can be achieved through "tighter" glucose and BP lowering; furthermore, such control is difficult to achieve and maintain.⁴ These results and those from other population-based studies⁵ suggest that processes other than hyperglycemia and elevated BP contribute to the development of DR.

Once sight-threatening retinopathy has developed, the current standard of treatment is laser photocoagulation. The Diabetic Retinopathy Study (DRS)^6,7 and the Early Treatment of DR study (ETDRS)⁸ have demonstrated that pan-retinal laser photocoagulation (PRP) significantly reduces the risk of severe vision loss from proliferative DR (PDR) by at least 50% and focal laser photocoagulation reduces the risk of moderate visual loss by 50% in eyes with clinically significant diabetic macular edema (CSME).⁸ However, despite laser intervention in the ETDRS, 12% of treated eyes with CSME still developed moderate vision loss. Furthermore, approximately 40% of treated eyes that had retinal thickening involving the center of the macula at baseline still had persistent thickening at one year.

Despite optimizing glycemic and BP control and applying laser when indicated, many patients will develop worsening retinopathy and sustain visual loss. Clearly there remains an unmet medical need to develop alternative methods of treatment, possibly used in combination with standard therapy, to improve visual outcomes and lessen or reverse the damaging effects of diabetes on the microvasculature of the retina. It is possible that dietary supplementation could be helpful in mitigating diabetic retinal damage.

Oxidative Stress

Under normal physiologic conditions, a very small percentage of oxygen that enters the electron transport chain is reduced to superoxide — a reactive oxygen species (ROS). Excess production of ROS or inefficient removal of ROS could result in pathological conditions. Oxidative stress occurs when the amount of ROS or molecular oxygen overwhelms the capacity of the cell to defend against these substances by an innate scavenging system. Chronic oxidative stress has the capacity to damage DNA, lipids, proteins and carbohydrates and disrupt cellular homeostasis and generate other ROS. Diabetes results in increased oxidative stress, and elevated oxidative stress plays an important role in the pathogenesis of diabetic complications.⁹

The retina has a high content of polyunsaturated fatty acids and the highest oxygen uptake and glucose oxidation relative to any other tissue, rendering particularly susceptible to oxidative stress,¹⁰ which is postulated to promote the development of DR.¹¹ The exact mechanism has not been fully elucidated and likely involves not only oxidative stress itself, but the complex interaction between excess ROS and the activation of other metabolic pathways that are detrimental to the retina. Oxidative stress is believed to interact with the polyol pathway, the advanced glycation end product (AGE) pathway, the protein kinase C pathway, and nuclear factor kB (NF-kB) which influences the synthesis and expression of many inflammatory factors. ROS also affects the hexoamine biosynthesis pathway and leads to alterations in the expression in VEGF and insulin-like growth factor-1 among others.¹² Since there is a strong understanding that if oxidative stress may be the instigator of all other dysmetabolisms implicated in the pathogenesis of DR, the use of appropriate antioxidants may have the potential to effect the progression of DR.¹²

Benefits of Green Tea

Green tea, rich in polyphenols with great antioxidant potency, inhibits lipid peroxidation and scavenges ROS.¹³ Green tea supplementation in diabetic rats increases free radical scavengers and improves retinopathy as evident by reductions in acellular capillaries and pericyte ghosts.¹⁴ Epigallocatechin-3-gallate (EGCG) is a particularly potent antioxidant flavonoid found in green tea. EGCG inhibited the expression of proinflammatory factors and repressed the deleterious effects of AGE's when studied in human monocytes under hyperglycemic conditions. The authors concluded that flavonoids such as EGCG might be an effective adjuvant strategy for delaying diabetic complications.¹⁵ EGCG is also believed to help control glucose levels.¹⁶

Essential Nutrients for the Eye

Carotenoids demonstrate a vast array of biologic activities including important roles in the eye. Lutein and zeaxanthin comprise the macular pigments, essential for normal vision and for the protection of photoreceptors from phototoxic blue light. Lutein has been shown to attenuate oxidative stress in experimental models of early DR. More specifically, lutein supplementation in diabetic mice inhibited NFkB activity, oxidative stress and prevented impairment of the electroretinogram compared to controls.¹⁷ Zeaxanthin given to diabetic rats inhibited diabetes-induced retinal oxidative damage, elevation in VEGF and the adhesion molecules, which lead to leukostasis. These are all abnormalities associated with the pathogenesis of DR. The authors conclude that zeaxanthin supplementation has the potential to inhibit the development of retinopathy in diabetic patients.¹⁸ Consistent with these findings, a recent prospective cohort study demonstrated that plasma levels of lutein and zeaxanthin were lower in diabetic patients who had retinopathy compared to those who did not. Similarly, a higher level of lutein and zeaxanthin plasma concentrations predicted a lower risk of diabetic retinopathy.¹⁹

Antioxidant vitamins C and E defend against the damaging effects of high oxidative stress owing to nonenzymatic glycosylation, autoxidative glycosylation, and metabolic stress in persons with diabetes. These processes are believed to be associated with diabetic complications.²⁰ Supporting the hypothesis that dietary supplementation of vitamins C and E may be beneficial in the management of diabetic eye disease are the findings from the Atherosclerosis Risk in Communities Study, which demonstrated that dietary supplementation with vitamins C and E did have a protective effect against retinopathy.²¹ Vitamin E refers to a group of phenols, more specifically tocopherols and tocotrienols. Tocotrienols have an enhanced mobility in the membrane bilayer, improving their ability to react with lipid radicals compared to tocopherols. For this reason tocotrienols are more powerful antioxidants than tocopherols. Therefore a dietary supplement that contains vitamin E would ideally contain a mixture of these two phenols.

A review of the literature suggests that vitamin D is likely to have a role in the management of diabetes or diabetic retinopathy. Vitamin D is a molecule with pleotropic effects. Apart from its role as a mediator of mineral homeostasis, vitamin D has antiproliferative, antiangiogenic and antioxidant properties.²² The vitamin D receptor is expressed in most cells of the retina including the vascular endothelial cells in animals and human beings.^23,24

One study of diabetic patients demonstrated that subjects with a certain variation of the vitamin D receptor are at low risk for developing severe diabetic retinopathy while those with a different variation of the receptor are at high risk for severe retinopathy.²⁵ Vitamin D was also shown to be antiangiogenic in an animal model of retinal neovascularization.²⁶ Furthermore, substantial evidence supports that low levels of vitamin D contributes to insulin resistance and higher levels of vitamin D are associated with improved insulin sensitivity in type 2 diabetes. Low vitamin D levels are also implicated in the development of type 1 diabetes.²⁷

The micronutrients zinc and copper also have antioxidant functions. Zinc acts as a co-factor for the antioxidant enzymes retinal dehydrogenase and is also involved in retinal metabolism.²⁸ A study of diabetic animals demonstrated the beneficial effects of zinc in both controlling hyperglycemia and the protection of the retina against oxidative stress in diabetes.²⁹ Zinc has also been shown to protect the retina from diabetes-induced increased lipid peroxidation and decreased glutathione levels, a free radical scavenger, in rats.³⁰

Zinc is essential for copper-zinc superoxide dismutase and inhibits diabetes-induced increases in plasma malondialdehyde and decreases in erythrocyte antioxidant defense enzymes. Copper oxide functions as the active center of many cuproenzymes, and copper deficiency results in oxidative damage to lipids, DNA and proteins. The exact mechanism by which zinc and copper exert their protective effects in an animal model of diabetic retinopathy is not clear. However the possibility that these nutrients are helping to decrease oxidative damage remains very strong.^31,32

Importance of Omega 3s

Omega 3 fatty acids, specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), play an important structural and a number of physiologic roles in the retina. These omega 3 fatty acids are found in the neural and vascular cell membranes.³³ DHA is a major structural lipid of retinal photoreceptor outer segment membranes. Our bodies do not have the capacity to meet tissue needs for these substances through biosynthesis, thus rendering us dependent on dietary intake.

Omega 3 fatty acids act as antioxidants. In human tissue, fish oil exposure is associated with a reduction in free radicals.³⁴ Furthermore, it has been shown that non-smoking, treated-hypertensive, type 2 diabetic patients consuming supplements of purified EPA and DHA had lower levels of a biomarker for lipid peroxidation and oxidative stress compared with control subjects who consumed olive oil.³⁵ Supplementation of omega-3-polyunsaturated fatty acids also had beneficial effects on inflammation in diabetes.³⁶

The complex inflammatory pathways are increasingly being recognized as a contributing factor in the development and progression of DR.³⁷ Therefore, it is reasonable to hypothesize that supplementation with DHA and EPA may be beneficial to diabetic patients and possibly have therapeutic value in the management of DR. Further support for this contention is the finding that DHA and EPA may function in vivo to regulate retinal vaso-obliteration and neovascularization.³⁸ DHA and EPA have also been demonstrated to be antiangiogenic. In an animal model of pathologic angiogenesis, DHA and EPA reduced pathologic neovascularization after vascular loss and injury.³² The reader is referred to a comprehensive review by Bhathena³⁹ of the putative role of omega fatty acids in modulating the factors and processes implicated in the pathogenesis of DR.

Consider Nutrition-Based Therapy

Although no large multicenter prospective randomized clinical trials of dietary supplements for the treatment of DR are currently available, significant evidence from animal studies, observational and interventional studies have been presented here. Eye care practitioners should give careful consideration to initiating nutritional-based therapy in their diabetic patients as an adjunct to the current standard of care.

Oxidative stress, acting alone as well as by promoting inflammation, appears related to the pathogenesis of diabetic eye disease. Current evidence suggests that dietary supplements have the potential to reduce oxidative stress, inflammation and pathologic angiogenesis and could be a valuable adjunct in managing diabetic eye disease. OM

References

1. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.
2. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352;837-853.
3. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes:UKPDS 38. UK Prospective Diabetes Study (UKPDS) Group. BMJ 1998;317:703-713.
4. ADVANCE Collaborative Group. Patel A, MacMahon S et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572.
5. Wong TY, Liew G, Tapp RJ, et al. Relationship between fasting glucose and retinopathy for the diagnosis of diabetes:three population-based crosssectional studies. Lancet 2008;371:736-743.
6. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Ophthalmology 1978;85:82-106.
7. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology 1981;88:583-600.
8. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991; 98(5 Suppl):766-785.
9. Baynes JW, Role of oxidative stress in the development of complications in diabetes. Diabetes 1991;40:405-412.
10. Anderson RE, Rapp LM, Wiegand RD. Lipid peroxidation and retinal degeneration. Current Eye Research 1984;3:223-227.
11. Kowluru RA. Effect of reinstitution of good glycaemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes 2003;52:818-823.
12. Kowluru RA, Chan PS. Oxidative stress and diabetic retinopathy. Experimental Diabetes Research 2007;doi:10.1155/2007/43603.
13. Sabu MC, Smitha K, Kuttan R. Anti-diabetic activity of green tea polyphenols and their role in reducing oxidative stress in experimental diabetes. J Ethnopharmacology 2002;83:109-116.
14. Mustata GT, Rosca K, Biemel M, et al. Paradoxical effects of green tea and antioxidant vitamins in diabetic rats:improved retinopathy and renal mitochondrial defects but deterioration of collagen matrix glycoxidation and cross-linking. Diabetes 2005;54:517-526.
15. Wu CH, Wu CF, Huang HW, et al. Naturally occurring flavonoids attenuate high glucose-induced expression of proinflammatory cytokines in human monocytic THP-1 cells. Mol Nutr Food Res 2009. DOI 10.1002/mnfr.200800495.
16. Thielecke F, Boschmann M. The potential role of green tea catechins in the prevention of the metabolic syndrome – A review. Phytochemistry 2009;70:11-24.
17. Muriach M, Bosch-Morell F, et al. Lutein effect on retina and hippocampus of diabetic mice. Free Radic Biol Med 2006;41:979-984.
18. Kowluru RA, Menon B, Gierhart DL. Beneficial effect of zeaxanthin on retinal metabolic abnormalities in diabetic rats. Invest Ophthalmol Vis Sci 2008;49:1645-1651.
19. Brazionis L, Rowley K. et al. Plasma carotenoids and diabetic retinopathy. British Journal of Nutrition 2009;101:270-277.
20. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999;48:1-9.
21. Millen AE, Klein R, et al. Relationship between intake of vitamins C and E and risk of diabetic retinopathy in the Atherosclerosis Risk in Communities Study. Am J Clin Nutr 2004;79:865-873.
22. Reichel H, Koeffler H, Norman AW. The role of vitamin D endocrine system in health and disease. N Eng J Med 1989;320:980-991.
23. Schreiner DS, Jande SS, Lawson DEM. Target cells of vitamin D in the vertebrate retina. Acta Anat 1985;121:153-162.
24. Johnson JA, Grande JP, et al. Immuno-localization of the calcitriol receptor, calbindin-D28 k and the plasma memebrane calcium pump in the human eye. Curr Eye Res 1995;14:101-108.
25. Taverna MJ, Sola A, et al. Taq I polymorphism of the vitamin D receptor and risk of severe diabetic retinopathy. Diabetologia 2002;45:436-442.
26. Albert DM, Scheef EA, Wang S, et al. Calcitriol is a potent inhibitor of retinal neovascularization. Invest Ophthalmol Vis Sci 2007;48:2327-2334.
27. Teegarden D, Donkin SS. Vitamin D:emerging new roles in insulin sensitivity. Nutrition Research Reviews 2009;22:82-92.
28. Bartlett HE, Eperjesi F. Nutritional supplementation for type 2 diabetes: a systemic review. Ophthal Physiol Opt 2008;28:503-523.
29. Moustafa SA. Zinc might protect oxidative changes in the retina and pancreas at the early stage of diabetic rats. Toxicology and Applied Pharmacology 2004;201:149-155.
30. Duzguner V, Kaya S. Effect of zinc on lipid peroxidation and the antioxidant defense systems of the alloxan-induced diabetic rabbits. Free Radic Biol Med 2007;42:1481-186.
31. Puig S, Thiele DJ. Molecular mechanisms of copper uptake and distribution. Curr Opin Chem Biol 2002;6:171-180.
32. Uriu-Adams JY, Keen CL. Copper oxidative stress, and human health. Mol Aspects Med 2005;26:268-298.
33. Connor KM, SanGiovanni JP, et al. Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nature Medicine 2007;13:868-873.
34. Luostarinen R, Saldeen T. Dietary fish oil decreases superoxide generation by human neutrophils: relation to cyclooxygenase and lysosomal release enzyme release. Prostaglandins Leukot Essent. Fatty Acids 1996;55:167-172.
35. Mori TA, Wooodman RJ, et al. Effect of eicosapentaenoic acid and docosahexaenoic acid on oxidative stress and inflammatory markers in treatedhypertensive type 2 diabetic subjects. Free Radic Biol Med 2003;35:772-781.
36. Gustavsson C, Agardh CD, et al. Inflammatory markers in nondiabetic and diabetic rats exposed to ischemia followed by reperfusion. Retina 2008;28:645-652.
37. Kern TS. Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Experimental Diabetes Research 2007;95-103.
38. Kermorvant-Duchemin E, et al. Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration. Nat Med 2005;11:1339-1345.
39. Bhathena SJ. Dietary fatty acids and fatty acid metabolism in diabetes. In: Chow KC (Ed.), Fatty Acids in Foods and their Health Implications. Marcel Dekker, Inc., New York, pp.915-961.