As most readers probably know, the landmark Age-Related Eye Disease Study (AREDS) demonstrated that a nutritional supplement could positively influence progression of AMD.1
Since that 2001 study appeared, a big question has been: might nutritional supplements also have a similar effect on diabetic retinopathy (DR)? Because vitamins, minerals and other micronutrients serve a variety of biological functions potentially beneficial in diabetes, there has been renewed interest in the possibility of these supplements treating a host of diabetes complications.
Long-term administration of AREDS antioxidants has yielded exciting results in preventing the pathogenesis of DR in rodent models.
“These results suggest the merit of testing the AREDS antioxidants in a clinical trial to prevent the development and/or progression of diabetic retinopathy, with the possibility of reducing the impact of this common vision-threatening disease,” wrote prominent retinal biologists in a 2011 Investigative Ophthalmology & Visual Science paper.2
We can safely say there is a plausible epidemiological basis for thinking that dietary supplementation might correct nutritional deficiencies common in diabetes. Studies suggest that patients with diabetes are more likely to suffer from deficiencies of potassium, calcium, magnesium, zinc, manganese, chromium, vitamin D and serum carotenoids.3-8
Such deficiencies may negatively affect glucose control, cell repair and survival, and may ultimately contribute to diabetes complications. Moreover, long-term use of the most widely prescribed oral anti-diabetic agent, metformin, has recently been linked with vitamin B12 deficiency, a risk factor for diabetic retinopathy.9,10
But will merely correcting micronutrient deficiencies make a meaningful difference in terms of the development and progression of DR in humans? Another, related question: might additional preventative micronutrients be helpful?
Of course, only a large, well-designed clinical trial would give us the answer. In the meantime, however, we combine our knowledge of the complex biological pathways that lead to diabetic retinopathy with evidence that shows how targeted micronutrients block these pathways to make scientifically rational recommendations to our patients with diabetes.
Current clinical algorithms for diabetic eye disease call for earlier diagnosis of diabetes, tighter metabolic control, annual dilated retinal examinations and treatment (e.g., laser, anti-VEGF drugs, steroids) if DR threatens vision. There is no doubt this “reactive” strategy has protected the vision of millions of diabetes patients, but we also know there is room for improvement. For example, despite the enormous effort put into education, many patients with diabetes do not undergo dilated exams or achieve their metabolic targets—and, furthermore, even those who strictly follow these guidelines may still develop sight-threatening diabetic retinopathy (STR).
A major strength of the targeted nutritional supplements discussed in this article is their ability to offer a proactive, rather than reactive, strategy in fighting this disease—an ounce of prevention that might ultimately be worth the proverbial pound of cure.
A Continuous Climb
Diabetic retinopathy remains the leading cause of new cases of blindness in Americans under age 74. This may be surprising to many practitioners who have noticed a long-term trend towards reduced rates of severe DR over the last several decades. Despite evidence that tighter control of blood glucose and blood pressure reduces the risk of microvascular diabetes complications, as well as tremendous advances in the clinical management of diabetic eye disease, rates of DR in the US have increased by 89% over the last decade (probably due to better detection and increasing rates of diabetes).11
Importantly, significant visual impairment associated with diabetes remains high, and recent estimates show that nearly 5% of US adults with diabetes have STR––with significantly higher rates amongst African, Latino and Native American populationss.12 Moreover, global estimates of DR and STR based on pooled analysis of population-based studies show 93 million cases of DR and 28 million cases of STR, which suggests that nearly 2.8 million Americans may have sight-threatening diabetic retinopathy today.13
Increasing the rates of dilated eye exams among patients with diabetes reduces blindness, yet nearly 40% of patients failed to have one performed in 2010.14 We also know that improving blood glucose and blood pressure control significantly reduces rates of DR and STR. Nonetheless, 12% of diabetes patients had HbA1c levels >9% in 2004, while more than 30% had HbA1c levels >8%.15 Although improving blood glucose control lowers risk, evidence shows that there is no level of average blood glucose that fully protects against DR.
Perhaps the single most important step we can take to combat DR is to reduce the incidence of diabetes (especially type 2) by addressing complex environmental factors like obesity, sedentary lifestyle and even sleep deprivation.16,17 Rates of diabetes continue to climb, and projections are that one in three American adults will have it by 2050.18
Working Model of DR
To better understand how and why nutritional supplements might benefit diabetic retinopathy, it is helpful to have a working model of the biology underlying the disease.
Diabetes causes a number of metabolic abnormalities, including hyperglycemia, dyslipidemia, hypertension and oxidative stress. These factors interact in a variety of ways to cause increased production of singlet oxygen (also known as reactive oxygen species [ROS]) by mitochondria, especially within the retina and other insulin-independent tissues (small-caliber neurons, renal glomeruli and aorta). These mitochondrial ROS activate specific and well-established biochemical pathways within retinal cells that directly lead to vascular and retinal ganglion cell damage (polyol, PKC, hexosamine flux and advanced glycation endproduct pathways).19,20
Release of inflammatory proteins and programmed destruction (apoptosis) of capillary endothelial cells and retinal ganglion cells may lead to breakdown of the blood/retinal barrier, resulting in vascular leakage, hypoxia and retinal neovascularization—the hallmarks of diabetic retinopathy. Accompanying deficits in visual function, including contrast sensitivity, visual field sensitivity and color vision, are common.
Elevated blood glucose plays a central role in DR, worsening dyslipidemia and hypertension, and driving oxidative stress that damages the retina. This is why control of blood sugar (as well as blood pressure and blood lipids) constitutes the foundation of preventing diabetes complications, including retinopathy. However, a number of biological processes that occur further downstream from hyperglycemia also can affect progression and thus give us additional targets for intervention.
The Benefits of Nutritional Supplementation
When considering evidence for micronutrient intervention in DR pathobiology, bear in mind that effects demonstrated in a laboratory, or associations seen in human beings, do not necessarily translate into
• Benfotiamine. A synthetic, lipophilic analog of vitamin B1 (thiamine), benfotiamine has been shown to elevate intracellular levels of transketolase––an enzyme that redirects glucose and the harmful glucose metabolites, fructose-6-phosphate and glyceraldehyde-3-phosphate, to the pentose phosphate shunt pathway. Increased transketolase levels reduce intracellular formation of protein kinase C, sorbitol, advanced glycation (AGE) and advanced lipo-oxidation (ALE) endproducts—substrates directly involved in the pathogenesis of diabetic microvascular damage, including diabetic retinopathy.21
Benfotiamine has been shown to block activity in the polyol, hexosamine flux, protein kinase C and advanced glycation endproduct pathways, helping to prevent diabetic retinopathy in a murine model of the disease.22 It also prevents glucose-dependent apoptosis of human retinal pericytes.23
Multiple studies have shown that benfotiamine improves vibratory sensation, nerve conduction and pain scores in patients with diabetic neuropathy.24,25 When combined with slow-release alpha-lipoic acid, benfotiamine normalized activity in the polyol, hexosamine and AGE pathways in patients with type 1 diabetes, as well as reduced levels of prostacyclin synthase––a protein implicated in atherosclerosis.26 Benfotiamine also prevented endothelial dysfunction and oxidative stress in patients with type 2 diabetes following a provocative high-AGE meal.27
• Pycnogenol. A patented extract of bark from the French Maritime Pine, Pinus pinaster, pycnogenol contains a number of polyphenolic procyanidins (anthocyanidins)––antioxidants that inhibit inflammation and selectively bind to collagen and elastin fibers to improve capillary fragility.28,29 Pycnogenol inhibits nuclear factor kappa beta (NF-kβ) and secretion of MMP-1, MMP-2 and MMP-9, of which the latter two have been implicated in breakdown of the blood/retinal barrier in diabetic retinopathy.30, 31
Pycnogenol also inhibits the digestive enzyme alpha-glucosidase, delaying the intestinal absorption of sugars to ameliorate post-prandial hyperglycemia.32 More than 30 randomized, controlled clinical trials have shown that pycnogenol improves a number of health conditions, ranging from tinnitus to chronic venous insufficiency to kidney dysfunction.33-35 In patients with type 2 diabetes, Pycnogenol improved glycosylated hemoglobin, blood pressure and dyslipidemia.36,37
Several studies suggest that Pycnogenol improves capillary leakage and retards retinopathy progression in patients with diabetes.38,39 Pycnogenol was shown to improve retinal blood flow, reduce retinal thickening and improve visual acuity in patients with early diabetic macular edema.40
• Non-provitamin A carotenoids. Lutein and zeaxanthin are the primary components of the macular pigment, which filters short-wavelength blue light, scavenges free radicals and suppresses inflammation in a number of disease models, including streptozotocin-induced diabetes and retinal ischemia.41
Type 2 diabetes patients with a higher ratio of serum non-pro-vitamin A carotenoids (lutein, zeaxanthin, lycopene) to pro-vitamin A carotenoids (alpha-carotene, beta-carotene and beta-cryptoxanthin) were associated with a 66% reduction in risk for diabetic retinopathy after adjustment for confounding variables.42 Moreover, macular pigment optical density (MPOD) has been reported to be lower in patients with type 2 diabetes than in age-matched controls, lower still in patients with type 2 diabetes and retinopathy, and inversely correlated with glycosylated hemoglobin.43
Lutein supplementation reduced retinal oxidative stress and activation of NF-kβ, and increased the neuroprotective cytokine brain-derived neurotrophic factor (BDNF) in a mouse model.44 Diabetic mice supplemented with lutein/zeaxanthin-rich wolfberry demonstrated normalized retinal thickness, RPE integrity and number of retinal ganglion cells via initiation of adenosine monophosphate-activated protein kinase and reduction of endoplasmic reticulum stress compared with controls.45
Supplementation with zeaxanthin also prevented oxidative damage and reduced production of VEGF and intracellular adhesion molecule (ICAM-1) in diabetic rats.46 Lutein (6mg per day) and zeaxanthin (0.5mg per day) supplementation over three months increased MPOD, improved visual acuity, contrast sensitivity and foveal thickness in subjects with non-proliferative diabetic retinopathy compared to controls.47
• Vitamin D. Low serum levels of vitamin D have been implicated in the development of both type 1 and type 2 diabetes.48-50 Vitamin D insufficiency also is a risk factor for atherosclerosis and cancer––both of which are more common in patients with diabetes.51,52 Recently, serum vitamin D status has been linked to the presence and severity of diabetic retinopathy in patients with both type 1 and type 2 diabetes; vitamin D deficiency also proved more predictive of DR than diabetes duration or glycosylated hemoglobin in Australian adolescents with type 1 diabetes.53,54
Vitamin D supplementation reduced both vascular endothelial growth factor (VEGF) and transforming growth factor beta-1 (TGF-β1) in a murine model of diabetic retinopathy, giving insight into its possible mechanism of action affecting DR.55 In a murine model of oxygen-induced ischemic retinopathy, supplementation with the active metabolite of vitamin D3 (1,25-dihydroxyvitamin D3) significantly inhibited retinal neovascularization without reducing ocular VEGF levels.56 Vitamin D also appears to block foam cell formation in serum samples from subjects with type 2 diabetes, suggesting improvement of the inflammatory dyslipidemia that contributes to DR.57,58
• Alpha-lipoic acid. Also known as thioctic acid, alpha-lipoic acid (ALA) is a naturally occurring compound synthesized by mitochondria that serves as a cofactor for enzymes producing ATP via the citric acid cycle.59 In addition to being a potent antioxidant, ALA stimulates synthesis of glutathione and regenerates other antioxidants by reducing their oxidized forms—including vitamin C, vitamin E and coenzyme Q10—an attribute that has given ALA a reputation as the “antioxidant of antioxidants.”
Because alpha-lipoic acid crosses the blood/brain barrier and distributes to mitochondria where its reduced form, dihyrolipoic acid (DHLA), is capable of regenerating other antioxidants, it may be particularly well-suited to pathologies characterized by excess mitochondrial production of reactive oxygen species, such as diabetes.19
ALA has been shown to reduce both small and large blood vessel complications of diabetes in animal models.60,61 ALA treatment reduced retinal capillary damage, oxidative stress, nuclear factor kappa-beta activation and VEGF in an animal model of diabetic retinopathy. 62 Also, long-term use prevented the development of retinopathy in diabetic rats.63
Human RPE cells are protected from hyperglycemic oxidative stress and mitochondrial dysfunction when treated with ALA.64 Recent evidence suggests ALA prevents deleterious “metabolic memory” (i.e., worsening of diabetic retinopathy after an initial period of poor blood glucose control, despite subsequent improved blood glucose control) by improving mitochondrial homeostasis.65 ALA supplementation improved “endothelial dysfunction” (flow-mediated vasodilation) in patients with metabolic syndrome and impaired fasting glucose.66 Though administration to human subjects with type 2 diabetes over two years did not result in statistically significant reductions in clinically significant macular edema, subjects in the treatment arm had a 14% lower relative risk of developing it.67
• Curcumin. This is a component of the Indian spice turmeric. It contains a number of polyphenolic molecules believed to modulate inflammation. Curcumin inhibited diabetes-induced elevation in levels of the retinopathic proteins IL-1β, VEGF and NF-kβ in a murine model of diabetes, without inducing amelioration of hyperglycemia, and prevents AGE-collagen cross linking in diabetic rats.68,69 Curcumin also was shown to normalize elevated VEGF and tumor necrosis factor-alpha (TNF-α), the inflammatory cytokine, as well as to prevent early basement membrane changes associated with diabetic retinopathy in an animal model.70
Additionally, lecithinized curcumin was shown to improve retinal blood flow, retinal edema and visual acuity in subjects with DR over four weeks of supplementation.71 It is noteworthy that DR rates are lower in Southern India––where turmeric consumption is highest––than in European and North American populations, after controlling for established risk factors.72
Yes, But Does Dietary Supplementation Work?
I have seen beneficial effects with some of these micronutrients in my practice. This, of course, proves nothing. Only a large clinical trial will tell, but I am currently undertaking a small trial in my office using a combination of these supplements in patients with diabetes and mild to moderate non-proliferative diabetic retinopathy. The study aims to determine effects on visual function, spectral-domain optical coherence tomography results, and serum markers of inflammation (the Diabetes Visual Function Supplement Study – DiVFuSS; ClinicalTrials.gov Identifier: NCT01646047; Sponsored by ZeaVision, LLC).
In a 2013 ARVO poster, the test formula was shown to improve or normalize retinal structure, metabolism and function in an animal model of DR.73 Specifically, it reduced mitochondrial damage, oxidative stress, activation of NF-kβ—as well as production of VEGF, ICAM-1 and MMP. Retinal function as assessed by β-wave ERG was preserved and, most significantly, apoptosis of retinal capillary cells was prevented without causing significant difference in blood glucose levels in treated and untreated animals.
Diabetic retinopathy continues to be a leading cause of vision loss, despite improvements in metabolic control and advancements in treatment. Though annual dilated eye exams make a tremendous difference in detecting and treating sight-threatening disease, many patients are still falling through the cracks. Though tighter blood sugar and blood pressure control certainly lowers patient risk, many do not achieve these goals, and some patients develop severe DR despite excellent control.
Use of targeted micronutrients may give us the opportunity to offer patients with diabetes something more than warnings about good disease control and regular dilated eye exams. It may give us a chance to do more than simply monitor for vision threatening diabetic retinopathy and eventual referral to retinal specialists for treatment. It offers an opportunity to be proactive, rather than merely reactive, by addressing some of the biological mechanisms underlying the disease.
Dr. Chous specializes in diabetes eye care and education in Tacoma, Wash. He is a consultant to several diabetes-related companies and is receiving support for DiVFuSS from ZeaVision, LLC.
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