Do diabetes, diabetic retinal disease contribute to macular degeneration?

Optometry Times JournalMarch digital edition 2023
Volume 15
Issue 03

These disorders account for most of the vision loss in working-age and elderly Americans.

A positive association between diabetes, diabetic retinopathy (DR), and age-related macular degeneration (AMD) has been suggested in multiple observational studies. Any connection is significant, of course, because diabetes is the leading cause of new vision loss in Americans aged 18-74 (often categorized as “working age”)1 and AMD is the leading cause of vision loss in adults aged 65 and above.2 Additionally, any common, underlying pathobiology might suggest interventions that could have profound public health implications. The current use of anti-VEGF therapies for neovascular AMD and diabetic retinopathy means that there is a biological connection between these disorders, although that does not necessarily mean that either portends an increased risk for the other.

The relationship between DR and AMD has been inconsistent among published studies. The Beaver Mountain Eye Study,conducted in the US, found that diabetes was not associated with early AMD or geographic atrophy (GA), although the prevalence of wet AMD was doubly high in those with diabetes than in those without.3 In contrast, the Australian Blue Mountains Eye Studyshowed that diabetes was associated only with GA, not with wet AMD or early AMD.4 Medicare data from 2013 analyzing 6621 patients over the age of 69 with recently diagnosed diabetes showed that nonproliferative diabetic retinopathy (NPDR) significantly increased the risk of both dry and wet AMD, while proliferative diabetic retinopathy (PDR) was associated only with an increased risk of wet AMD.5

Large, population-based data from Taiwan showed an association between diabetes and exudative AMD (HR 1.37; P = 0.023) but especially between diabetic retinopathy and both dry (HR 3.89; P = .001) and wet AMD (HR 3.42; P < .001). This analysis evaluated roughly 72,000 adults over 50 with diabetes and 270,000 adults over 50 without diabetes.6 Most recently, cross-sectional data from the Kailuan Eye Study conducted in China has suggested, after all adjustments, that diabetic retinopathy, but not diabetes alone, was a statistically significant risk factor for dry but not wet AMD.7

Biological links between AMD and DR abound, including deposition of advanced glycation end products (AGEs) in multiple tissues because of acute and chronic hyperglycemia, including retinal pigment epithelium (RPE) and photoreceptors, which are implicated in the pathogenesis of DR and AMD.8 Hyperglycemia and dyslipidemia in patients with diabetes also induces cascading retinal inflammation, including activation of the complement pathway,9 which also has been strongly implicated in AMD.10 Moreover, anatomical and circulatory changes that occur with aging, such as reduced blood flow and retinal thickness, may contribute to the pathogenesis of concurrent DR and AMD in the elderly population.11

To the extent that cardiometabolic processes contribute to AMD and DR, lifestyle modification and pharmacologic therapies that inhibit pathologic mechanisms and/or augment retinoprotective mechanisms might be useful in both entities. Studies in animal models show that AGEs—irreversible glycoprotein aggregates—prevent clearance of drusen12 and that a high glycemic index diet induces AMD changes including basal laminar deposits, photoreceptor degeneration, RPE atrophy, and choriocapillaris loss, whereas a low glycemic index diet was protective against these changes.13 Of significance, post hoc analysis of the original Age-Related Eye Disease Study (AREDS) found that a dietary glycemic index intake below the same-sex median reduced progression to advanced AMD by 49% and would be expected to result in 100,000 fewer cases of advanced AMD over 5 years.14 More specifically, self-reported, daily consumption of 100% fruit juice compared with little or no juice consumption was recently associated with an 18-fold increased risk of advanced AMD, after all adjustments.15

Diets high in refined carbohydrates and hydrogenated oils, a sedentary lifestyle, and smoking have all been linked to increased risk of eye disease and systemic diseases that contribute to eye disease.16 In my view, these overlapping contributors to DR and AMD make patient counseling easier (Figure 1). Whether a patient has—or is at-risk for—either diagnosis, and especially when patients carry both diagnoses, it makes sense to recommend a plant-based, anti-inflammatory, low glycemic index diet, moderate physical activity, smoking avoidance, and vigilant eye care.

This article is dedicated to my colleague and mentor, Stuart P. Richer, OD, PhD, who steadfastly encouraged me to think big and outside of the box.

1. Vision Loss and Age. Center for Disease Control and Prevention.
June 12, 2020. Accessed Feb. 22, 2023.
2. GBD 2019 Blindness and Vision Impairment Collaborators; Vision Loss Expert Group of the Global Burden of Disease Study. Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study. Lancet Glob Health. 2021;9(2):e144-e160. doi:10.1016/S2214-109X(20)30489-7
3. Klein R, Klein BE, Moss SE. Diabetes, hyperglycemia, and age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992;99(10):1527-1534. doi:10.1016/s0161-6420(92)31770-1
4. Mitchell P, Wang JJ. Diabetes, fasting blood glucose and age-related maculopathy: The Blue Mountains Eye Study. Aust N Z J Ophthalmol. 1999;27(3-4):197-199. doi:10.1046/j.1440-1606.1999.00211.x
5. Hahn P, Acquah K, Cousins SW, Lee PP, Sloan FA. Ten-year incidence of age-related macular degeneration according to diabetic retinopathy classification among Medicare beneficiaries. Retina. 2013;33(5):911-919. doi:10.1097/IAE.0b013e3182831248
6. He MS, Chang FL, Lin HZ, Wu JL, Hsieh TC, Lee YC. The association between diabetes and age-related macular degeneration among the elderly in Taiwan. Diabetes Care. 2018;41(10):2202-2211. doi:10.2337/dc18-0707
7. Yongpeng Z, Yaxing W, Jinqiong Z, et al. The association between diabetic retinopathy and the prevalence of age-related macular degeneration-The Kailuan Eye Study. Front Public Health. 2022;10:922289. doi:10.3389/fpubh.2022.922289
8. Kandarakis SA, Piperi C, Topouzis F, Papavassiliou AG. Emerging role of advanced glycation-end products (AGEs) in the pathobiology of eye diseases. Prog Retin Eye Res. 2014;42:85-102. doi:10.1016/j.preteyeres.2014.05.002
9. Shim K, Begum R, Yang C, Wang H. Complement activation in obesity, insulin resistance, and type 2 diabetes mellitus. World J Diabetes. 2020;11(1):1-12. doi:10.4239/wjd.v11.i1.1
10. Tan LX, Germer CJ, La Cunza N, Lakkaraju A. Complement activation, lipid metabolism, and mitochondrial injury: converging pathways in age-related macular degeneration. Redox Biol. 2020;37:101781. doi:10.1016/j.redox.2020.101781
11. Grossniklaus HE, Nickerson JM, Edelhauser HF, Bergman LA,
Berglin L. Anatomic alterations in aging and age-related diseases of the eye. Invest Ophthalmol Vis Sci. 2013;54(14):ORSF23-ORSF27. doi:10.1167/iovs.13-12711
12. Uchiki T, Weikel KA, Jiao W, et al. Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease (in nondiabetics). Aging Cell. 2012;11(1):1-13. doi:10.1111/j.1474-9726.2011.00752.x
13. Rowan S, Jiang S, Chang ML, et al. A low glycemic diet protects disease-prone NRF2-deficient mice against age-related macular degeneration. Free Radic Biol Med. 2020;150:75-86. doi:10.1016/j.freeradbiomed.2020.02.010
14. Chiu C-J, Milton RC, Klein R, Gensler G, Taylor A. Dietary glycemic index is related to progression of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2007;48(13):2101.
15. Song M, Chen B. The association between consumption of 100% fruit juice and risk of age-related macular degeneration: data from the National Health and Nutrition Examination Survey Database. Front Nutr. 2022;9:812476. doi:10.3389/fnut.2022.812476
16. Francisco SG, Smith KM, Aragonès G, et al. Dietary patterns, carbohydrates, and age-related eye diseases. Nutrients. 2020;12(9):2862. doi:10.3390/nu12092862
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