**5.3. Basic research**

**5. Lutein and DR**

184 Progress in Carotenoid Research

economics, diet habit, physical exercise, and so on.

as a natural, noninvasive, long-term medication for DR.

including lutein and zeaxanthin on DR.

of vision loss in patients with diabetes.

and angiogenesis.

**5.2. Clinical trials**

DR is the most common microvascular complication in diabetes. For individuals with diabetes aged 40 years and older, the estimated number of DR patients is 93 million around the world, of which 17 million are proliferative DR and 28 million are vision-threatening DR [76]. In the USA, approximately 2.8 million individuals may develop sight-threatening DR. DR used to be considered as high of prevalence in western countries, however, there is a rising prevalence of DR occurred in Asian countries (such as China and India) due to the changes in

According to the presence of microvascular lesions in the retina, DR is classified into early nonproliferative stage, featured with microaneurysms, vascular tortuosity, retinal hemorrhages, "hard" lipid exudates and microinfarcts in the NFL (known as the "cotton wool spots"), and late proliferative stage, characterized by the formation of new aberrant fragile blood vessels in the retina. Another important manifestation of DR is diabetic macular edema present at any stage, causing the abnormal thickening of retina and cystoid edema in the macula. Diabetic macular edema, together with retinal neovascularization, is the major cause

DR is considered to be a multifactorial disease with its exact pathogenesis being still uncertain. It has been proved that increased blood glucose concentration is the key factor in the onset and development of DR, leading to exacerbation of hypertension and dyslipidemia, overproduction of ROS that subsequently damages the retina. Oxidative stress disrupts retinal mitochondrial functions by inner membrane oxidation and mitochondrial DNA damage, which in turn lead to apoptosis of retinal capillary cells [77]. In addition, inflammation is also involved in the pathogenesis of DR. Increased retinal pro-inflammatory mediators such as intracellular adhesion molecule-1 (ICAM-1), TNF-α, and IL-1β are induced in diabetes. In clinical studies, presence and progression of DR were associated with the increased plasma levels of TNF-α, IL-1β and VEGF [78]. VEGF is also an important factor in the development of DR, which leads to the increased permeability of retinal blood vessel

Current major treatments for DR include laser photocoagulation and/or intravitreal injection of anti-VEGF drugs. However, these therapies are expensive, invasive, and need to visit ophthalmologists at certain intervals. Therefore, lutein, a powerful antioxidant, may be adopted

Although tremendous clinical studies have been performed to evaluate the relationship between carotenoids and diabetes, only a few have examined the effects of carotenoids

**5.1. DR**

In animal models of DR, lutein has been reported to have beneficial effects on affected retinal layers and visual functions by its antioxidant, anti-inflammation, and neuroprotection properties. The animal models used to study DR usually include mice or rats injected with alloxan or streptozotocin (STZ) that can directly destroy β cells in pancreas to halt insulin production and subsequently induce diabetes, and spontaneous diabetic mice (db/db mice), a type 2 diabetic animal model.

In alloxan-induced DR mice, oxidative makers (NF-κB and malondialdehyde) were increased, while antioxidants including glutathione (a powerful endogenous antioxidant) and glutathione peroxidase were decreased. Decreased b-wave amplitude in ERG was also observed. Supplementation of lutein (0.2 mg/kg) prevented all the diabetes-induced changes [85]. The same results were reported in STZ-induced diabetic rats after administration of lutein together with DHA. Moreover, prevention of histological changes including decreased ONL, INL, and GCL thickness was also observed [86]. In STZ-induced murine models, Sasaki et al. [87] demonstrated changes in oxidative stress-related factors (increase of ROS, extracellular signal-regulated kinase activation, and depletion of brain-derived neurotrophic factor), retinal morphological changes (reduction of IPL, INL, and ganglion cells), and visual functions (decrease of oscillatory potentials in ERG, indicating dysfunction of neurons in inner retina). Likewise, lutein supplements (0.1 mg wt/wt) restored all the diabetes-induced damages in the retina [87]. Similarly, supplements containing lutein, zeaxanthin, omega-3 fatty acids, and other nutrients demonstrated protective effects on progression of DR in STZ-induced diabetic rats. Decreased ROS level, mitochondrial DNA damage, and inflammatory factors such as VEGF, IL-1β, and NF-κB, as well as reduction of retinal apoptosis, abnormal capillaries formation were demonstrated in treatment group compared with placebo control group. Furthermore, nutrient supplements ameliorated decreased amplitudes of a- and b-wave in ERG, suggesting prevention of retinal functions in diabetic rats with DR [88].

**Acknowledgements**

**Conflict of interest**

**Author details**

Shen Nian1

Hong Kong

**References**

The authors declare no conflict of interest.

and Amy C.Y. Lo2

\*Address all correspondence to: amylo@hku.hk

\*

2005;**38**:70-88 . Epub 2004/12/18. DOI: 10.1159/000082768

Nutrition. 2006;**84**(5):971-974. DOI: 10.1093/ajcn/84.5.971

Health. 2017;**5**(9):e888-ee97. DOI: 10.1016/S2214-109X(17)30293-0.

This work is supported by the Project of Dominant Discipline Construction in Universities of Shaanxi Province-Basic Medicine, Shaanxi Province, China awarded to Xi'an Medical University and Health and Medical Research Fund, Hong Kong (03142256) awarded to Amy C.Y. Lo.

Lutein and the Aging Eye

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http://dx.doi.org/10.5772/intechopen.79604

1 Department of Pathology, Xi'an Medical University, Xi'an, Shaanxi Province, China

2 Department of Ophthalmology, LKS Faculty of Medicine, The University of Hong Kong,

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[2] Bernstein PS, Khachik F, Carvalho LS, Muir GJ, Zhao D-Y, Katz NB. Identification and quantitation of carotenoids and their metabolites in the tissues of the human eye.

[3] Trumbo PR, Ellwood KC. Lutein and zeaxanthin intakes and risk of age-related macular degeneration and cataracts: An evaluation using the food and drug administration's evidence-based review system for health claims. The American Journal of Clinical

[4] Bourne RRA, Flaxman SR, Braithwaite T, Cicinelli MV, Das A, Jonas JB, et al. Magnitude, temporal trends, and projections of the global prevalence of blindness and distance and near vision impairment: A systematic review and meta-analysis. The Lancet Global

[5] Akuffo KO, Beatty S, Peto T, Stack J, Stringham J, Kelly D, et al. The impact of supplemental antioxidants on visual function in nonadvanced age-related macular degeneration: A

Experimental Eye Research. 2001;**72**(3):215-223. DOI: 10.1006/exer.2000.0954

Wolfberry, a Chinese traditional fruit consumed for eye protection, is high in zeaxanthin (176 mg/100 g) and lutein (5 mg/100 g). In db/db mice, wolfberry elevated lutein and zeaxanthin levels in retina and liver, attenuated mitochondrial dysfunction and endoplasmic reticulum stress caused by hyperglycemia-induced oxidative stress, and restored retinal structure abnormalities [89, 90]. Furthermore, Lutein and zeaxanthin was able to protect cultured ARPE-19 cells from a high glucose challenge through the similar mechanisms, suggesting wolfberry's protection effects were at least partly due to high contents of lutein and zeaxanthin [89].
