**5. Lutein and DR**

#### **5.1. DR**

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

In a prospective study, Hu et al. [7] demonstrated that plasma levels of lutein and zeaxanthin was significantly lower in nonproliferative DR patients than in subjects without diabetes. Similarly, Brazionis et al. [79] assessed the serum concentration of different carotenoids in relation to the DR in type 2 diabetes and found significant lower blood levels of combined lutein and zeaxanthin and lycopene in diabetic patients with DR compared to these without DR. Moreover, a significant inverse correlation between odds of DR and plasma concentration

Lutein and the Aging Eye

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Retinal level of xanthophylls was examined via measurement of MPOD. Patients with DR had decreased MPOD in comparison with diabetic patients without DR [80]. Furthermore, MPOD in individuals with type 2 diabetes was significantly lower than in subjects with type 1 diabetes and normal control, despite similar dietary uptake of carotenoids among these groups [81]. The lower MPOD in patients with type 2 diabetes may probably be associated with obesity, where enhanced competition of lutein and zeaxanthin intake with higher body fat occurred (retina vs. adipose tissue). In type 2 diabetic patients with or without DR, MPOD was inversely associated with glycosylated hemoglobin, a more stable indicator for

On basis of the above observational studies, influence of lutein and zeaxanthin supplementation on DR was evaluated. Administration of lutein (6 mg/day) plus zeaxanthin (0.5 mg/day) for 3 months led to a significant increase of serum lutein and zeaxanthin level, as well as the improvement in visual acuity, contrast sensitivity, and diabetic macular edema in nonproliferative DR [7]. This study was consistent with the results conclude from supplementation of 10 mg/day lutein for 36 weeks in patients with nonproliferative DR [83]. A recent study has shown an increased thickness in the central fovea and improved retinal response density after 2-year supplementation of combined lutein (10 mg/day), zeaxanthin (2 mg/day), and mesozeaxanthin (10 mg/day) in type 2 diabetic patients without DR, indicating beneficial effects of

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),

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

of combined lutein and zeaxanthin and lycopene was shown in this study [79].

diabetes [82].

**5.3. Basic research**

a type 2 diabetic animal model.

xanthophylls on visual functions in diabetes [84].

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 of vision loss in patients with diabetes.

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 and angiogenesis.

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

#### **5.2. Clinical trials**

Although tremendous clinical studies have been performed to evaluate the relationship between carotenoids and diabetes, only a few have examined the effects of carotenoids including lutein and zeaxanthin on DR.

In a prospective study, Hu et al. [7] demonstrated that plasma levels of lutein and zeaxanthin was significantly lower in nonproliferative DR patients than in subjects without diabetes. Similarly, Brazionis et al. [79] assessed the serum concentration of different carotenoids in relation to the DR in type 2 diabetes and found significant lower blood levels of combined lutein and zeaxanthin and lycopene in diabetic patients with DR compared to these without DR. Moreover, a significant inverse correlation between odds of DR and plasma concentration of combined lutein and zeaxanthin and lycopene was shown in this study [79].

Retinal level of xanthophylls was examined via measurement of MPOD. Patients with DR had decreased MPOD in comparison with diabetic patients without DR [80]. Furthermore, MPOD in individuals with type 2 diabetes was significantly lower than in subjects with type 1 diabetes and normal control, despite similar dietary uptake of carotenoids among these groups [81]. The lower MPOD in patients with type 2 diabetes may probably be associated with obesity, where enhanced competition of lutein and zeaxanthin intake with higher body fat occurred (retina vs. adipose tissue). In type 2 diabetic patients with or without DR, MPOD was inversely associated with glycosylated hemoglobin, a more stable indicator for diabetes [82].

On basis of the above observational studies, influence of lutein and zeaxanthin supplementation on DR was evaluated. Administration of lutein (6 mg/day) plus zeaxanthin (0.5 mg/day) for 3 months led to a significant increase of serum lutein and zeaxanthin level, as well as the improvement in visual acuity, contrast sensitivity, and diabetic macular edema in nonproliferative DR [7]. This study was consistent with the results conclude from supplementation of 10 mg/day lutein for 36 weeks in patients with nonproliferative DR [83]. A recent study has shown an increased thickness in the central fovea and improved retinal response density after 2-year supplementation of combined lutein (10 mg/day), zeaxanthin (2 mg/day), and mesozeaxanthin (10 mg/day) in type 2 diabetic patients without DR, indicating beneficial effects of xanthophylls on visual functions in diabetes [84].
