Inhibition of Retinopathy and Retinal Metabolic Abnormalities in Diabetic Rats With AREDS-Based Micronutrients

Abstract

To investigate whether the micronutrients that were shown to reduce the risk of development of age-related macular degeneration in the Age-Related Eye Disease Study (AREDS) can have the same effect on the development of diabetic retinopathy in rats, and to understand the possible mechanisms.Methods: Streptozotocin-induced diabetic rats received a powdered diet with or without supplemental micronutrients (ascorbic acid, vitamin E, beta-carotene, zinc, and copper). The retina was used after the rats had diabetes for 12 months to detect vascular histopathology and to measure the biochemical parameters and messenger RNA levels of the genes involved in oxidative and nitrative stress. Results:The AREDS-based micronutrients prevented a diabetes-induced increase in the number of retinal acel-lular capillaries. In the same rats, micronutrients inhibited increases in retinal oxidatively modified DNA and nitrotyrosine and decreases in manganese superoxide dismutase. Diabetes-induced alterations in the messenger RNA expression of mitochondrial electron transport complex III (coenzyme Q cytochrome-c reductase) and inducible nitric oxide synthase were also prevented. Conclusion:Age-Related Eye Disease Study-based micronutrients inhibit the development of diabetic retinopathy in rodents by inhibiting oxidative and nitrative stress.Clinical Relevance: Micronutrients that slow down the onset and progression of age-related macular degeneration have the potential to inhibit the development of diabetic retinopathy.

Nutritional and medical food therapies for diabetic retinopathy

“…Diabetes-induced increased nitric oxide synthetase was blocked. This mechanistically supports the use of such vitamin antioxidant combinations for DR [44,50].…”

Nutritional and medical food therapies for diabetic retinopathy

“…Diabetes-induced increased nitric oxide synthetase was blocked. This mechanistically supports the use of such vitamin antioxidant combinations for DR [44,50].…”

A Systematic Review of Carotenoids in the Management of Diabetic Retinopathy

“…There is an increasing amount of research and animal trials that substantiate the neuroprotective effects of carotenoids lutein and zeaxanthin in rodent models of DR using either chemical induction or genetic modes to engender diabetic state ( Table 2 ) [ 102 , 103 , 104 , 105 , 106 , 107 , 108 ]. Pharmacological injection of alloxan or streptozotocin (STZ) are often used to recapitulate T1DM pathology in both mice and rats through death of pancreatic beta cells and subsequent insulin deficiency [ 102 , 103 , 104 , 105 , 106 , 117 , 118 , 119 , 120 ]. Genetic modes offer unique models to examine pathophysiological mechanisms of metabolic perturbations that may contribute to incident retinopathy; in particular, leptin receptor deficient (db/db) mice develop morbid obesity and hypoinsulinemia, making them a desirable model for replicating conditions found in T2DM [ 107 , 108 , 118 , 119 , 120 ].…”

“…The importance of macular carotenoid’s antioxidant properties is evident by their enhanced capacity to ameliorate the extent of oxidative injury caused by hyperglycemia in diabetic retina. Supplementation with lutein and/or zeaxanthin was shown to protect against measures of oxidative and nitrosative stress, marked by significant reductions in malondialdehyde, 8-OHdG (oxidatively-modified DNA), and nitrotyrosine, respectively [ 102 , 103 , 105 , 117 , 121 , 122 , 123 ]. Additionally, one study found that micronutrients containing carotenoids prevented a significant rise in retinal ROS levels in T1DM rats following treatment with the EyePromise Diabetes and Visual Function Study (DVS) formula (ZeaVision LLC, Chesterfield, MO, USA) [ 104 , 124 ].…”

“…These findings suggest that the mechanism of protection against oxidative damage to the retina may involve improving mitochondrial dysfunction, the primary source of aberrant free radical production as a consequence of hyperglycemia [ 26 , 125 , 126 , 127 , 128 , 129 ]. In fact, lutein and zeaxanthin were shown to protect against mitochondrial stress induced by T1DM pathology, and improved retinal expression of mtDNA-encoded proteins involved in oxidative phosphorylation and mitochondrial biogenesis [ 26 , 102 , 103 , 108 , 117 ]. Thus, dietary treatment using lutein and zeaxanthin supplementation may prevent early lesions of retinopathy by alleviating pro-oxidant stressors and redox imbalance propagated by hyperglycemic state.…”

“…Dietary augmentation of the compromised endogenous antioxidant defenses has been considered the key modulator in the pathogenesis of DR. Multiple studies found that lutein and zeaxanthin recovered enzymatic activity and expression levels of glutathione, glutathione peroxidase and manganese superoxide dismutase [ 102 , 103 , 105 , 107 , 117 ]; indicating a reversal of hyperglycemic-induced impairment in free radical detoxification and clearance mechanisms [ 26 , 121 , 130 , 131 ]. Similarly, one animal model demonstrated that an AREDS-based micronutrient formulation improved total antioxidant capacity in the retina, as well as metabolic abnormalities associated with early stages of retinopathy progression [ 104 ].…”

Nutritional and medical food therapies for diabetic retinopathy

“…Diabetes-induced increased nitric oxide synthetase was blocked. This mechanistically supports the use of such vitamin antioxidant combinations for DR [44,50].…”

A Systematic Review of Carotenoids in the Management of Diabetic Retinopathy

“…There is an increasing amount of research and animal trials that substantiate the neuroprotective effects of carotenoids lutein and zeaxanthin in rodent models of DR using either chemical induction or genetic modes to engender diabetic state ( Table 2 ) [ 102 , 103 , 104 , 105 , 106 , 107 , 108 ]. Pharmacological injection of alloxan or streptozotocin (STZ) are often used to recapitulate T1DM pathology in both mice and rats through death of pancreatic beta cells and subsequent insulin deficiency [ 102 , 103 , 104 , 105 , 106 , 117 , 118 , 119 , 120 ]. Genetic modes offer unique models to examine pathophysiological mechanisms of metabolic perturbations that may contribute to incident retinopathy; in particular, leptin receptor deficient (db/db) mice develop morbid obesity and hypoinsulinemia, making them a desirable model for replicating conditions found in T2DM [ 107 , 108 , 118 , 119 , 120 ].…”

“…The importance of macular carotenoid’s antioxidant properties is evident by their enhanced capacity to ameliorate the extent of oxidative injury caused by hyperglycemia in diabetic retina. Supplementation with lutein and/or zeaxanthin was shown to protect against measures of oxidative and nitrosative stress, marked by significant reductions in malondialdehyde, 8-OHdG (oxidatively-modified DNA), and nitrotyrosine, respectively [ 102 , 103 , 105 , 117 , 121 , 122 , 123 ]. Additionally, one study found that micronutrients containing carotenoids prevented a significant rise in retinal ROS levels in T1DM rats following treatment with the EyePromise Diabetes and Visual Function Study (DVS) formula (ZeaVision LLC, Chesterfield, MO, USA) [ 104 , 124 ].…”

“…These findings suggest that the mechanism of protection against oxidative damage to the retina may involve improving mitochondrial dysfunction, the primary source of aberrant free radical production as a consequence of hyperglycemia [ 26 , 125 , 126 , 127 , 128 , 129 ]. In fact, lutein and zeaxanthin were shown to protect against mitochondrial stress induced by T1DM pathology, and improved retinal expression of mtDNA-encoded proteins involved in oxidative phosphorylation and mitochondrial biogenesis [ 26 , 102 , 103 , 108 , 117 ]. Thus, dietary treatment using lutein and zeaxanthin supplementation may prevent early lesions of retinopathy by alleviating pro-oxidant stressors and redox imbalance propagated by hyperglycemic state.…”

“…Dietary augmentation of the compromised endogenous antioxidant defenses has been considered the key modulator in the pathogenesis of DR. Multiple studies found that lutein and zeaxanthin recovered enzymatic activity and expression levels of glutathione, glutathione peroxidase and manganese superoxide dismutase [ 102 , 103 , 105 , 107 , 117 ]; indicating a reversal of hyperglycemic-induced impairment in free radical detoxification and clearance mechanisms [ 26 , 121 , 130 , 131 ]. Similarly, one animal model demonstrated that an AREDS-based micronutrient formulation improved total antioxidant capacity in the retina, as well as metabolic abnormalities associated with early stages of retinopathy progression [ 104 ].…”

Nutritional and medical food therapies for diabetic retinopathy

“…Diabetes-induced increased nitric oxide synthetase was blocked. This mechanistically supports the use of such vitamin antioxidant combinations for DR [44,50].…”

A Systematic Review of Carotenoids in the Management of Diabetic Retinopathy

“…There is an increasing amount of research and animal trials that substantiate the neuroprotective effects of carotenoids lutein and zeaxanthin in rodent models of DR using either chemical induction or genetic modes to engender diabetic state ( Table 2 ) [ 102 , 103 , 104 , 105 , 106 , 107 , 108 ]. Pharmacological injection of alloxan or streptozotocin (STZ) are often used to recapitulate T1DM pathology in both mice and rats through death of pancreatic beta cells and subsequent insulin deficiency [ 102 , 103 , 104 , 105 , 106 , 117 , 118 , 119 , 120 ]. Genetic modes offer unique models to examine pathophysiological mechanisms of metabolic perturbations that may contribute to incident retinopathy; in particular, leptin receptor deficient (db/db) mice develop morbid obesity and hypoinsulinemia, making them a desirable model for replicating conditions found in T2DM [ 107 , 108 , 118 , 119 , 120 ].…”

“…The importance of macular carotenoid’s antioxidant properties is evident by their enhanced capacity to ameliorate the extent of oxidative injury caused by hyperglycemia in diabetic retina. Supplementation with lutein and/or zeaxanthin was shown to protect against measures of oxidative and nitrosative stress, marked by significant reductions in malondialdehyde, 8-OHdG (oxidatively-modified DNA), and nitrotyrosine, respectively [ 102 , 103 , 105 , 117 , 121 , 122 , 123 ]. Additionally, one study found that micronutrients containing carotenoids prevented a significant rise in retinal ROS levels in T1DM rats following treatment with the EyePromise Diabetes and Visual Function Study (DVS) formula (ZeaVision LLC, Chesterfield, MO, USA) [ 104 , 124 ].…”

“…These findings suggest that the mechanism of protection against oxidative damage to the retina may involve improving mitochondrial dysfunction, the primary source of aberrant free radical production as a consequence of hyperglycemia [ 26 , 125 , 126 , 127 , 128 , 129 ]. In fact, lutein and zeaxanthin were shown to protect against mitochondrial stress induced by T1DM pathology, and improved retinal expression of mtDNA-encoded proteins involved in oxidative phosphorylation and mitochondrial biogenesis [ 26 , 102 , 103 , 108 , 117 ]. Thus, dietary treatment using lutein and zeaxanthin supplementation may prevent early lesions of retinopathy by alleviating pro-oxidant stressors and redox imbalance propagated by hyperglycemic state.…”

“…Dietary augmentation of the compromised endogenous antioxidant defenses has been considered the key modulator in the pathogenesis of DR. Multiple studies found that lutein and zeaxanthin recovered enzymatic activity and expression levels of glutathione, glutathione peroxidase and manganese superoxide dismutase [ 102 , 103 , 105 , 107 , 117 ]; indicating a reversal of hyperglycemic-induced impairment in free radical detoxification and clearance mechanisms [ 26 , 121 , 130 , 131 ]. Similarly, one animal model demonstrated that an AREDS-based micronutrient formulation improved total antioxidant capacity in the retina, as well as metabolic abnormalities associated with early stages of retinopathy progression [ 104 ].…”