The elderly population in the United States is projected to almost double by the year 2050. In addition, the numbers of diabetics are rising, along with its most common complication, diabetic retinopathy (DR). To effectively treat DR within the elderly population, it is essential first to consider the retinal changes that occur due to aging, such as decreased blood flow, retinal thinning, and microglial changes, and understand that these changes can render the retina more vulnerable to oxidative and ischemic damage. Given these considerations, as well as the pathogenesis of DR, specific pathways could play a heightened role in DR progression in elderly patients, such as the polyol pathway and the vascular endothelial growth factor (VEGF) axis. Current ocular treatments include intravitreal corticosteroids, intravitreal anti-VEGF agents, laser photocoagulation and surgical interventions, in addition to better control of underlying diabetes with an expanding range of systemic treatments. While using therapeutics, it is also essential to consider how pharmacokinetics and pharmacodynamics change with aging; oral drug absorption can decrease, and ocular drug metabolism might affect the dosing and delivery methods. Also, elderly patients may more likely be nonadherent to their medication regimen or appointments than younger patients, and undertreatment with anti-VEGF drugs often leads to suboptimal outcomes. With a rising number of elderly DR patients, understanding how aging affects disease progression, pharmacological metabolism, and adherence are crucial to ensuring that this population receives adequate care.
The widespread nature of diabetes affects all organ systems of an individual including the bone marrow. Long-term damage to the cellular and extracellular components of the bone marrow leads to a rapid decline in the bone marrow-hematopoietic stem/progenitor cells (HS/PCs) compartment. This review will highlight the importance of bone marrow microenvironment in maintaining bone marrow HS/PC populations and the contribution of these key populations in microvascular repair during the natural history of diabetes. The autonomic nervous system can initiate and propagate bone marrow dysfunction in diabetes. Systemic pharmacological strategies designed to protect the bone marrow-HS/PC population from diabetes induced-oxidative stress and advanced glycation end product accumulation represent a new approach to target diabetic retinopathy progression. Protecting HS/PCs ensures their participation in vascular repair and reduces the risk of vasogdegeneration occurring in the retina.
IntroductionDapagliflozin, a sodium-glucose transporter inhibitor, effectively reduces blood glucose and is indicated for individuals with kidney diseases and cardiovascular disorders. In this study, we further expand the therapeutic benefit of dapagliflozin in the neural and vascular retina, with the potential to effectively manage diabetic retinopathy (DR), the most common complication of diabetes.Research design and methodsDb/db mice, an animal model of type 2 diabetes, were treated with dapagliflozin orally, and the electroretinogram (ERG) response and acellular capillary numbers were assessed. Messenger RNA levels of inflammatory cytokines were studied using real-time quantitative (q)PCR. We assessed endothelial cell migration in a scratch wound assay and retinal glucose uptake using human retinal endothelial cells.ResultsThe dapagliflozin treatment improved the ERG b-wave amplitude and decreased acellular capillary numbers. The scratch wound assay demonstrated a reduction in wound closure after dapagliflozin treatment. Retinal glucose uptake reduced after dapagliflozin treatment compared with the respective controls.ConclusionsOur studies suggest that dapagliflozin treatment effectively corrects neural and vascular dysfunction of the retina in diabetes. This effect is mediated by a decrease in inflammation and improved glycemic control. In addition, dapagliflozin exhibits decreased wound healing and glucose uptake, which could benefit the retina. Thus, dapagliflozin could be helpful in the management of DR, with multimodal therapeutic effects.
Introduction: Diabetes is the leading cause of microvascular disorders such as diabetic retinopathy (DR). There are no treatments for DR and finding new drug targets is of considerable interest. SGLT2 inhibitors, a newer class of antidiabetics are promising in the management of diabetes, however, the potential role of SGLT2 in diabetic retinal microvasculature remains unknown. We hypothesized that diabetes will lead to an increase in SGLT2 in the retina and that its inhibition will be beneficial in protecting retinal vasculature from the insult of diabetes milieu. Methods: The retinal sections of diabetic (db/db; an animal model of type 2 diabetes) and control (db/m) mice were analyzed for SGLT2 expression using confocal microscopy. In parallel, the mRNA levels of SGLT2 were determined using qRT-PCR. Human retinal endothelial cells (HRECs) were treated with the SGLT2 inhibitor dapagliflozin (0.1, 1, 10 nM) to perform a glucose uptake assay and to determine its effects on mRNA levels of SGLT2. Results: The mRNA levels of SGLT2 were significantly higher (p<0.05) in the retina of db/db mice, 1.1 ± 0.46, n=5, when compared to db/m retinas, 0.06 ± 0.02, n=4. The confocal microscopy revealed SGLT2 expression throughout the retina and around the retinal blood vessels, brighter fluorescence was observed in the db/db retina. Treatment of HRECs with 10 nM dapagliflozin led to a significant decrease in SGLT2 mRNA (p<0.05); dapagliflozin: 7.95 ± 4.7, n=4; vehicle: 26 ± 3.6, n=8. The dapagliflozin inhibition demonstrated a profound decrease in glucose uptake in HRECs at all concentrations. Untreated: 2012 ± 388, n=3; 0.1 nM: 545.7 ± 296, 1 nM: 358.2 ± 241.5, 10 nM: 70.67 ± 138.9; p<0.01 as compared to untreated; n=6. Conclusion: Our studies suggest that SGLT2 is significantly upregulated in the retina during diabetes and that SGLT2 potentially plays a critical role in retinal glucose transport. In future, SGLT2 inhibition could be a useful treatment option to slow down or prevent the onset of diabetic retinopathy. Disclosure S.P. Leley: None. Q. Luo: None. A.L. Alex: None. A.D. Bhatwadekar: None. Funding National Eye Institute; Indiana University Center for Diabetes and Metabolic Diseases
Background and Hypothesis: Diabetic retinopathy (DR), a microvascular complication of diabetes, is the leading cause of blindness in the working-age population, and its prevalence is increasing. New treatment modalities must be developed to slow the progression of DR. SGLT2 inhibition has shown promise in treating other diabetic complications; however, its effect on DR remains unknown, therefore, for this study, we hypothesize that SGLT2 inhibition will reduce the harmful effects of DR. Methods: Diabetic (db/db) mice were fed 10 mg/kg of the SGLT2 inhibitor dapagliflozin in their diet for 6 months, non-diabetic (db/m) mice on a regular diet served as controls. In parallel, human retinal endothelial cells (HREC) were used as in-vitro models and treated with dapagliflozin to assess glucose uptake via a 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) assay. Results: Our studies show that db/db mice with dapagliflozin had significantly fewer acellular capillaries compared to untreated db/db mice. Furthermore, Dapagliflozin treatment at 1 and 10 µM concentrations of dapagliflozin yielded a significant decrease in glucose uptake compared to respective vehicle controls. Conclusion: Our study shows that SGLT2 inhibition has a promise in treating DR by reducing acellular capillaries and retinal glucose transport suggesting the potential of dapagliflozin treatment in DR.
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