Subrata  Chakrabarti

Diabetic Retinopathy: From Pathogenesis to Treatment

High prevalence rates of type 2 diabetes are being observed in native Canadian communities. It is believed that native populations have a higher prevalence rate of vascular complications than nonnatives. The Southern Alberta Study of Diabetic Retinopathy (DR) examined the prevalence and incidence of DR and associated metabolic abnormalities in native and nonnative subjects. Prevalence rates of DR in type 2 diabetic native and nonnative subjects were identical, with a prevalence rate of 40%. Native subjects with retinopathy, however, tended to have more advanced changes of retinopathy compared to the nonnative subjects. Key factors such as A1c, blood pressure, duration of diabetes, and lipid values were not significantly different between the two cohorts. These data indicate that ethnicity does play a role in the development and severity of DR but potential risk factors that may affect the development of retinopathy are not significantly different between native and nonnative groups.

Stuart A. Ross

Anne McKenna

Sheila Mozejko

Gordon H. Fick

Diabetic Retinopathy in Native and Nonnative Canadians

Dysfunction and death of microvascular cells and imbalance between the production and the degradation of extracellular matrix (ECM) proteins are a characteristic feature of diabetic retinopathy (DR). Glucose-induced biochemical alterations in the vascular endothelial cells may activate a cascade of signaling pathways leading to increased production of ECM proteins and cellular dysfunction/death. Chronic diabetes leads to the activation of a number of signaling proteins including protein kinase C, protein kinase B, and mitogen-activated protein kinases. These signaling cascades are activated in response to hyperglycemia-induced oxidative stress, polyol pathway, and advanced glycation end product formation among others. The aberrant signaling pathways ultimately lead to activation of transcription factors such as nuclear factor-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03BA;</mml:mi></mml:math>B and activating protein-1. The activity of these transcription factors is also regulated by epigenetic mechanisms through transcriptional coactivator p300. These complex signaling pathways may be involved in glucose-induced alterations of endothelial cell phenotype leading to the production of increased ECM proteins and vasoactive effector molecules causing functional and structural changes in the microvasculature. Understanding of such mechanistic pathways will help to develop future adjuvant therapies for diabetic retinopathy.

Zia A. Khan

Cellular Signaling and Potential New Treatment Targets in Diabetic Retinopathy

Diabetes causes metabolic and physiologic abnormalities in the retina, and these changes suggest a role for inflammation in the development of diabetic retinopathy. These changes include upregulation of iNOS, COX-2, ICAM-1, caspase 1, VEGF, and NF-<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>κ</mml:mi></mml:math>B, increased production of nitric oxide, prostaglandin E2, IL-1<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>, and cytokines, as well as increased permeability and leukostasis. Using selective pharmacologic inhibitors or genetically modified animals, an increasing number of therapeutic approaches have been identified that significantly inhibit development of at least the early stages of diabetic retinopathy, especially occlusion and degeneration of retinal capillaries. A common feature of a number of these therapies is that they inhibit production of inflammatory mediators. The concept that localized inflammatory processes play a role in the development of diabetic retinopathy is relatively new, but evidence that supports the hypothesis is accumulating rapidly. This new hypothesis offers new insight into the pathogenesis of diabetic retinopathy, and offers novel targets to inhibit the ocular disease.

Timothy S. Kern

Contributions of Inflammatory Processes to the Development of the Early Stages of Diabetic Retinopathy

The polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol, which is then converted to fructose. It is one of the most attractive candidate mechanisms to explain, at least in part, the cellular toxicity of diabetic hyperglycemia because (i) it becomes active when intracellular glucose concentrations are elevated, (ii) the two enzymes are present in human tissues and organs that are sites of diabetic complications, and (iii) the products of the pathway and the altered balance of cofactors generate the types of cellular stress that occur at the sites of diabetic complications. Inhibition (or ablation) of aldose reductase, the first and rate-limiting enzyme in the pathway, reproducibly prevents diabetic retinopathy in diabetic rodent models, but the results of a major clinical trial have been disappointing. Since then, it has become evident that truly informative indicators of polyol pathway activity and/or inhibition are elusive, but are likely to be other than sorbitol levels if meant to predict accurately tissue consequences. The spectrum of abnormalities known to occur in human diabetic retinopathy has enlarged to include glial and neuronal abnormalities, which in experimental animals are mediated by the polyol pathway. The endothelial cells of human retinal vessels have been noted to have aldose reductase. Specific polymorphisms in the promoter region of the aldose reductase gene have been found associated with susceptibility or progression of diabetic retinopathy. This new knowledge has rekindled interest in a possible role of the polyol pathway in diabetic retinopathy and in methodological investigation that may prepare new clinical trials. Only new drugs that inhibit aldose reductase with higher efficacy and safety than older drugs will make possible to learn if the resilience of the polyol pathway means that it has a role in human diabetic retinopathy that should not have gone undiscovered.

Mara Lorenzi

The Polyol Pathway as a Mechanism for Diabetic Retinopathy: Attractive, Elusive, and Resilient

Diabetic retinopathy remains a major cause of worldwide preventable blindness. Measures to avoid blindness include medical management (control of blood sugar, blood pressure, and serum lipids) and ocular management (laser photocoagulation and pars plana vitrectomy). Adjunctive pharmacologic therapies (intravitreal triamcinolone acetonide and anti-vascular endothelial growth factor agents) have shown early promise in the treatment of both diabetic macular edema and proliferative diabetic retinopathy. Other medications under investigation include the fluocinolone acetonide implantable device, extended-release dexamethasone implant, oral ruboxistaurin, and intravitreal hyaluronidase.

Stephen G. Schwartz

Harry W. Flynn

Pharmacotherapies for Diabetic Retinopathy: Present and Future

Elevated glutamate is implicated in the pathology of PDR. The ability to rapidly assess the glutamate and amino acid content of vitreous provides a more complete picture of the chemical changes occurring at the diabetic retina and may lead to a better understanding of the pathology of PDR. Vitreous humor was collected following vitrectomies of patients with PDR and control conditions of macular hole or epiretinal membrane. A capillary electrophoresis method was developed to quantify glutamate and arginine. The analysis is relatively fast (<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mo>&lt;</mml:mo></mml:math>6 minutes) and utilizes a poly(ethylene)oxide and sodium dodecylsulfate run buffer. Both amino acid levels show significant increases in PDR patients versus controls and are comparable to other reports. The levels of vitreal glutamate vary inversely with the degree of observed hemorrhage. The results demonstrate a rapid method for assessment of a number of amino acids to characterize the chemical changes at the diabetic retina to better understand tissue changes and potentially identify new treatments.

Miao-Jen Lu

Jose S. Pulido

Colin A. McCannel

Jose E. Pulido

R. Mark Hatfield

Robert F. Dundervill

Scott A. Shippy

Detection of Elevated Signaling Amino Acids in Human Diabetic Vitreous by Rapid Capillary Electrophoresis

Aim. Diabetic retinopathy resists reversal after good glycemic control (GC) is reinitiated, and preexisting damage at the time of intervention is considered as the major factor in determining the outcome of the GC. This study is to investigate the role of peroxynitrite accumulation in the retinal capillaries in the failure of retinopathy to reverse after reestablishment of GC, and to determine the effect of this reversal on the activity of the enzyme responsible for scavenging mitochondrial superoxide, MnSOD. Methods. In streptozotocin-diabetic rats, 6 months of poor glycemic control (PC, glycated hemoglobin, <mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>GHb</mml:mtext><mml:mo>&gt;</mml:mo><mml:mn>12.0</mml:mn><mml:mi>%</mml:mi></mml:mrow></mml:math>) was followed by 6 additional months of GC (GHb about 6<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>%</mml:mi></mml:math>). The trypsin-digested retinal microvessels were prepared for immunostaining of nitrotyrosine (a measure of peroxynitrite) and for counting the number of acellular capillaries (a measure of histopathology). The retina from the other eye was used to quantify nitrotyrosine concentration, MnSOD activity and the total antioxidant capacity. Results. 
Reversal of hyperglycemia after 6 months of PC had no significant effect on nitrotyrosine concentration in the retina, on the nitrotyrosine-positive retinal capillary cells and on the number of acellular capillaries; the values were similar in PC-GC and PC groups. In the same rats retinal MnSOD activity remained inhibited and the total antioxidant capacity was subnormal 6 months after cessation of PC. Conclusions. Peroxynitrite accumulation in the retinal microvasculature, the site of histopathology, fails to normalize after reversal of hyperglycemia, and superoxide remains inadequately scavenged. This failure of reversal of peroxynitrite accumulation could be, in part, responsible for the resistance of diabetic retinopathy to reverse after termination of PC.

Renu A. Kowluru

Mamta Kanwar

Alexander Kennedy

Metabolic Memory Phenomenon and Accumulation of Peroxynitrite in Retinal Capillaries

Diabetic retinopathy is a leading cause of vision loss. The primary clinical hallmarks are vascular changes that appear to contribute to the loss of sight. In a number of neurodegenerative disorders there is an appreciation that increased levels of excitatory amino acids are excitotoxic. The primary amino acid responsible appears to be the neurotransmitter glutamate. This review examines the nature of glutamatergic signaling at the retina and the growing evidence from clinical and animal model studies that glutamate may be playing similar excitotoxic roles at the diabetic retina.

Jay C. Erie

Jorge Arroyo

Kurt Bertram

A Role for Excitatory Amino Acids in Diabetic Eye Disease

Oxygen metabolism is essential for sustaining aerobic life, and normal cellular homeostasis works on a fine balance between the formation and elimination of reactive oxygen species (ROS). Oxidative stress, a cytopathic consequence of excessive production of ROS and the suppression of ROS removal by antioxidant defense system, is implicated in the development of many diseases, including Alzheimer&#39;s disease, and diabetes and its complications. Retinopathy, a debilitating microvascular complication of diabetes, is the leading cause of acquired blindness in developed countries. Many diabetes-induced metabolic abnormalities are implicated in its development, and appear to be influenced by elevated oxidative stress; however the exact mechanism of its development remains elusive. Increased superoxide concentration is considered as a causal link between elevated glucose and the other metabolic abnormalities important in the pathogenesis of diabetic complications. Animal studies have shown that antioxidants have beneficial effects on the development of retinopathy, but the results from very limited clinical trials are somewhat ambiguous. Although antioxidants are being used for other chronic diseases, controlled clinical trials are warranted to investigate potential beneficial effects of antioxidants in the development of retinopathy in diabetic patients.

Pooi-See  Chan

Oxidative Stress and Diabetic Retinopathy

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Journal of Diabetes Research publishes articles related to type 1 and type 2 diabetes. Topics include etiology, pathogenesis, management, and prevention of diabetes, as well as associated complications such as nephropathy.

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Chief Editor Dr Mark Yorek, from the University of Iowa, is currently researching vascular and neural disease related to obesity and diabetes. His active research studies focus on etiology, treatment and prevention of nerve damage.

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Journal of Diabetes Research

Diabetic Retinopathy: From Pathogenesis to Treatment

Diabetic Retinopathy: From Pathogenesis to Treatment

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