Pathophysiology of diabetic retinopathy.

Diabetes is now regarded as an epidemic, with the population of patients expected to rise to 380 million by 2025. Tragically, this will lead to approximately 4 million people around the world losing their sight from diabetic retinopathy, the leading cause of blindness in patients aged 20 to 74 years. The risk of development and progression of diabetic retinopathy is closely associated with the type and duration of diabetes, blood glucose, blood pressure, and possibly lipids.

Retinopathy in diabetes.

With the incidence, and prevalence of diabetes mellitus increasing worldwide, diabetic retinopathy is expected to reach epidemic proportions. The aim of this chapter is to introduce diabetic retinopathy, a leading cause of blindness in people of the working age. The clinical course of retinopathy, anatomical changes, its pathogenesis and current treatment are described, followed by an overview of the emerging drug therapies for the potential treatment of this sight-threatening complication of diabetes.

Introduction to diabetes mellitus.

The chronic metabolic disorder diabetes mellitus is a fast-growing global problem with huge social, health, and economic consequences. It is estimated that in 2010 there were globally 285 million people (approximately 6.4% of the adult population) suffering from this disease.

Diabetic retinopathy and atherosclerosis: is there a link?

Diabetic retinopathy (DR) is the leading cause of blindness amongst the working-age population, and diabetes accelerated cardiovascular disease (CVD) the commonest cause of death in diabetic patients. Although, there is evidence suggesting a close association between DR and CVD, particularly in patients with Type 2 diabetes, the pathophysiology underlying the link is unclear. Here we review common risk factors and pathogenic mechanisms linking DR and CVD, and aim to highlight the need for a more holistic view of the management of diabetes and its complications.

Cellular crosstalk between TNF-α, NADPH oxidase, PKCβ2, and C2GNT in human leukocytes.

Increasing evidence suggests that chronic, sub-clinical inflammation plays an important role in the pathogenesis of diabetic retinopathy. We have established the potential role of the inflammatory enzyme, core 2 β-1, 6-N-acetylglucosaminyltransferase (C2GNT) in diabetic retinopathy. The present study was designed to explore the NADPH oxidase signaling pathway in the tumor necrosis factor-alpha (TNF-α)-induced activity of C2GNT in leukocytes.

NADPH Oxidase versus Mitochondria-Derived ROS in Glucose-Induced Apoptosis of Pericytes in Early Diabetic Retinopathy.

Objectives. Using apocynin (inhibitor of NADPH oxidase), and Mitoquinol 10 nitrate (MitoQ; mitochondrial-targeted antioxidant), we addressed the importance of mitochondria versus NADPH oxidase-derived ROS in glucose-induced apoptosis of pericytes. Methods.

Is inflammation a common retinal-renal-nerve pathogenic link in diabetes?

The global diabetes burden is predicted to rise to 380 million by 2025 and would present itself as a major health challenge. However, both Type 1 and Type 2 diabetes increase the risk of developing micro-vascular complications and macro-vascular complications which in turn will have a devastating impact on quality of life of the patients and challenge health services Worldwide. The micro-vascular complications that affect small blood vessels are the leading cause of blindness (diabetic retinopathy) in the people of the working-age, end-stage renal disease (diabetic nephropathy) the most common cause of kidney failure today, and foot amputation (diabetic neuropathy) in patients with Type 1 and Type 2 diabetes.

Leukocytes in diabetic retinopathy.

Diabetic retinopathy is one of the most common diabetic complications, and is a major cause of new blindness in the working-age population of developed countries. Progression of vascular abnormalities, including the selective loss of pericytes, formation of acellular capillaries, thickening of the basement membrane, and increased vascular permeability characterizes early nonproliferative diabetic retinopathy (NPDR). Capillary occlusion, as shown on fluorescein angiograms, is also one of the earliest clinically recognizable lesion of NPDR.

21st Century treatment of diabetic retinopathy.

Despite marked improvements in the treatment of diabetes and its retinal complications, diabetic retinopathy remains a leading cause of blindness and vision impairment in working-age adults. Control of blood glucose and blood pressure will remain important means to prevent the onset and progression of diabetic retinopathy. Current and improved surgical treatments, such as laser therapy and vitrectomy, have also proved highly effective in preventing major visual loss in advanced stages of retinopathy.

Glycated proteins stimulate reactive oxygen species production in cardiac myocytes: involvement of Nox2 (gp91phox)-containing NADPH oxidase.

Background: Nonenzymatic glycation that results in the production of early-glycation Amadori-modified proteins and advanced-glycation end products may be important in the pathogenesis of diabetic complications. However, the effects of early-glycated proteins, such as glycated serum albumin (Gly-BSA), are poorly defined. In this study, we investigated the effects of Gly-BSA on reactive oxygen species (ROS) production by cardiomyocytes.

Tumor necrosis factor-alpha in diabetic plasma increases the activity of core 2 GlcNAc-T and adherence of human leukocytes to retinal endothelial cells: significance of core 2 GlcNAc-T in diabetic retinopathy.

A large body of evidence now implicates increased leukocyte-endothelial cell adhesion as a key early event in the development of diabetic retinopathy. We recently reported that raised activity of the glycosylating enzyme core 2 beta 1,6-N-acetylglucosaminyltransferase (GlcNAc-T) through protein kinase C (PKC)beta2-dependent phosphorylation plays a fundamental role in increased leukocyte-endothelial cell adhesion and capillary occlusion in retinopathy. In the present study, we demonstrate that following exposure to plasma from diabetic patients, the human promonocytic cell line U937 exhibits a significant elevation in core 2 GlcNAc-T activity and increased adherence to cultured retinal capillary endothelial cells.

Protein kinase C beta2-dependent phosphorylation of core 2 GlcNAc-T promotes leukocyte-endothelial cell adhesion: a mechanism underlying capillary occlusion in diabetic retinopathy.

Increased leukocyte-endothelial cell adhesion is a key early event in the development of retinopathy and atherogenesis in diabetic patients. We recently reported that raised activity of glycosylating enzyme [beta]1,6 acetylglucosaminyltransferase (core 2 GlcNAc-T) is responsible for increased leukocyte-endothelial cell adhesion and capillary occlusion in retinopathy. Here, we demonstrate that elevated glucose increases the activity of core 2 GlcNAc-T and adhesion of human leukocytes to retinal capillary endothelial cells, in a dose-dependent manner, through diabetes-activated serine/threonine protein kinase C beta2 (PKCbeta2)-dependent phosphorylation.

Impairment of vascular endothelial nitric oxide synthase activity by advanced glycation end products.

Endothelial damage is believed to play a key role in the development of both micro- and macrovascular disease in diabetes, and advanced glycation end products (AGEs) may contribute importantly to this. To determine whether glucose-derived AGEs can cause endothelial dysfunction, we examined the effects of albumin AGE-modified by glucose (AGE-Glu) both in vivo, after injection into rabbit femoral artery, and in vitro on rabbit aortic rings and cultured human umbilical vein endothelial cells (HUVEC). Exposure of blood vessels to AGE-Glu, in vivo and in vitro, inhibited endothelium-dependent vasorelaxation, whereas unmodified albumin did not.