Advanced glycation end products and diabetic retinopathy

Diabetic retinopathy (DR) has a complex pathogenesis which is impacted by a raft of systemic abnormalities and tissue-specific alterations occurring in response to the diabetes milieu. Many pathogenic processes play key roles in retinal damage in diabetic patients. One such pathway is the formation and accumulation of advanced glycation endproducts (AGEs) and advanced lipoxidation end products (ALEs) which are relevant modifications with roles in the initiation and progression of pathology. In this review, AGE/ALE formation in the diabetic retina is discussed alongside their impact on retinal cell function. In addition, various inhibitors of the AGE-RAGE system and their therapeutic utility for DR will also be evaluated.

Antioxidants and diabetic retinopathy

The biochemical perturbations in diabetes mellitus (DM) create the conditions for the production of free radicals, the consequence of which is increased oxidative stress. Evidence has accrued over the past 2 decades that suggests that oxidative stress is an important pathogenetic factor in the development of diabetic retinopathy (DR). Experimental data show that the use of strategies that ameliorate oxidative stress can prevent and retard the development of DR in the animal model. Clinical observations also suggest that reducing oxidative stress may help to reverse pathological manifestations of DR. The present article constitutes an examination of the role of antioxidants in the management of DR and the current state of clinically relevant knowledge. © 2013 Springer Science+Business Media New York.

Nerve pathology in the type 1 diabetic dog: effects of treatment with sulindac

The purpose of this study was to define pathological abnormalities in the peripheral nerve of a large animal model of long-duration type 1 diabetes and also to determine the effects of treatment with sulindac. Detailed morphometric studies were performed to define nerve fiber and endoneurial capillary pathology in 6 control dogs, 6 type 1 diabetic dogs treated with insulin, and 6 type 1 diabetic dogs treated with insulin and sulindac for 4 years. Myelinated fiber and regenerative cluster density showed a non-significant trend toward a reduction in diabetic compared to control animals, which was prevented by treatment with sulindac. Unmyelinated fiber density did not differ among groups. However, diabetic animals showed a non-significant trend toward an increase in axon diameter (p <0.07), with a shift of the size frequency distribution towards larger axons, which was not prevented by treatment with sulindac. Endoneurial capillary density and luminal area showed a non-significant trend toward an increase in diabetic animals, which was prevented with sulindac treatment. Endoneurial capillary basement membrane area was significantly increased (p <0.05) in diabetic animals, but was not prevented with sulindac treatment. We conclude that the type 1 diabetic dog demonstrates minor structural abnormalities in the nerve fibers and endoneurial capillaries of the sciatic nerve, and treatment with sulindac ameliorates some but not all of these abnormalities.

Diabetic retinopathy: morphometric analysis of basement membrane thickening of capillaries in different retinal layers within arterial and venous environments

AIMS: To assess quantitatively variations in the extent of capillary basement membrane (BM) thickening between different retinal layers and within arterial and venous environments during diabetes. METHODS: One year after induction of experimental (streptozotocin) diabetes in rats, six diabetic animals together with six age-matched control animals were sacrificed and the retinas fixed for transmission electron microscopy (TEM). Blocks of retina straddling the major arteries and veins in the central retinal were dissected out, embedded in resin, and sectioned. Capillaries in close proximity to arteries or veins were designated as residing in either an arterial (AE) or a venous (VE) environment respectively, and the retinal layer in which each capillary was located was also noted. The thickness of the BM was then measured on an image analyser based two dimensional morphometric analysis system. RESULTS: In both diabetics and controls the AE capillaries had consistently thicker BMs than the VE capillaries. The BMs of both AE and VE capillaries from diabetics were thicker than those of capillaries in the corresponding retinal layer from the normal rats (p <or = 0.005). Also, in normal AE and VE capillaries and diabetic AE capillaries the BM in the nerve fibre layer (NFL) was thicker than that in either the inner (IPL) or outer (OPL) plexiform layers (p <or = 0.001). However, in diabetic VE capillaries the BMs of capillaries in the NFL were thicker than those of capillaries in the IPL (p <or = 0.05) which, in turn, had thicker BMs than capillaries in the OPL (p <or = 0.005). CONCLUSIONS: The variation in the extent of capillary BM thickening between different retinal layers within AE and VE environments may be related to differences in levels of oxygen tension and oxidative stress in the retina around arteries compared with that around veins.

Stereological estimation of Weibel-Palade bodies in the retinal vasculature of normal and diabetic dogs

The absolute volume of Weibel-Palade (WP) bodies, the storage organelles of von Willebrand factor (vWF), was estimated by a stereological method in a known volume of central retina from normal and 5-year diabetic dogs. The results showed that the volume of WP bodies present in the endothelium of the retinal vasculature varies with blood vessel type and in diabetes. In both diabetic and normal dogs the endothelium of the retinal veins contained a higher volume of WP bodies than that of the retinal arteries. In dogs which had been diabetic for a duration of 5 years the volume of WP bodies present in the endothelium of retinal veins was significantly greater than in the endothelium of veins from the control animals. However, there was no significant difference in the volume of WP bodies present in the endothelium of retinal arteries or capillaries between the two groups of animals.

Selective loss of vascular smooth muscle cells in the retinal microcirculation of diabetic dogs

This study was undertaken to further characterise the fine structural changes occurring in the retinal circulation in early diabetes. The eyes of eight alloxan/streptozotocin and three spontaneously diabetic dogs were examined by trypsin digest and electron microscopy after durations of diabetes of between 1 and 7 years. Basement membrane (BM) thickening in the retinal capillaries was the only obvious fine structural change identified during the first 3 years of diabetes and was established within 1 year of induction. Widespread pericyte loss was noted after 4 years of diabetes and was paralleled by loss of smooth muscle (SM) cells, in the retinal arterioles. SM cell loss was most obvious in the smaller arterioles of the central retina. No microaneurysms were noted in the experimental diabetic dogs with up to 5 years' duration of diabetes but were widespread in a spontaneously diabetic animal at 7 years. This study has shown that SM cell loss, a hitherto unrecognised feature of diabetic microangiopathy, accompanies pericyte loss in the retinal circulation of diabetic dogs.

A morphologic and autoradiographic study of cell death and regeneration in the retinal microvasculature of normal and diabetic rats

Cell loss and regeneration were investigated and compared in the retinal microvasculature of age- and sex-matched normal and streptozotocin diabetic rats. Selective pericyte loss in the diabetic rat was characterized by changes in the pericyte to endothelial cell ratio in retinal capillaries isolated for microscopy by the trypsin digest technique. A comparison of 3- and 9-month-old normal rats showed no significant change in the pericyte to endothelial cell ratio (1:2.7). In diabetic animals the ratio was reduced to 1:4.03, which was statistically significant (P less than .001). Premitotic retinal vascular cells in normal and diabetic rats were labelled with tritiated thymidine and the labelling indices calculated from cell counts of trypsin digest preparations. Methyl H3 thymidine was infused continuously over an eight-day period using osmotic mini pumps. The labelling index of endothelial cells (0.33%) in normal rats increased to 0.91% in diabetic animals (P less than .05). The labelling index of pericyte cells in normal animals (0.16%) did not increase significantly (P greater than .05) in diabetic animals (0.19%). A special stain was used to exclude labelled polymorphonuclear leukocytes from the cell counts.

Genetic and Epigenetic Risk Factors for Diabetic Kidney Disease

Diabetes is increasing at daunting rates worldwide, and approximately 40% of affected individuals will develop kidney complications. Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and there are significant healthcare costs providing appropriate renal replacement therapies to affected individuals. For several decades, investigators have sought to discover inherited risk factors and biomarkers for DKD. In recent years, advances in high-throughput laboratory techniques and computational analyses, coupled with the establishment of multicenter consortia, have helped to identify genetic loci that are replicated across multiple populations. Several genome-wide association studies (GWAS) have been conducted for DKD with further meta-analysis of GWAS and comprehensive ”single gene” meta-analyses now published. Despite these efforts, much of the inherited predisposition to DKD remains unexplained. Meta-analyses and integrated–omics pathway studies are being used to help elucidate underlying genetic risks. Epigenetic phenomena are increasingly recognized as important drivers of disease risk, and several epigenome-wide association studies have now been completed. This review describes key findings and ongoing genetic and epigenetic initiatives for DKD.

Epigenetics of diabetic nephropathy

Diabetes is responsible for a large proportion of chronic kidney disease and end-stage renal disease worldwide. Careful monitoring and balanced control of blood glucose for individuals with type 1 diabetes can delay or prevent the onset of micro- and macro-vascular complications, however hyperglycaemia does not explain all of the risk for these diabetic complications. Genetic risk factors for diabetic nephropathy are being identified through international collaborations. However despite these advances a significant proportion of susceptibility remains unexplained, the so-called ‘missing heritability’.

Serum apolipoprotein AI and B are stronger biomarkers of diabetic retinopathy than traditional lipids

OBJECTIVE - To describe and compare the associations of serum lipoproteins and apolipoproteins with diabetic retinopathy. RESEARCH DESIGN AND METHODS - This was a cross-sectional study of 224 diabetic patients (85 type 1 and 139 type 2) froma diabetes clinic. Diabetic retinopathy was graded from fundus photographs according to the Airlie House Classification system and categorized into mild, moderate, and vision-threatening diabetic retinopathy (VTDR). Serum traditional lipids (total, LDL, non-HDL, and HDL cholesterol and triglycerides) and apolipoprotein AI (apoAI), apolipoprotein B (apoB), and the apoB-to-apoAI ratio were assessed. RESULTS - Diabetic retinopathy was present in 133 (59.4%) individuals. After adjustment for age, sex, diabetes duration, A1C, systolic blood pressure, and diabetes medications, the HDL cholesterol level was inversely associated with diabetic retinopathy (odds ratio 0.39 [95% CI 0.16-0.94], highest versus lowest quartile; P = 0.017). The ApoAI level was inversely associated with diabetic retinopathy (per SD increase, 0.76 [95% CI 0.59-0.98]), whereas apoB (per SD increase, 1.31 [1.02-1.68]) and the apoB-to-apoAI ratio (per SD increase, 1.48 [1.13-1.95]) were positively associated with diabetic retinopathy. Results were similar for mild to moderate diabetic retinopathy and VTDR. Traditional lipid levels improved the area under the receiver operating curve by 1.8%, whereas apolipoproteins improved the area by 8.2%. CONCLUSIONS - ApoAI and apoB and the apoB-to-apoAI ratio were significantly and independently associated with diabetic retinopathy and diabetic retinopathy severity and improved the ability to discriminate diabetic retinopathy by 8%. Serum apolipoprotein levels may therefore be stronger biomarkers of diabetic retinopathy than traditional lipid measures. © 2011 by the American Diabetes Association.