Retinal vascular changes and diabetic retinopathy

Recent studies support the concept that the retinal vasculature may provide a summary measure of lifetime exposure to the effects of hyperglycemia. Advances in retinal photographic techniques and in image analysis have allowed objective and precise in vivo measurement of retinal vascular changes. In particular, quantitative assessment of retinopathy signs and measurement of retinal vascular caliber have greatly increased our knowledge of early microcirculatory alterations in prediabetes, diabetes, and diabetic micro- and macrovascular complications. Data from recent population-based studies suggest that retinal arteriolar and venular caliber changes reflect different pathophysiologic processes. Retinal arteriolar narrowing, for example, is associated with risk of diabetes and coronary artery disease, whereas retinal venular widening is associated with development and progression of diabetic retinopathy and risk of stroke. Studying these changes offers the potential to improve our understanding of the early pathophysiologic pathways of diabetes development and its complications. Future research will assess the ability of retinal vascular imaging to provide clinically useful prognostic information for patients with diabetes.     

Serum IGF-1 concentration in diabetic retinopathy

Growth factors such as growth hormone and insulin-like growth factor 1 (IGF-1) may be important in the pathogenesis of diabetic retinopathy. We measured serum IGF-1 in 371 diabetic patients attending a diabetic retinopathy clinic and in 73 non-diabetic control subjects. No significant difference was observed in IGF-1 level between the diabetic and control groups (168 +/- 3.9 vs 177 +/- 7.4 micrograms/l [mean +/- SE]). Within the diabetic group, there was no difference between patients with no retinopathy and those with proliferative change (198.7 +/- 8.8 vs 190.5 +/- 11 micrograms/l). After adjusting for differences in age, duration of diabetes, and presence of proteinuria, only the inactive previously proliferative group showed any significant difference from the other patient subgroups (151.8 +/- 11.5 micrograms/l; p less than 0.05). Serum IGF-1 correlated with age in the control group (r = 0.49; p less than 0.001) and to a lesser extent in the diabetic group (r = -0.23; p less than 0.05). IGF-1 levels were higher in patients with proteinuria than in those without proteinuria (196.8 +/- 10.3 vs 138.8 +/- 4.4 micrograms/l; p less than 0.001).     

Glut1-mediated glucose transport regulates HIV infection

Cell cycle entry is commonly considered to positively regulate HIV-1 infection of CD4 T cells, raising the question as to how quiescent lymphocytes, representing a large portion of the viral reservoir, are infected in vivo. Factors such as the homeostatic cytokine IL-7 have been shown to render quiescent T cells permissive to HIV-1 infection, presumably by transiently stimulating their entry into the cell cycle. However, we show here that at physiological oxygen (O(2)) levels (2-5% O(2) tension in lymphoid organs), IL-7 stimulation generates an environment permissive to HIV-1 infection, despite a significantly attenuated level of cell cycle entry. We identify the IL-7-induced increase in Glut1 expression, resulting in augmented glucose uptake, as a key factor in rendering these T lymphocytes susceptible to HIV-1 infection. HIV-1 infection of human T cells is abrogated either by impairment of Glut1 signal transduction or by siRNA-mediated Glut1 down-regulation. Consistent with this, we show that the susceptibility of human thymocyte subsets to HIV-1 infection correlates with Glut1 expression; single-round infection is markedly higher in the Glut1-expressing double-positive thymocyte population than in any of the Glut1-negative subsets. Thus, our studies reveal the Glut1-mediated metabolic pathway as a critical regulator of HIV-1 infection in human CD4 T cells and thymocytes.     

Antithrombin III activity and other coagulation changes in proliferative diabetic retinopathy

Antithrombin III, factor VIII, fibrinogen and fibrinolytic activity were measured in two groups of long-standing insulin-dependent diabetic subjects (24 with proliferative retinopathy, 24 without detectable retinopathy) and 24 non-diabetic controls. Mean antithrombin III (+/- 1 SD) was 115.9 (+/- 15.1), 109.8 (+/- 18.1) and 101.4% (+/- 12.5), respectively, in the retinopathy, non-retinopathy and control groups. Statistical significance was obtained when comparing the retinopathy and control groups (p < 0.001) and when comparing all 48 diabetics collectively with controls (p < 0.01). Mean factor VIII coagulant activity was 137.5 (+/- 37.0), 126.2 (+/- 58.2) and 97.0% (+/- 38.7), respectively, in the three groups. Again the differences between all diabetics and controls (p < 0.01) were statistically significant. Similar increases were observed for other modalities of factor VIII activity. Fibrinolytic activity was significantly increased in both diabetic groups but fibrinogen levels, although increased, were not statistically different from levels in controls. It is suggested that the observed changes are more likely to be secondary to the development of retinopathy and that the increase in antithrombin III activity is due to an increase in alpha 2-macroglobulin.     

血清miR-29c、bFGF水平与糖尿病视网膜病变的关系

目的 探讨血清微小RNA-29c(miR-29c)、碱性成纤维细胞生长因子(bFGF)水平与糖尿病视网膜病变(DR)的关系。方法 选取154例2型糖尿病(T2DM)患者,根据是否合并视网膜病变分为DR组(n=65)和NDR组(n=89),另选取同期64例体检健康者为对照组。Spearman相关性分析DR组血清miR-29c与bFGF水平的相关性,多因素Logistic回归分析DR发生影响因素,ROC曲线分析血清miR-29c、bFGF水平对DR的诊断价值。结果 对照组、NDR组、DR组血清miR-29c、bFGF水平逐渐升高(P＜0.05)。Spearman相关性分析显示,DR组血清miR-29c与bFGF水平呈正相关(r_s=0.593,P＜0.001)。多因素Logistic回归分析显示,病程(OR=1.132,95%CI:1.046～1.226)、糖化血红蛋白(HbA1c)(OR=2.021,95%CI:1.499～2.725)、miR-29c(OR=2.113,95%CI:1.132～3.943)、bFGF(OR=3.808,95%CI:1.178～5.304)为DR独立危险因素(P＜0.05)。ROC曲线显示,miR-29c与bFGF联合诊断DR的灵敏度、特异度(76.92%和83.15%)均高于单独miR-29c(64.62%和78.65%)、bFGF(75.38%和60.67%)诊断。结论 T2DM患者血清miR-29c、bFGF水平明显升高,两者密切相关,共同参与了视网膜病变发生,联合检测血清miR-29c、bFGF水平可提升DR诊断效能。     

Evaluation of metabolite changes in visual cortex in diabetic retinopathy by MR-spectroscopy

PurposeTo evaluate metabolite changes in the visual cortex of diabetic patients with nonproliferative or proliferative diabetic retinopathy by Magnetic Resonance Spectroscopy (MRS).Materials and Methods15 normal subjects (group 1), 15 patients with diabetes who did not have diabetic retinopathy (group 2), 15 patients with nonproliferative diabetic retinopathy (NPDR) (group 3), and 15 patients with proliferative diabetic retinopathy (PDR) (group 4) were included in the study. Furthermore, diabetic patients were divided into two groups according to HbA1c levels (Group A: 20 patients, HbA1c < 8%; Group B: 20 patients, HbA1c > 8%). In all cases' left visual cortex, amounts of N-acetyl-aspartate (NAA), choline (Cho), and creatine (Cr) were measured by MRS. NAA/Cr, Cho/Cr, and NAA/Cho ratios were calculated. Furthermore, all cases' complete blood count (CBC) and biochemical parameters were evaluated.ResultsThere was no statistically significant difference for NAA/Cr, Cho/Cr, and NAA/Cho ratios between groups 1, 2, 3, and 4 (P > 0.05). However there was a statistically significant difference for NAA/Cr and NAA/Cho ratios between groups A and B (P < 0.05). There was no statistically significant difference for Cho/Cr ratio between groups A and B (P > 0.05).ConclusionAlthough NAA/Cr and NAA/Cho ratios decrease in the visual cortex while diabetic retinopathy progresses, these decreases are not statistically significant. While HbA1c levels increase, the NAA concentration decreases in the visual cortex which indicates neuronal loss. The metabolite changes in the visual cortex are associated with acute events rather than chronic.     

Photoreceptors in diabetic retinopathy

Although photoreceptors account for most of the mass and metabolic activity of the retina, their role in the pathogenesis of diabetic retinopathy has been largely overlooked. Recent studies suggest that photoreceptors might play a critical role in the diabetes‐induced degeneration of retinal capillaries, and thus can no longer be ignored. The present review summarizes diabetes‐induced alterations in photoreceptor structure and function, and provides a rationale for further study of a role of photoreceptors in the pathogenesis of the retinopathy.     

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. In response to capillary non-perfusion, there is dilation of neighbouring capillaries, leading to early blood-retinal barrier breakdown, capillary non-perfusion, and endothelial cell injury and death. The resulting ischemia leads to increased production of growth factors, and the development of proliferative diabetic retinopathy (PDR), which is characterized by growth of new vessels and potential severe and irreversible visual loss. The exact pathogenic mechanism by which capillary non-perfusion occurs is still unclear but growing evidence now suggests that increased leukocyte-endothelial cell adhesion and entrapment (retinal leukostasis) in retinal capillaries is an early event associated with areas of vascular non-perfusion and the development of diabetic retinopathy. The leukocytes in diabetic patients are less deformable more activated, and demonstrate increased adhesion to the vascular endothelium. This review summarizes the current literature on the role of leukocytes in the pathogenesis of capillary occlusion, and discusses the potential of leukostasis as a new promising target in the treatment of diabetic retinopathy.     

Role of vasoactive factors in the pathogenesis of early changes in diabetic retinopathy

Several interactive and mutually perpetuating abnormal biochemical pathways, such as protein kinase C (PKC) activation, augmented polyol pathway, and non-enzymatic glycation, may be activated as a result of sustained hyperglycemia in diabetes. These abnormal pathways may in turn influence several vasoactive factors, which are probably instrumental in the production of functional and morphological changes in the retina in diabetes. The vasoactive factors such as endothelins, nitric oxide, vascular endothelial growth factors, etc., are of importance in mediating functional and structural alterations in early diabetic retinopathy. Intricate and interactive regulatory mechanism(s) among these factors may control ultimate availability of these molecules to produce biologically significant effects. A better understanding of these factors and their interactions would aid the development of adjuvant therapies for the treatment of diabetic retinopathy.     

Progression of retinopathy in type 1 diabetic women during pregnancy

Progression of diabetic retinopathy (DR) occurs at least temporarily during pregnancy and postpartum. The pathogenetic mechanisms of DR progression during pregnancy are not fully understood. Several factors related to metabolic changes (hyperglycaemia), diabetes itself (duration of diabetes before conception, baseline status of DR), pregnancy physiology (hypervolaemia and hypercoagulation, impaired retinal autoregulation) and pregnancy complications (pre-eclampsia) seem to play important roles in the progression of DR during pregnancy. On the other hand, systemic angiopoietic and vasoactive factors seem to have minor role in the deterioration of DR during that time period. Good glycaemic control, normotension, lack of nephropathy as well as lack of pre-proliferative/proliferative changes of DR are good prognostic factors as regards the progression of DR during pregnancy. However, pregnancy seems to have no long-term detrimental effects as regards the progression of DR unless it has proceeded to pre-proliferative and proliferative phases.     

Increased serum pigment epithelium-derived factor levels in type 1 diabetic patients with diabetic retinopathy

Serum pigment epithelium-derived factor (PEDF) levels were significantly higher in type 1 diabetic patients with retinopathy (n = 20, 10.38 ± 3.87 μg/ml) compared to the patients without it (n = 57, 7.68 ± 2.80 μg/ml) (p = 0.0013). Elevated PEDF levels may be related to the progression of diabetic retinopathy.     

Recent advances in diabetic retinopathy

Despite the fact that we still do not understand what causes the development of retinopathy in diabetic subjects, major advances in its treatment have taken place. Photocoagulation clearly reduces the development of severe visual loss in eyes with proliferative diabetic retinopathy although how early treatment should be initiated has not been clearly defined. Vitrectomy is capable of restoring vision in many already blind eyes but at some risk. We are inching closer to an understanding of the pathophysiology of retinopathy with development of retinal endothelial and pericyte cell-culture techniques, studies of vascular permeability, flow and angiogenesis. Diabetic retinopathy is more common at early durations of diabetes than previously realized. This may allow for prospective intervention studies, using development of retinopathy as an endpoint. Diabetic retinopathy may be a reasonable index of short-term survival.