Diabetic Retinopathy and Diabetic Neuropathy

Bloomgarden, Zachary T.

doi:10.2337/dc07-zb03

Cited by 23 publications

(30 citation statements)

References 45 publications

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“…Oxidized LDL-mediated inflammation and vascular damage are critical in the pathogenesis of atherosclerosis as well as diabetic complications, [32][33][34][35][36] including diabetic retinopathy, as witnessed by our own studies. Diabetes may amplify LDL oxidation and exacerbate its complications by increasing glycation of plasma LDL 37 and rendering the lipoprotein more susceptible to oxidation.…”

Section: Discussionmentioning

confidence: 97%

Tyrosine Nitration of Prostacyclin Synthase Is Associated with Enhanced Retinal Cell Apoptosis in Diabetes

Zou

et al. 2011

The American Journal of Pathology

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The risk of diabetic retinopathy is associated with the presence of both oxidative stress and toxic eicosanoids. Whether oxidative stress actually causes diabetic retinopathy via the generation of toxic eicosanoids, however, remains unknown. The aim of the present study was to determine whether tyrosine nitration of prostacyclin synthase (PGIS) contributes to retinal cell death in vitro and in vivo. Exposure of human retinal pericytes to heavily oxidized and glycated LDL (HOG-LDL), but not native forms of LDL (N-LDL), for 24 hours significantly increased pericyte apoptosis, accompanied by increased tyrosine nitration of PGIS and decreased PGIS activity. Inhibition of the thromboxane receptor or cyclooxygenase-2 dramatically attenuated HOG-LDL-induced apoptosis without restoring PGIS activity. Administration of superoxide dismutase (to scavenge superoxide anions) or L-N G -nitroarginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) restored PGIS activity and attenuated pericyte apoptosis. In Akita mouse retinas, diabetes increased intraretinal levels of oxidized LDL and glycated LDL, induced PGIS nitration, enhanced apoptotic cell death, and impaired blood-retinal barrier function. Chronic administration of tempol, a superoxide scavenger, reduced intraretinal oxidized LDL and glycated LDL levels, PGIS nitration, and retina cell apoptosis, thereby preserving the integrity of blood-retinal barriers. In conclusion, oxidized LDL-mediated PGIS nitration and associated thromboxane receptor stimulation might be important in the initiation and progression of dia- Loss of pericytes from retinal microvessels is an important event in the early stage of diabetic retinopathy, which is associated with increased pericyte apoptosis. Although the mechanisms responsible for pericyte apoptosis remain unclear, several studies have shown associations between dyslipidemia and the severity of diabetic retinopathy.1,2 Specifically, elevated levels of triglycerides, low density lipoprotein (LDL), and apolipoprotein B, a principal lipoprotein component of LDL, have been associated with diabetic retinopathy.1 However, these associations are relatively weak, leading us to hypothesize that the key contribution of lipoproteins to the propagation of diabetic retinopathy is not through changes in their plasma levels but, rather, through extravasation via a disrupted blood-retinal barrier and subsequent modification by glycation and oxidation. In support of this model, we have demonstrated that oxidized LDL is present in the retina in diabetic humans in proportion to the severity of diabetic retinopathy, 3 and in cell culture studies we have shown that oxidized LDL has injurious effects on retinal pericytes. 4,5

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Section: Discussionmentioning

confidence: 97%

Tyrosine Nitration of Prostacyclin Synthase Is Associated with Enhanced Retinal Cell Apoptosis in Diabetes

Zou

et al. 2011

The American Journal of Pathology

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“…eripheral sensory neuropathy (PSN) is a well-known complication of diabetes attributed to chronic hyperglycemia (1,2). However, the risk of PSN is also increased by advancing age and affected by height and possibly by sex (3) and poorly defined factors, such as processes coupled to regulation of IGF-1 (4,5).…”

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confidence: 99%

“…This makes it difficult to identify specific diabetes components of neuropathy. Retinopathy, on the other hand, is a complication of diabetes strictly coupled to metabolic control and is also more easily investigated (1). It could be conjectured that metabolic control would be a strong determinant of PSN in subjects with both retinopathy and neuropathy but less so in diabetic subjects with neuropathy alone.…”

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confidence: 99%

Peripheral Sensory Neuropathy Associates With Micro- or Macroangiopathy

Kärvestedt

Mårtensson²,

Grill

et al. 2009

Diabetes Care

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OBJECTIVE -To assess associations between peripheral sensory neuropathy (PSN) and other diabetes-related complications.RESEARCH DESIGN AND METHOD -In an area-based cohort of type 2 diabetic subjects, we investigated 156 subjects (age 61.7 Ϯ 7.2 years and diabetes duration 7.0 Ϯ 5.7 years) by questionnaires, clinical examinations, blood and urine sampling, and review of medical records.RESULTS -Prevalence of PSN, assessed by monofilament and neurothesiometer testing, increased with severity of retinopathy (50% frequency in moderate and 100% in severe or proliferative retinopathy; P ϭ 0.02). Vibration perception threshold was higher in subjects with retinopathy (25.6 Ϯ 8.9 vs. 20.5 Ϯ 8.9 V; P ϭ 0.007). PSN was more common in subjects with overt nephropathy, with higher vibration perception thresholds, than in subjects without overt nephropathy. Subjects with PSN but no retinopathy had twice the prevalence of peripheral vascular disease (PVD) (52%) as subjects with both PSN and retinopathy (19%; P ϭ 0.05). In subjects with PSN alone, PVD was three times more likely (52%) than in subjects without PSN (16%; P ϭ 0.001). In multivariate analysis, PSN was independently associated with PVD (odds ratio 2.31; P ϭ 0.007), age (1.12; P ϭ 0.008), male sex (2.01; P ϭ 0.02), and HDL cholesterol (0.21; P Ͻ 0.05) and tended to be independently associated with IGF-1 binding protein (1.03; P ϭ 0.05) but not with diabetes duration or A1C.CONCLUSIONS -In a representative population of type 2 diabetes, PSN is related to microvascular and macrovascular pathology. PSN is possibly affected by the IGF axis.

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“…Endothelium-specific knockout of platelet-derived growth factor β (PDGFβ) that trumps PDGFβ/PDGFRb signaling required for PC survival yields a variable degree of retinal pericyte loss with DR-like lesions located in the areas of greatest loss (155,157,158). It has therefore been suggested that pericyte dropout in the retina due to hyperglycemia-induced apoptosis is a sufficient cause for capillary occlusion, regression and, ultimately, retinal ischemia which leads to the onset of PDR complications (45,159).…”

Section: Discussionmentioning

confidence: 99%

“…The maintenance of blood-barriers, BBB and BRB, in the CNS is crucial for the proper functioning of the brain and retina, respectively, and their breakdown is associated with the etiology of several pathologies, including diabetic neuropathy and retinopathy, amyotrophic lateral sclerosis and stroke (14,(45)(46)(47). One pericyte is typically associated with several ECs, suggesting a role in the coordination and integration of cellular communication among neighboring ECs.…”

mentioning

confidence: 99%