Lower Somatostatin Expression Is an Early Event in Diabetic Retinopathy and Is Associated With Retinal Neurodegeneration

Abstract

OBJECTIVE -To test the hypothesis that a reduction of somatostatin (SST) in the retina exists in patients without clinically detectable diabetic retinopathy and that it is associated with retinal neurodegeneration.RESEARCH DESIGN AND METHODS -Human diabetic postmortem eyes (n ϭ 10) without clinically detectable retinopathy were compared with eyes (n ϭ 10) from nondiabetic donors. SST mRNA (RT-PCR) and SST-28 immunoreactivity (confocal laser) were measured separately in neuroretina and retinal pigment epithelium (RPE). In addition, SST-28 (radioimmunoassay) was measured in the vitreous fluid. Glial fibrillar acidic protein (GFAP) was assessed by immunofluorescence and Western blot. Apoptotic cells were quantified using transferasemediated dUTP nick-end labeling.RESULTS -A higher expression of SST was detected in RPE than neuroretina in both groups. SST mRNA levels and SST-28 immunoreactivity were significantly lower in both RPE and the neuroretina from diabetic donors compared with nondiabetic donors. These results were in agreement with those obtained by measuring SST-28 in the vitreous fluid of the same donors. Increased GFAP and a higher degree of apoptosis were observed in diabetic retinas compared with nondiabetic retinas. These changes were most evident in patients with the higher deficit of SST.CONCLUSIONS -Underproduction of SST is an early event in the eyes of diabetic patients and is associated with glial activation and neural death. In addition, our results suggest that RPE is an important source of SST in the human eye. The possible role of the lower production of SST in the pathogenesis of diabetic retinopathy requires further investigation. Diabetes Care 30:2902-2908, 2007D iabetic retinopathy is the most common complication of diabetes and remains the leading cause of new blindness among working-age individuals in developed countries (1). Although diabetic retinopathy has been traditionally viewed as a disorder of retinal vasculature, retinal neurodegeneration may be a primary pathology that gives rise to microvascular changes (2,3). The degenerative changes in the neuroretina include increased apoptosis, glial cell reactivity, microglial activation, and altered glutamate metabolism. When occurring together, these changes may explain some of the functional deficits in vision appearing in diabetes before the onset of vascular abnormalities. In fact, abnormal electroretinograms have been found in patients with type 1 diabetes previous to the development of clinically detectable vascular retinal pathology (4), as well as in rats at short time intervals after the onset of experimental diabetes (5).Somatostatin (SST) is a widely distributed peptide, and its diverse biological functions include neurotransmission and antisecretory and antiproliferative activities (6). SST and its receptors are found in the neuroretina of various species, including humans, and growing evidence suggests that in the retina, SST acts both as a neuromodulator and antiangiogenic factor (7). SST production in the human retina ha...

Interphotoreceptor retinoid-binding protein (IRBP) is downregulated at early stages of diabetic retinopathy

“…However, before any microcirculatory abnormalities can be detected, retinal neurodegeneration is already present [1][2][3][4]. In fact, we have detected apoptosis and glial activation, two characteristic features of retinal neurodegeneration, in retinas from diabetic donors, which were free of microcirculatory abnormalities in ophthalmoscopic examinations performed in the 2 years preceding death [5,6]. Therefore, the study of the mechanisms that lead to neurodegeneration and of their effects on essential proteins involved in the visual cycle could be crucial for identifying new therapeutic targets in the early stages of diabetic retinopathy.…”

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

“…In fact, neural apoptosis and reactive gliosis, the hallmarks of retinal neurodegeneration, have already been observed in diabetic donors without microcirculatory abnormalities [7,8]. There are several possible approaches to treating neurodegeneration (i.e.…”

Vitreous levels of somatostatin in patients with chronic uveitic macular oedema

“…In a previous study, we found that patients with diabetic macular oedema and no significant ischaemia on angiography had lower vitreous SST-28 levels than controls, and that this deficit may be attributable to decreased production by neuroretina and RPE cells due to degeneration. 5,6 Chronic inflammation can cause retinal degeneration. Cytokines with pivotal roles in inflammatory processes such as tumour necrosis factor-a and interferon-g induce apoptosis in RPE cells.…”

“…7 In addition, we showed that retinal neurodegeneration, which occurs before vascular alterations develop, could be responsible for the decreased SST production in diabetic patients. 5 The aim of the present study was to determine the vitreous levels of SST in patients with chronic uveitic macular oedema (CUMO) and quiescent intraocular inflammation to evaluate whether there is a relationship between SST deficit and the development of this complication. As SST-28 is the main molecular variant in the vitreous fluid 8 it was selected as the best candidate to examine for this purpose.…”

“…3 SST and its receptors are expressed in the uvea, retinal pigment epithelium (RPE) and neuroretina, and the receptors are expressed in the vascular endothelium. [4][5][6] A role for SST in the maintenance of blood-retinal barrier integrity has been suggested based on its positive effect on apical-to-basal fluid transport across RPE cells. 4 In a previous study, we found lower vitreous levels and lower intraocular production of SST in patients with diabetic macular oedema, suggesting that SST deficit may contribute to oedema formation.…”