Vitreous levels of the insulin-like growth factors I and II, and the insulin-like growth factor binding proteins 2 and 3, increase in neovascular eye disease. Studies in nondiabetic and diabetic subjects.

Meyer-Schwickerath, R; Pfeiffer, Andreas F. H.; Blum, Werner; Freyberger, H; Klein, M.; Lösche, C; Röllmann, R; Schatz, H.

doi:10.1172/jci116877

Cited by 202 publications

(140 citation statements)

References 22 publications

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“…43 Vitreous IGF-I levels are increased in diabetic retinopathy. 26 In agreement, we now demonstrate that inhibition of IGF-I signaling down-regulates Akt activity and ICAM-1 expression, as well as the transcriptional activity of NF-B, AP-1, and HIF-1␣ in our in vivo diabetic model.…”

Section: Discussionsupporting

confidence: 88%

“…21,[23][24][25] Yet, aside from hypoxia, additional factors may also regulate VEGF expression in vivo. Insulin-like growth factor (IGF)-I is one such candidate: vitreous IGF-I levels correlate with the presence and severity of ischemia-associated diabetic retinal neovascularization; 26 intravitreal IGF-I injection dose-dependently causes retinal neovascularization and microangiopathy; 27 whereas reduction of serum IGF-I levels inhibits retinal neovascularization in an ischemic murine model. 28 Pituitary ablation acutely improved visual acuity and suppressed proliferative diabetic retinopathy in some diabetic retinopathy patients, raising the hypothesis that decreases in growth hormone and IGF-I underlie this phenomenon.…”

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confidence: 99%

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Insulin-Like Growth Factor-I Plays a Pathogenetic Role in Diabetic Retinopathy

Poulaki

Joussen

Mitsiades

et al. 2004

The American Journal of Pathology

137

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Although the molecular pathophysiology of diabetic retinopathy, the current leading cause of blindness in Western societies, 1 is not fully elucidated, studies have documented a pivotal role for leukocyte adherence within the retinal vasculature. The adhesion of leukocytes to the retinal endothelium is a process that depends on ␤ 2 integrin-intercellular adhesion molecule (ICAM)-1 interactions and leads to breakdown of the blood-retinal barrier. 2 These data, in combination with our previous findings that aggressive anti-inflammatory therapy suppressed leukocyte adhesion and blood retinal breakdown in a relevant animal model, 3 support the hypothesis that a chronic subclinical inflammation may underlie much of the vascular pathology of diabetic retinopathy. 4 These vascular pathological findings are orchestrated by vascular endothelial growth factor (VEGF), a factor that potently promotes the growth and maintenance of endothelial cells and the formation of new vessels, and is implicated in both background and proliferative diabetic retinopathy. 5-11 Intraocular VEGF levels are increased in diabetic patients with blood-retinal barrier breakdown and neovascularization, 5,10,12,13 whereas the specific inhibition of VEGF prevents these complications in animal models. 7,11,14 Therefore, regulation of VEGF expression could conceivably be both a mediator for converging local and systemic stimuli modulating vessel pathophysiology, as well as a target for therapeutic intervention. Within a constellation of known modulators of VEGF expression that can possibly function at the transcriptional [through AP-1, AP-2, steroid hormone receptors, p53, and nuclear factor (NF-B)] or posttranscriptional level, [15][16][17][18] hypoxia is the most potent inducer of VEGF transcription in vivo; its effects are mainly mediated by the helix-loop helix (bHLH)-PAS transcription factor HIF-1␣, which heterodimerizes with the bHLH-PAS protein ARNT or HIF-1␤, 19 -22 and binds to consensus and ancillary hypoxia-response elements (HREs) in the VEGF promoter. 21,[23][24][25]

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Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

Insulin-Like Growth Factor-I Plays a Pathogenetic Role in Diabetic Retinopathy

Poulaki

Joussen

Mitsiades

et al. 2004

The American Journal of Pathology

137

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“…Recent studies suggest that interactions between IGF-I and its receptors enhance the angiogenic effects of VEGF [45]. These findings are consistent with the documented association between IGF-I and diabetic retinopathy [46] and suggest that both IGF-I and VEGF may contribute to the pathogenesis of vision-threatening retinal disease in diabetes. Thus, although a reduction in VEGF expression with ACE inhibitor treatment was noted in our study it is also possible that other intra-ocular growth factors such as IGF-I were also affected by modulation of the RAS as in the kidney [47].…”

Section: Discussionsupporting

confidence: 77%

Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes

et al. 2000

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Despite laser photocoagulation therapy, diabetic retinopathy remains a common cause of visual impairment and blindness [1], principally as a consequence of proliferative retinopathy and macular oedema. Although the pathogenesis of these retinal disorders characterized by retinal neovascularization and exudation is incompletely understood, recent evidence has implicated the vascular endothelial growth factor (VEGF), a permeability-inducing and endothelial cell selective angiogenic glycoprotein as a key factor [2±4].Although plasma renin is suppressed in diabetes, experimental evidence suggests that the tissue reninangiotensin system (RAS) is activated in the setting of chronic hyperglycaemia [5] and that its blockade underlies the beneficial effects of angiotensin converting enzyme (ACE) inhibition in diabetic nephropathy [6] and cardiovascular disease [7]. Previous

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“…With regard to the IGF system, in vivo studies show conflicting results: IGF-I concentrations in the vitreous of diabetic patients correlated positively with its serum concentrations (Grant et al 1986), whereas a weak increase in serum IGF-I was observed in patients with proliferative diabetic retinopathy (Bach & Rechler 1992), suggesting that locally high concentrations of IGF-I may be more important than systemic concentrations. In addition, IGFBPs were increased in the vitreous of neovascularised diabetic eyes (Meyer Schwickerath et al 1993). In vitro studies, indeed, have shown the IGF system to have a role in retinal endothelial cell proliferation.…”

Section: Introductionmentioning

confidence: 95%

IGFBPs modulate IGF-I- and high glucose-controlled growth of human retinal endothelial cells

Giannini¹,

Cresci²,

Pala³

et al. 2001

Journal of Endocrinology

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Insulin-like growth factor binding proteins (IGFBPs) are important local factors in the development of proliferative diabetic retinopathy. We investigated the effects of IGF-I and increased glucose concentrations on the release of IGFBPs and the growth of human retinal endothelial cells (HRECs). HRECs secrete IGFBPs-2 to -5. IGF-I stimulated thymidine incorporation and modified the pattern of IGFBPs, decreasing the inhibitory IGFBP-4 through down-regulation of its mRNA, and increasing IGFBP-5 which, per se, was able to modulate HREC growth, exerting post-transcriptional control. Studies using an antibody ( IR3) against the IGF-I receptor, and compounds with low affinity for IGFBPs, such as insulin and des(1-3)IGF-I, showed that an interaction between IGF-I and IGFBP-5 was necessary to detach this IGFBP from its binding sites. The dose of IGF-I that significantly decreased the IGFBP-4/IGFBP-5 ratio was the same that stimulated HREC growth. Chronic exposure to high concentrations of glucose was able to reduce HREC mitogenesis, interacting with the IGF system through a decrease in the stimulatory IGFBPs-2, -3 and -5, leaving the concentration of the inhibitory IGFBP-4 constant. These results extend our previous observations in endothelial cells and suggest that the IGFBP-4/IGFBP-5 ratio regulates IGF-I-induced growth of HRECs, whereas a general decrease in IGFBPs (except for IGFBP-4) was the anti-proliferative effect of chronic exposure to high glucose concentrations.

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Vitreous levels of the insulin-like growth factors I and II, and the insulin-like growth factor binding proteins 2 and 3, increase in neovascular eye disease. Studies in nondiabetic and diabetic subjects.

Cited by 202 publications

References 22 publications

Insulin-Like Growth Factor-I Plays a Pathogenetic Role in Diabetic Retinopathy

Insulin-Like Growth Factor-I Plays a Pathogenetic Role in Diabetic Retinopathy

Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes

IGFBPs modulate IGF-I- and high glucose-controlled growth of human retinal endothelial cells

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