Different effects of low- and high-dose insulin on ROS production and VEGF expression in bovine retinal microvascular endothelial cells in the presence of high glucose

Wu, Hao; Jiang, Chunhui; Gan, Dekang; Liao, Yujun; Ren, Hui; Sun, Zhenzhong; Zhang, Meng; Xu, Gezhi

doi:10.1007/s00417-011-1677-x

Cited by 18 publications

(15 citation statements)

References 33 publications

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“…In addition this finding was also similar as previous study by our group which demonstrated that diabetic BM-EPC has higher expression of fetal liver kinase-1 (Flk-1 or VEGFR2) [14]. Although the expression of VEGFR2 was significantly higher in diabetic BM-EPC, however in this study we did not rule out whether this transcript [53]. Therefore lack of insulin (as a common consequence of type-1 diabetic model due to deleterious effect of STZ on beta cell islet) may also contribute to the less expression of VEGF in diabetes.…”

Section: Accepted Manuscriptsupporting

confidence: 91%

The role of Notch signaling in diabetic endothelial progenitor cells dysfunction

Sukmawati

Tanaka

Ito‐Hirano

et al. 2016

Journal of Diabetes and its Complications

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Section: Accepted Manuscriptsupporting

confidence: 91%

The role of Notch signaling in diabetic endothelial progenitor cells dysfunction

Sukmawati

Tanaka

Ito‐Hirano

et al. 2016

Journal of Diabetes and its Complications

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“…These results support an involvement of Nox4-derived ROS in insulin-induced angiogenesis in vitro . In fact, Nox4 has been associated with angiogenesis, overexpression of Nox4 was sufficient to promote endothelial proliferation, migration, and tube formation [6]. A recent study has shown that Nox4 (−/−) mice exhibited attenuated angiogenesis, further confirming the important role of Nox4 in angiogenesis [38].…”

Section: Discussionmentioning

confidence: 93%

“…Insulin-induced VEGF expression has been reported to be mediated through the activation of PI 3-kinase/AKT and p44/42 MAPK pathways, and hypoxia-inducible factor-1α (HIF-1α) [2]. Insulin has been shown to increase intracellular reactive oxygen species (ROS) production in many cell types such as HepG2 cells [3], 3T3L1 adipocytes [4], human fibroblasts [5], and retinal microvascular endothelial cells [6]. ROS produced by insulin are involved in HIF-1α and VEGF expression [3], [7].…”

Section: Introductionmentioning

confidence: 99%

NADPH Oxidase 4 Mediates Insulin-Stimulated HIF-1α and VEGF Expression, and Angiogenesis In Vitro

et al. 2012

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Acute intensive insulin therapy causes a transient worsening of diabetic retinopathy in type 1 diabetes patients and is related to VEGF expression. Reactive oxygen species (ROS) have been shown to be involved in HIF-1α and VEGF expression induced by insulin, but the role of specific ROS sources has not been fully elucidated. In this study we examined the role of NADPH oxidase subunit 4 (Nox4) in insulin-stimulated HIF-1α and VEGF expression, and angiogenic responses in human microvascular endothelial cells (HMVECs). Here we demonstrate that knockdown of Nox4 by siRNA reduced insulin-stimulated ROS generation, the tyrosine phosphorylation of IR-β and IRS-1, but did not change the serine phosphorylation of IRS-1. Nox4 gene silencing had a much greater inhibitory effect on insulin-induced AKT activation than ERK1/2 activation, whereas it had little effect on the expression of the phosphatases such as MKP-1 and SHIP. Inhibition of Nox4 expression inhibited the transcriptional activity of VEGF through HIF-1. Overexpression of wild-type Nox4 was sufficient to increase VEGF transcriptional activity, and further enhanced insulin-stimulated the activation of VEGF. Downregulation of Nox4 expression decreased insulin-stimulated mRNA and protein expression of HIF-1α, but did not change the rate of HIF-1α degradation. Inhibition of Nox4 impaired insulin-stimulated VEGF expression, cell migration, cell proliferation, and tube formation in HMVECs. Our data indicate that Nox4-derived ROS are essential for HIF-1α-dependent VEGF expression, and angiogenesis in vitro induced by insulin. Nox4 may be an attractive therapeutic target for diabetic retinopathy caused by intensive insulin treatment.

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“…In an in vitro study, insulin was found to increase reactive oxygen species (ROS) in bovine retinal endothelial cells. This increased insulin‐induced ROS production and VEGF expression, in the presence of high glucose, may explain early worsening DR (Table ) …”

Section: Theories Concerning the Paradoxical Early Worsening Of Drmentioning

confidence: 99%

Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: A review

Bain

Klufas

et al. 2018

Diabetes Obesity Metabolism

185

101

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Worsening of diabetic retinopathy (DR) is associated with the initiation of effective treatment of glycaemia in some patients with diabetes. It has been associated with risk factors such as poor blood-glucose control and hypertension, and it manifests prior to the long-term benefits of optimizing glycaemic control. The majority of evidence supports an association of large and rapid reductions in blood-glucose levels with early worsening of DR. Despite a general awareness of early worsening within the diabetes community, mechanisms to explain the phenomenon remain speculative. We provide an overview of early worsening of DR and its pathophysiology based on current data. We describe the phenomenon in various settings, including in patients receiving insulin- or non-insulin-based treatments, in those undergoing bariatric surgery, and in pregnant women. We discuss various mechanisms and theories that have been suggested to explain this paradoxical phenomenon, and we summarize the implications of these in clinical practice.

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Different effects of low- and high-dose insulin on ROS production and VEGF expression in bovine retinal microvascular endothelial cells in the presence of high glucose

Abstract: High-dose insulin-induced ROS production and VEGF expression in BRECs in the presence of high glucose might be one of the reasons for the transient worsening of diabetic retinopathy during intensive insulin treatment.

Cited by 18 publications

References 33 publications

The role of Notch signaling in diabetic endothelial progenitor cells dysfunction

The role of Notch signaling in diabetic endothelial progenitor cells dysfunction

NADPH Oxidase 4 Mediates Insulin-Stimulated HIF-1α and VEGF Expression, and Angiogenesis In Vitro

Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: A review

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