Intravitreal injection of IGFBP-3 restores normal insulin signaling in diabetic rat retina.
Diabetes-induced changes in growth factor binding protein 3 (IGFBP-3) and tumor necrosis factor alpha (TNFα) have been linked to decreased insulin receptor signaling in diabetic retinopathy. Our previous studies in retinas of diabetic rats have shown that Compound 49b, a novel β-adrenergic receptor...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3973588?pdf=render |
| _version_ | 1811342176956710912 |
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| author | Youde Jiang Qiuhua Zhang Jena J Steinle |
| author_facet | Youde Jiang Qiuhua Zhang Jena J Steinle |
| author_sort | Youde Jiang |
| collection | DOAJ |
| description | Diabetes-induced changes in growth factor binding protein 3 (IGFBP-3) and tumor necrosis factor alpha (TNFα) have been linked to decreased insulin receptor signaling in diabetic retinopathy. Our previous studies in retinas of diabetic rats have shown that Compound 49b, a novel β-adrenergic receptor agonist, prevented diabetic changes by increasing IGFBP-3 and decreasing TNFα, thus restoring insulin signaling and protection against diabetic retinopathy. The current study was designed to determine whether boosted expression of IGFBP-3 NB (a non-IGF-1 binding form of IGFBP-3) alone is sufficient to mimic the full actions of Compound 49b in protecting against diabetic retinopathy, as well as testing whether IGFBP-3 NB is linked to a restoration of normal insulin signal transduction. Two months after initiation of streptozotocin-induced diabetes, rats received a single intravitreal injection of IGFBP-3 NB plasmid in the right eye. Four days after injection, electroretinogram (ERG) analyses were performed prior to sacrifice. Whole retinal lysates from control, diabetic, diabetic + control plasmid, and diabetic+ IGFBP-3 NB were analyzed for IGFBP-3, TNFα, suppressor of cytokine signaling 3 (SOCS3), and insulin receptor signaling partners using Western blotting or ELISA. Data show that a single intraocular injection of IGFBP-3 NB in diabetic animals significantly reduced TNFα levels, concomitant with reductions in IRS-1Ser307, SOCS3, and pro-apoptotic markers, while restoring insulin receptor phosphorylation and increasing anti-apoptotic marker levels. These cellular changes were linked to restoration of retinal function. Our findings establish IGFBP-3 as a pivotal regulator of the insulin receptor/TNFα pathway and a potential therapeutic target for diabetic retinopathy. |
| first_indexed | 2024-04-13T19:06:53Z |
| format | Article |
| id | doaj.art-5197956379744219b6a6d1ca12c4ee11 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T19:06:53Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-5197956379744219b6a6d1ca12c4ee112022-12-22T02:33:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0194e9378810.1371/journal.pone.0093788Intravitreal injection of IGFBP-3 restores normal insulin signaling in diabetic rat retina.Youde JiangQiuhua ZhangJena J SteinleDiabetes-induced changes in growth factor binding protein 3 (IGFBP-3) and tumor necrosis factor alpha (TNFα) have been linked to decreased insulin receptor signaling in diabetic retinopathy. Our previous studies in retinas of diabetic rats have shown that Compound 49b, a novel β-adrenergic receptor agonist, prevented diabetic changes by increasing IGFBP-3 and decreasing TNFα, thus restoring insulin signaling and protection against diabetic retinopathy. The current study was designed to determine whether boosted expression of IGFBP-3 NB (a non-IGF-1 binding form of IGFBP-3) alone is sufficient to mimic the full actions of Compound 49b in protecting against diabetic retinopathy, as well as testing whether IGFBP-3 NB is linked to a restoration of normal insulin signal transduction. Two months after initiation of streptozotocin-induced diabetes, rats received a single intravitreal injection of IGFBP-3 NB plasmid in the right eye. Four days after injection, electroretinogram (ERG) analyses were performed prior to sacrifice. Whole retinal lysates from control, diabetic, diabetic + control plasmid, and diabetic+ IGFBP-3 NB were analyzed for IGFBP-3, TNFα, suppressor of cytokine signaling 3 (SOCS3), and insulin receptor signaling partners using Western blotting or ELISA. Data show that a single intraocular injection of IGFBP-3 NB in diabetic animals significantly reduced TNFα levels, concomitant with reductions in IRS-1Ser307, SOCS3, and pro-apoptotic markers, while restoring insulin receptor phosphorylation and increasing anti-apoptotic marker levels. These cellular changes were linked to restoration of retinal function. Our findings establish IGFBP-3 as a pivotal regulator of the insulin receptor/TNFα pathway and a potential therapeutic target for diabetic retinopathy.http://europepmc.org/articles/PMC3973588?pdf=render |
| spellingShingle | Youde Jiang Qiuhua Zhang Jena J Steinle Intravitreal injection of IGFBP-3 restores normal insulin signaling in diabetic rat retina. PLoS ONE |
| title | Intravitreal injection of IGFBP-3 restores normal insulin signaling in diabetic rat retina. |
| title_full | Intravitreal injection of IGFBP-3 restores normal insulin signaling in diabetic rat retina. |
| title_fullStr | Intravitreal injection of IGFBP-3 restores normal insulin signaling in diabetic rat retina. |
| title_full_unstemmed | Intravitreal injection of IGFBP-3 restores normal insulin signaling in diabetic rat retina. |
| title_short | Intravitreal injection of IGFBP-3 restores normal insulin signaling in diabetic rat retina. |
| title_sort | intravitreal injection of igfbp 3 restores normal insulin signaling in diabetic rat retina |
| url | http://europepmc.org/articles/PMC3973588?pdf=render |
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