Differential roles of hyperglycemia and hypoinsulinemia in diabetes induced retinal cell death: evidence for retinal insulin resistance
Diabetes pathology derives from the combination of hyperglycemia and hypoinsulinemia or insulin resistance leading to diabetic complications including diabetic neuropathy, nephropathy and retinopathy. Diabetic retinopathy is characterized by numerous retinal defects affecting the vasculature and the...
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description | Diabetes pathology derives from the combination of hyperglycemia and hypoinsulinemia or insulin resistance leading to diabetic complications including diabetic neuropathy, nephropathy and retinopathy. Diabetic retinopathy is characterized by numerous retinal defects affecting the vasculature and the neuro-retina, but the relative contributions of the loss of retinal insulin signaling and hyperglycemia have never been directly compared. In this study we tested the hypothesis that increased retinal insulin signaling and glycemic normalization would exert differential effects on retinal cell survival and retinal physiology during diabetes. We have demonstrated in this study that both subconjunctival insulin administration and systemic glycemic reduction using the sodium-glucose linked transporter inhibitor phloridzin affected the regulation of retinal cell survival in diabetic rats. Both treatments partially restored the retinal insulin signaling without increasing plasma insulin levels. Retinal transcriptomic and histological analysis also clearly demonstrated that local administration of insulin and systemic glycemia normalization use different pathways to counteract the effects of diabetes on the retina. While local insulin primarily affected inflammation-associated pathways, systemic glycemic control affected pathways involved in the regulation of cell signaling and metabolism. These results suggest that hyperglycemia induces resistance to growth factor action in the retina and clearly demonstrate that both restoration of glycemic control and retinal insulin signaling can act through different pathways to both normalize diabetes-induced retinal abnormality and prevent vision loss. |
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Y.</contributor><creatorcontrib>Fort, Patrice E ; Losiewicz, Mandy K ; Reiter, Chad E N ; Singh, Ravi S J ; Nakamura, Makoto ; Abcouwer, Steven F ; Barber, Alistair J ; Gardner, Thomas W ; Lo, Amy C. Y.</creatorcontrib><description>Diabetes pathology derives from the combination of hyperglycemia and hypoinsulinemia or insulin resistance leading to diabetic complications including diabetic neuropathy, nephropathy and retinopathy. Diabetic retinopathy is characterized by numerous retinal defects affecting the vasculature and the neuro-retina, but the relative contributions of the loss of retinal insulin signaling and hyperglycemia have never been directly compared. In this study we tested the hypothesis that increased retinal insulin signaling and glycemic normalization would exert differential effects on retinal cell survival and retinal physiology during diabetes. We have demonstrated in this study that both subconjunctival insulin administration and systemic glycemic reduction using the sodium-glucose linked transporter inhibitor phloridzin affected the regulation of retinal cell survival in diabetic rats. Both treatments partially restored the retinal insulin signaling without increasing plasma insulin levels. Retinal transcriptomic and histological analysis also clearly demonstrated that local administration of insulin and systemic glycemia normalization use different pathways to counteract the effects of diabetes on the retina. While local insulin primarily affected inflammation-associated pathways, systemic glycemic control affected pathways involved in the regulation of cell signaling and metabolism. These results suggest that hyperglycemia induces resistance to growth factor action in the retina and clearly demonstrate that both restoration of glycemic control and retinal insulin signaling can act through different pathways to both normalize diabetes-induced retinal abnormality and prevent vision loss.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0026498</identifier><identifier>PMID: 22046295</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Animals ; Apoptosis ; Biochemistry ; Biology ; Blood glucose ; Cell Death ; Cell survival ; Complications ; Complications and side effects ; Control ; Diabetes mellitus ; Diabetes Mellitus - physiopathology ; Diabetic neuropathies ; Diabetic neuropathy ; Diabetic retinopathy ; Diabetic Retinopathy - pathology ; Glucose ; Glucose transporter ; Hyperglycemia ; Hyperglycemia - physiopathology ; Insulin ; Insulin - metabolism ; Insulin - pharmacology ; Insulin Resistance ; Kinases ; Medicine ; Metabolism ; Nephropathy ; Neuropathy ; Phlorhizin - pharmacology ; Rats ; Resistance factors ; Restoration ; Retina ; Retina - pathology ; Retinopathy ; Rodents ; Signal Transduction ; Signaling ; Sodium ; Survival</subject><ispartof>PloS one, 2011-10, Vol.6 (10), p.e26498-e26498</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-22aecf7d6c58757f40eb018180d59d3e40bffd52095ebe9181e099ca0bdcfa423</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202547/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202547/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22046295$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Lo, Amy C. Y.</contributor><creatorcontrib>Fort, Patrice E</creatorcontrib><creatorcontrib>Losiewicz, Mandy K</creatorcontrib><creatorcontrib>Reiter, Chad E N</creatorcontrib><creatorcontrib>Singh, Ravi S J</creatorcontrib><creatorcontrib>Nakamura, Makoto</creatorcontrib><creatorcontrib>Abcouwer, Steven F</creatorcontrib><creatorcontrib>Barber, Alistair J</creatorcontrib><creatorcontrib>Gardner, Thomas W</creatorcontrib><title>Differential roles of hyperglycemia and hypoinsulinemia in diabetes induced retinal cell death: evidence for retinal insulin resistance</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Diabetes pathology derives from the combination of hyperglycemia and hypoinsulinemia or insulin resistance leading to diabetic complications including diabetic neuropathy, nephropathy and retinopathy. Diabetic retinopathy is characterized by numerous retinal defects affecting the vasculature and the neuro-retina, but the relative contributions of the loss of retinal insulin signaling and hyperglycemia have never been directly compared. In this study we tested the hypothesis that increased retinal insulin signaling and glycemic normalization would exert differential effects on retinal cell survival and retinal physiology during diabetes. We have demonstrated in this study that both subconjunctival insulin administration and systemic glycemic reduction using the sodium-glucose linked transporter inhibitor phloridzin affected the regulation of retinal cell survival in diabetic rats. Both treatments partially restored the retinal insulin signaling without increasing plasma insulin levels. Retinal transcriptomic and histological analysis also clearly demonstrated that local administration of insulin and systemic glycemia normalization use different pathways to counteract the effects of diabetes on the retina. While local insulin primarily affected inflammation-associated pathways, systemic glycemic control affected pathways involved in the regulation of cell signaling and metabolism. These results suggest that hyperglycemia induces resistance to growth factor action in the retina and clearly demonstrate that both restoration of glycemic control and retinal insulin signaling can act through different pathways to both normalize diabetes-induced retinal abnormality and prevent vision loss.</description><subject>Analysis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Blood glucose</subject><subject>Cell Death</subject><subject>Cell survival</subject><subject>Complications</subject><subject>Complications and side effects</subject><subject>Control</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus - physiopathology</subject><subject>Diabetic neuropathies</subject><subject>Diabetic neuropathy</subject><subject>Diabetic retinopathy</subject><subject>Diabetic Retinopathy - pathology</subject><subject>Glucose</subject><subject>Glucose transporter</subject><subject>Hyperglycemia</subject><subject>Hyperglycemia - 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physiopathology</topic><topic>Diabetic neuropathies</topic><topic>Diabetic neuropathy</topic><topic>Diabetic retinopathy</topic><topic>Diabetic Retinopathy - pathology</topic><topic>Glucose</topic><topic>Glucose transporter</topic><topic>Hyperglycemia</topic><topic>Hyperglycemia - physiopathology</topic><topic>Insulin</topic><topic>Insulin - metabolism</topic><topic>Insulin - pharmacology</topic><topic>Insulin Resistance</topic><topic>Kinases</topic><topic>Medicine</topic><topic>Metabolism</topic><topic>Nephropathy</topic><topic>Neuropathy</topic><topic>Phlorhizin - pharmacology</topic><topic>Rats</topic><topic>Resistance factors</topic><topic>Restoration</topic><topic>Retina</topic><topic>Retina - pathology</topic><topic>Retinopathy</topic><topic>Rodents</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Sodium</topic><topic>Survival</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fort, Patrice E</creatorcontrib><creatorcontrib>Losiewicz, Mandy K</creatorcontrib><creatorcontrib>Reiter, Chad E N</creatorcontrib><creatorcontrib>Singh, Ravi S J</creatorcontrib><creatorcontrib>Nakamura, Makoto</creatorcontrib><creatorcontrib>Abcouwer, Steven F</creatorcontrib><creatorcontrib>Barber, Alistair J</creatorcontrib><creatorcontrib>Gardner, Thomas W</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Y.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Differential roles of hyperglycemia and hypoinsulinemia in diabetes induced retinal cell death: evidence for retinal insulin resistance</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-10-26</date><risdate>2011</risdate><volume>6</volume><issue>10</issue><spage>e26498</spage><epage>e26498</epage><pages>e26498-e26498</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Diabetes pathology derives from the combination of hyperglycemia and hypoinsulinemia or insulin resistance leading to diabetic complications including diabetic neuropathy, nephropathy and retinopathy. Diabetic retinopathy is characterized by numerous retinal defects affecting the vasculature and the neuro-retina, but the relative contributions of the loss of retinal insulin signaling and hyperglycemia have never been directly compared. In this study we tested the hypothesis that increased retinal insulin signaling and glycemic normalization would exert differential effects on retinal cell survival and retinal physiology during diabetes. We have demonstrated in this study that both subconjunctival insulin administration and systemic glycemic reduction using the sodium-glucose linked transporter inhibitor phloridzin affected the regulation of retinal cell survival in diabetic rats. Both treatments partially restored the retinal insulin signaling without increasing plasma insulin levels. Retinal transcriptomic and histological analysis also clearly demonstrated that local administration of insulin and systemic glycemia normalization use different pathways to counteract the effects of diabetes on the retina. While local insulin primarily affected inflammation-associated pathways, systemic glycemic control affected pathways involved in the regulation of cell signaling and metabolism. These results suggest that hyperglycemia induces resistance to growth factor action in the retina and clearly demonstrate that both restoration of glycemic control and retinal insulin signaling can act through different pathways to both normalize diabetes-induced retinal abnormality and prevent vision loss.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22046295</pmid><doi>10.1371/journal.pone.0026498</doi><tpages>e26498</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Analysis Animals Apoptosis Biochemistry Biology Blood glucose Cell Death Cell survival Complications Complications and side effects Control Diabetes mellitus Diabetes Mellitus - physiopathology Diabetic neuropathies Diabetic neuropathy Diabetic retinopathy Diabetic Retinopathy - pathology Glucose Glucose transporter Hyperglycemia Hyperglycemia - physiopathology Insulin Insulin - metabolism Insulin - pharmacology Insulin Resistance Kinases Medicine Metabolism Nephropathy Neuropathy Phlorhizin - pharmacology Rats Resistance factors Restoration Retina Retina - pathology Retinopathy Rodents Signal Transduction Signaling Sodium Survival |
title | Differential roles of hyperglycemia and hypoinsulinemia in diabetes induced retinal cell death: evidence for retinal insulin resistance |
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