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A Central Role of RLIP76 in Regulation of Glycemic Control
OBJECTIVE: Pathology associated with oxidative stress frequently results in insulin resistance. Glutathione (GSH) and GSH-linked metabolism is a primary defense against oxidative stress. Electrophilic lipid alkenals, such as 4-hydroxy-t-2-nonenal (4HNE), generated during oxidative stress are metabol...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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American Diabetes Association
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828645/ https://www.ncbi.nlm.nih.gov/pubmed/20007934 http://dx.doi.org/10.2337/db09-0911 |
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author | Awasthi, Sanjay Singhal, Sharad S. Yadav, Sushma Singhal, Jyotsana Vatsyayan, Rit Zajac, Ewa Luchowski, Rafal Borvak, Jozef Gryczynski, Karol Awasthi, Yogesh C. |
author_facet | Awasthi, Sanjay Singhal, Sharad S. Yadav, Sushma Singhal, Jyotsana Vatsyayan, Rit Zajac, Ewa Luchowski, Rafal Borvak, Jozef Gryczynski, Karol Awasthi, Yogesh C. |
author_sort | Awasthi, Sanjay |
collection | PubMed |
description | OBJECTIVE: Pathology associated with oxidative stress frequently results in insulin resistance. Glutathione (GSH) and GSH-linked metabolism is a primary defense against oxidative stress. Electrophilic lipid alkenals, such as 4-hydroxy-t-2-nonenal (4HNE), generated during oxidative stress are metabolized primarily to glutathione electrophile (GS-E) conjugates. Recent studies show that RLIP76 is the primary GS-E conjugate transporter in cells, and a regulator of oxidative-stress response. Because RLIP76(−/−) mice are hypoglycemic, we studied the role of RLIP76 in insulin resistance. RESEARCH DESIGN AND METHODS: Blood glucose, insulin, lipid measurements, and hyperinsulinemic-euglycemic and hyperglycemic clamp experiments were performed in RLIP76(+/+) and RLIP76(−/−) C57B mice, using Institutional Animal Care and Use Committee–approved protocols. Time-resolved three-dimensional confocal fluorescence microscopy was used to study insulin endocytosis. RESULTS: The plasma insulin/glucose ratio was ordered RLIP76(−/−) < RLIP76(+/−) < RLIP76(+/+); administration of purified RLIP76 in proteoliposomes to RLIP76(+/+) animals further increased this ratio. RLIP76 was induced by oxidative or hyperglycemic stress; the concomitant increase in insulin endocytosis was completely abrogated by inhibiting the transport activity of RLIP76. Hydrocortisone could transiently correct hypoglycemia in RLIP76(−/−) animals, despite inhibited activity of key glucocorticoid-regulated hepatic gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose 1,6-bisphosphatase, in RLIP76(−/−). CONCLUSIONS: The GS-E conjugate transport activity of RLIP76 mediates insulin resistance by enhancing the rate of clathrin-dependent endocytosis of insulin. Because RLIP76 is induced by oxidative stress, it could play a role in insulin resistance seen in pathological conditions characterized by increased oxidative stress. |
format | Text |
id | pubmed-2828645 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-28286452011-03-01 A Central Role of RLIP76 in Regulation of Glycemic Control Awasthi, Sanjay Singhal, Sharad S. Yadav, Sushma Singhal, Jyotsana Vatsyayan, Rit Zajac, Ewa Luchowski, Rafal Borvak, Jozef Gryczynski, Karol Awasthi, Yogesh C. Diabetes Original Article OBJECTIVE: Pathology associated with oxidative stress frequently results in insulin resistance. Glutathione (GSH) and GSH-linked metabolism is a primary defense against oxidative stress. Electrophilic lipid alkenals, such as 4-hydroxy-t-2-nonenal (4HNE), generated during oxidative stress are metabolized primarily to glutathione electrophile (GS-E) conjugates. Recent studies show that RLIP76 is the primary GS-E conjugate transporter in cells, and a regulator of oxidative-stress response. Because RLIP76(−/−) mice are hypoglycemic, we studied the role of RLIP76 in insulin resistance. RESEARCH DESIGN AND METHODS: Blood glucose, insulin, lipid measurements, and hyperinsulinemic-euglycemic and hyperglycemic clamp experiments were performed in RLIP76(+/+) and RLIP76(−/−) C57B mice, using Institutional Animal Care and Use Committee–approved protocols. Time-resolved three-dimensional confocal fluorescence microscopy was used to study insulin endocytosis. RESULTS: The plasma insulin/glucose ratio was ordered RLIP76(−/−) < RLIP76(+/−) < RLIP76(+/+); administration of purified RLIP76 in proteoliposomes to RLIP76(+/+) animals further increased this ratio. RLIP76 was induced by oxidative or hyperglycemic stress; the concomitant increase in insulin endocytosis was completely abrogated by inhibiting the transport activity of RLIP76. Hydrocortisone could transiently correct hypoglycemia in RLIP76(−/−) animals, despite inhibited activity of key glucocorticoid-regulated hepatic gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose 1,6-bisphosphatase, in RLIP76(−/−). CONCLUSIONS: The GS-E conjugate transport activity of RLIP76 mediates insulin resistance by enhancing the rate of clathrin-dependent endocytosis of insulin. Because RLIP76 is induced by oxidative stress, it could play a role in insulin resistance seen in pathological conditions characterized by increased oxidative stress. American Diabetes Association 2010-03 2009-12-10 /pmc/articles/PMC2828645/ /pubmed/20007934 http://dx.doi.org/10.2337/db09-0911 Text en © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Original Article Awasthi, Sanjay Singhal, Sharad S. Yadav, Sushma Singhal, Jyotsana Vatsyayan, Rit Zajac, Ewa Luchowski, Rafal Borvak, Jozef Gryczynski, Karol Awasthi, Yogesh C. A Central Role of RLIP76 in Regulation of Glycemic Control |
title | A Central Role of RLIP76 in Regulation of Glycemic Control |
title_full | A Central Role of RLIP76 in Regulation of Glycemic Control |
title_fullStr | A Central Role of RLIP76 in Regulation of Glycemic Control |
title_full_unstemmed | A Central Role of RLIP76 in Regulation of Glycemic Control |
title_short | A Central Role of RLIP76 in Regulation of Glycemic Control |
title_sort | central role of rlip76 in regulation of glycemic control |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828645/ https://www.ncbi.nlm.nih.gov/pubmed/20007934 http://dx.doi.org/10.2337/db09-0911 |
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