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Exendin-4 Suppresses Src Activation and Reactive Oxygen Species Production in Diabetic Goto-Kakizaki Rat Islets in an Epac-Dependent Manner
OBJECTIVE: Reactive oxygen species (ROS) is one of most important factors in impaired metabolism secretion coupling in pancreatic β-cells. We recently reported that elevated ROS production and impaired ATP production at high glucose in diabetic Goto-Kakizaki (GK) rat islets are effectively ameliorat...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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American Diabetes Association
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012174/ https://www.ncbi.nlm.nih.gov/pubmed/20978090 http://dx.doi.org/10.2337/db10-0021 |
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author | Mukai, Eri Fujimoto, Shimpei Sato, Hiroki Oneyama, Chitose Kominato, Rieko Sato, Yuichi Sasaki, Mayumi Nishi, Yuichi Okada, Masato Inagaki, Nobuya |
author_facet | Mukai, Eri Fujimoto, Shimpei Sato, Hiroki Oneyama, Chitose Kominato, Rieko Sato, Yuichi Sasaki, Mayumi Nishi, Yuichi Okada, Masato Inagaki, Nobuya |
author_sort | Mukai, Eri |
collection | PubMed |
description | OBJECTIVE: Reactive oxygen species (ROS) is one of most important factors in impaired metabolism secretion coupling in pancreatic β-cells. We recently reported that elevated ROS production and impaired ATP production at high glucose in diabetic Goto-Kakizaki (GK) rat islets are effectively ameliorated by Src inhibition, suggesting that Src activity is upregulated. In the present study, we investigated whether the glucagon-like peptide-1 signal regulates Src activity and ameliorates endogenous ROS production and ATP production in GK islets using exendin-4. RESEARCH DESIGN AND METHODS: Isolated islets from GK and control Wistar rats were used for immunoblotting analyses and measurements of ROS production and ATP content. Src activity was examined by immunoprecipitation of islet lysates followed by immunoblotting. ROS production was measured with a fluorescent probe using dispersed islet cells. RESULTS: Exendin-4 significantly decreased phosphorylation of Src Tyr416, which indicates Src activation, in GK islets under 16.7 mmol/l glucose exposure. Glucose-induced ROS production (16.7 mmol/l) in GK islet cells was significantly decreased by coexposure of exendin-4 as well as PP2, a Src inhibitor. The Src kinase–negative mutant expression in GK islets significantly decreased ROS production induced by high glucose. Exendin-4, as well as PP2, significantly increased impaired ATP elevation by high glucose in GK islets. The decrease in ROS production by exendin-4 was not affected by H-89, a PKA inhibitor, and an Epac-specific cAMP analog (8CPT-2Me-cAMP) significantly decreased Src Tyr416 phosphorylation and ROS production. CONCLUSIONS: Exendin-4 decreases endogenous ROS production and increases ATP production in diabetic GK rat islets through suppression of Src activation, dependently on Epac. |
format | Text |
id | pubmed-3012174 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-30121742012-01-01 Exendin-4 Suppresses Src Activation and Reactive Oxygen Species Production in Diabetic Goto-Kakizaki Rat Islets in an Epac-Dependent Manner Mukai, Eri Fujimoto, Shimpei Sato, Hiroki Oneyama, Chitose Kominato, Rieko Sato, Yuichi Sasaki, Mayumi Nishi, Yuichi Okada, Masato Inagaki, Nobuya Diabetes Islet Studies OBJECTIVE: Reactive oxygen species (ROS) is one of most important factors in impaired metabolism secretion coupling in pancreatic β-cells. We recently reported that elevated ROS production and impaired ATP production at high glucose in diabetic Goto-Kakizaki (GK) rat islets are effectively ameliorated by Src inhibition, suggesting that Src activity is upregulated. In the present study, we investigated whether the glucagon-like peptide-1 signal regulates Src activity and ameliorates endogenous ROS production and ATP production in GK islets using exendin-4. RESEARCH DESIGN AND METHODS: Isolated islets from GK and control Wistar rats were used for immunoblotting analyses and measurements of ROS production and ATP content. Src activity was examined by immunoprecipitation of islet lysates followed by immunoblotting. ROS production was measured with a fluorescent probe using dispersed islet cells. RESULTS: Exendin-4 significantly decreased phosphorylation of Src Tyr416, which indicates Src activation, in GK islets under 16.7 mmol/l glucose exposure. Glucose-induced ROS production (16.7 mmol/l) in GK islet cells was significantly decreased by coexposure of exendin-4 as well as PP2, a Src inhibitor. The Src kinase–negative mutant expression in GK islets significantly decreased ROS production induced by high glucose. Exendin-4, as well as PP2, significantly increased impaired ATP elevation by high glucose in GK islets. The decrease in ROS production by exendin-4 was not affected by H-89, a PKA inhibitor, and an Epac-specific cAMP analog (8CPT-2Me-cAMP) significantly decreased Src Tyr416 phosphorylation and ROS production. CONCLUSIONS: Exendin-4 decreases endogenous ROS production and increases ATP production in diabetic GK rat islets through suppression of Src activation, dependently on Epac. American Diabetes Association 2011-01 2010-10-26 /pmc/articles/PMC3012174/ /pubmed/20978090 http://dx.doi.org/10.2337/db10-0021 Text en © 2011 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 | Islet Studies Mukai, Eri Fujimoto, Shimpei Sato, Hiroki Oneyama, Chitose Kominato, Rieko Sato, Yuichi Sasaki, Mayumi Nishi, Yuichi Okada, Masato Inagaki, Nobuya Exendin-4 Suppresses Src Activation and Reactive Oxygen Species Production in Diabetic Goto-Kakizaki Rat Islets in an Epac-Dependent Manner |
title | Exendin-4 Suppresses Src Activation and Reactive Oxygen Species Production in Diabetic Goto-Kakizaki Rat Islets in an Epac-Dependent Manner |
title_full | Exendin-4 Suppresses Src Activation and Reactive Oxygen Species Production in Diabetic Goto-Kakizaki Rat Islets in an Epac-Dependent Manner |
title_fullStr | Exendin-4 Suppresses Src Activation and Reactive Oxygen Species Production in Diabetic Goto-Kakizaki Rat Islets in an Epac-Dependent Manner |
title_full_unstemmed | Exendin-4 Suppresses Src Activation and Reactive Oxygen Species Production in Diabetic Goto-Kakizaki Rat Islets in an Epac-Dependent Manner |
title_short | Exendin-4 Suppresses Src Activation and Reactive Oxygen Species Production in Diabetic Goto-Kakizaki Rat Islets in an Epac-Dependent Manner |
title_sort | exendin-4 suppresses src activation and reactive oxygen species production in diabetic goto-kakizaki rat islets in an epac-dependent manner |
topic | Islet Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012174/ https://www.ncbi.nlm.nih.gov/pubmed/20978090 http://dx.doi.org/10.2337/db10-0021 |
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