GLP-1 modulates insulin-induced relaxation response through β-arrestin2 regulation in diabetic mice aortas
© 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd..
AIMS: Diabetes impairs insulin-induced endothelium-dependent relaxation by reducing nitric oxide (NO) production. GLP-1, an incretin hormone, has been shown to prevent the development of endothelial dysfunction. In this study, we hypothesized that GLP-1 would improve the impaired insulin-induced relaxation response in diabetic mice. We also examined the underlying mechanisms.
METHODS: Using aortic rings from ob/ob mice, an animal model of obesity and type 2 diabetes, and from lean mice, vascular relaxation responses and protein expressions were evaluated using insulin, GLP-1, and pathway-specific inhibitors to elucidate the mechanisms of response. In parallel experiments, β-arrestin2 siRNA-transfected aortas were treated with GLP-1 to evaluate its effects on aortic response pathways.
RESULTS: When compared to that of untreated ob/ob aortas, GLP-1 increased insulin-induced vasorelaxation and NO production. AMPK inhibition did not alter this vasorelaxation in both GLP-1-treated lean and ob/ob aortas, while Akt inhibition reduced vasorelaxation in both groups, and co-treatment with GLP-1 and insulin caused Akt/eNOS activation. Additionally, GLP-1 decreased GRK2 activity and enhanced β-arrestin2 translocation from the cytosol to membrane in ob/ob aortas. β-Arrestin2 siRNA decreased insulin-induced relaxation both in lean aortas and GLP-1-treated ob/ob aortas.
CONCLUSIONS: We demonstrated that insulin-induced relaxation is dependent on β-arrestin2 translocation and Akt activation via GLP-1-stimulated GRK2 inactivation in ob/ob aortas. We showed a novel cross-talk between GLP-1-responsive β-arrestin2 and insulin signalling in diabetic aortas.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:231 |
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| Enthalten in: |
Acta physiologica (Oxford, England) - 231(2021), 3 vom: 08. März, Seite e13573 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Taguchi, Kumiko [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.08.2021 Date Revised 18.08.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/apha.13573 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Taguchi, Kumiko |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a GLP-1 modulates insulin-induced relaxation response through β-arrestin2 regulation in diabetic mice aortas |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Revised 18.08.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd. | ||
| 520 | |a AIMS: Diabetes impairs insulin-induced endothelium-dependent relaxation by reducing nitric oxide (NO) production. GLP-1, an incretin hormone, has been shown to prevent the development of endothelial dysfunction. In this study, we hypothesized that GLP-1 would improve the impaired insulin-induced relaxation response in diabetic mice. We also examined the underlying mechanisms | ||
| 520 | |a METHODS: Using aortic rings from ob/ob mice, an animal model of obesity and type 2 diabetes, and from lean mice, vascular relaxation responses and protein expressions were evaluated using insulin, GLP-1, and pathway-specific inhibitors to elucidate the mechanisms of response. In parallel experiments, β-arrestin2 siRNA-transfected aortas were treated with GLP-1 to evaluate its effects on aortic response pathways | ||
| 520 | |a RESULTS: When compared to that of untreated ob/ob aortas, GLP-1 increased insulin-induced vasorelaxation and NO production. AMPK inhibition did not alter this vasorelaxation in both GLP-1-treated lean and ob/ob aortas, while Akt inhibition reduced vasorelaxation in both groups, and co-treatment with GLP-1 and insulin caused Akt/eNOS activation. Additionally, GLP-1 decreased GRK2 activity and enhanced β-arrestin2 translocation from the cytosol to membrane in ob/ob aortas. β-Arrestin2 siRNA decreased insulin-induced relaxation both in lean aortas and GLP-1-treated ob/ob aortas | ||
| 520 | |a CONCLUSIONS: We demonstrated that insulin-induced relaxation is dependent on β-arrestin2 translocation and Akt activation via GLP-1-stimulated GRK2 inactivation in ob/ob aortas. We showed a novel cross-talk between GLP-1-responsive β-arrestin2 and insulin signalling in diabetic aortas | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a GLP-1 | |
| 650 | 4 | |a Insulin | |
| 650 | 4 | |a diabetes | |
| 650 | 4 | |a endothelial dysfunction | |
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| 700 | 1 | |a Okudaira, Kanami |e verfasserin |4 aut | |
| 700 | 1 | |a Matsumoto, Takayuki |e verfasserin |4 aut | |
| 700 | 1 | |a Kobayashi, Tsuneo |e verfasserin |4 aut | |
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