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Glucose-Dependent Insulinotropic Polypeptide Prevents the Progression of Macrophage-Driven Atherosclerosis in Diabetic Apolipoprotein E-Null Mice
AIM: We recently reported that glucose-dependent insulinotropic polypeptide (GIP) prevents the development of atherosclerosis in apolipoprotein E-null (Apoe (−/−)) mice. GIP receptors (GIPRs) are found to be severely down-regulated in diabetic animals. We examined whether GIP can exert anti-atheroge...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335006/ https://www.ncbi.nlm.nih.gov/pubmed/22536426 http://dx.doi.org/10.1371/journal.pone.0035683 |
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author | Nogi, Yukinori Nagashima, Masaharu Terasaki, Michishige Nohtomi, Kyoko Watanabe, Takuya Hirano, Tsutomu |
author_facet | Nogi, Yukinori Nagashima, Masaharu Terasaki, Michishige Nohtomi, Kyoko Watanabe, Takuya Hirano, Tsutomu |
author_sort | Nogi, Yukinori |
collection | PubMed |
description | AIM: We recently reported that glucose-dependent insulinotropic polypeptide (GIP) prevents the development of atherosclerosis in apolipoprotein E-null (Apoe (−/−)) mice. GIP receptors (GIPRs) are found to be severely down-regulated in diabetic animals. We examined whether GIP can exert anti-atherogenic effects in diabetes. METHODS: Nondiabetic Apoe (−/−) mice, streptozotocin-induced diabetic Apoe (−/−) mice, and db/db mice were administered GIP (25 nmol/kg/day) or saline (vehicle) through osmotic mini-pumps for 4 weeks. The animals were assessed for aortic atherosclerosis and for oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages. RESULTS: Diabetic Apoe (−/−) mice of 21 weeks of age exhibited more advanced atherosclerosis than nondiabetic Apoe (−/−) mice of the same age. GIP infusion in diabetic Apoe (−/−) mice increased plasma total GIP levels by 4-fold without improving plasma insulin, glucose, or lipid profiles. GIP infusion significantly suppressed macrophage-driven atherosclerotic lesions, but this effect was abolished by co-infusions with [Pro(3)]GIP, a GIPR antagonist. Foam cell formation was stimulated by 3-fold in diabetic Apoe (−/−) mice compared with their nondiabetic counterparts, but this effect was halved by GIP infusion. GIP infusion also attenuated the foam cell formation in db/db mice. In vitro treatment with GIP (1 nM) reduced foam cell formation by 15% in macrophages from diabetic Apoe (−/−) mice, and this attenuating effect was weaker than that attained by the same treatment of macrophages from nondiabetic counterparts (35%). While GIPR expression was reduced by only about a half in macrophages from diabetic mice, it was reduced much more dramatically in pancreatic islets from the same animals. Incubation with high glucose (500 mg/dl) for 9–10 days markedly reduced GIPR expression in pancreatic islet cells, but not in macrophages. CONCLUSIONS: Long-term infusion of GIP conferred significant anti-atherogenic effects in diabetic mice even though the GIPR expression in macrophages was mildly down-regulated in the diabetic state. |
format | Online Article Text |
id | pubmed-3335006 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33350062012-04-25 Glucose-Dependent Insulinotropic Polypeptide Prevents the Progression of Macrophage-Driven Atherosclerosis in Diabetic Apolipoprotein E-Null Mice Nogi, Yukinori Nagashima, Masaharu Terasaki, Michishige Nohtomi, Kyoko Watanabe, Takuya Hirano, Tsutomu PLoS One Research Article AIM: We recently reported that glucose-dependent insulinotropic polypeptide (GIP) prevents the development of atherosclerosis in apolipoprotein E-null (Apoe (−/−)) mice. GIP receptors (GIPRs) are found to be severely down-regulated in diabetic animals. We examined whether GIP can exert anti-atherogenic effects in diabetes. METHODS: Nondiabetic Apoe (−/−) mice, streptozotocin-induced diabetic Apoe (−/−) mice, and db/db mice were administered GIP (25 nmol/kg/day) or saline (vehicle) through osmotic mini-pumps for 4 weeks. The animals were assessed for aortic atherosclerosis and for oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages. RESULTS: Diabetic Apoe (−/−) mice of 21 weeks of age exhibited more advanced atherosclerosis than nondiabetic Apoe (−/−) mice of the same age. GIP infusion in diabetic Apoe (−/−) mice increased plasma total GIP levels by 4-fold without improving plasma insulin, glucose, or lipid profiles. GIP infusion significantly suppressed macrophage-driven atherosclerotic lesions, but this effect was abolished by co-infusions with [Pro(3)]GIP, a GIPR antagonist. Foam cell formation was stimulated by 3-fold in diabetic Apoe (−/−) mice compared with their nondiabetic counterparts, but this effect was halved by GIP infusion. GIP infusion also attenuated the foam cell formation in db/db mice. In vitro treatment with GIP (1 nM) reduced foam cell formation by 15% in macrophages from diabetic Apoe (−/−) mice, and this attenuating effect was weaker than that attained by the same treatment of macrophages from nondiabetic counterparts (35%). While GIPR expression was reduced by only about a half in macrophages from diabetic mice, it was reduced much more dramatically in pancreatic islets from the same animals. Incubation with high glucose (500 mg/dl) for 9–10 days markedly reduced GIPR expression in pancreatic islet cells, but not in macrophages. CONCLUSIONS: Long-term infusion of GIP conferred significant anti-atherogenic effects in diabetic mice even though the GIPR expression in macrophages was mildly down-regulated in the diabetic state. Public Library of Science 2012-04-20 /pmc/articles/PMC3335006/ /pubmed/22536426 http://dx.doi.org/10.1371/journal.pone.0035683 Text en Nogi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Nogi, Yukinori Nagashima, Masaharu Terasaki, Michishige Nohtomi, Kyoko Watanabe, Takuya Hirano, Tsutomu Glucose-Dependent Insulinotropic Polypeptide Prevents the Progression of Macrophage-Driven Atherosclerosis in Diabetic Apolipoprotein E-Null Mice |
title | Glucose-Dependent Insulinotropic Polypeptide Prevents the Progression of Macrophage-Driven Atherosclerosis in Diabetic Apolipoprotein E-Null Mice |
title_full | Glucose-Dependent Insulinotropic Polypeptide Prevents the Progression of Macrophage-Driven Atherosclerosis in Diabetic Apolipoprotein E-Null Mice |
title_fullStr | Glucose-Dependent Insulinotropic Polypeptide Prevents the Progression of Macrophage-Driven Atherosclerosis in Diabetic Apolipoprotein E-Null Mice |
title_full_unstemmed | Glucose-Dependent Insulinotropic Polypeptide Prevents the Progression of Macrophage-Driven Atherosclerosis in Diabetic Apolipoprotein E-Null Mice |
title_short | Glucose-Dependent Insulinotropic Polypeptide Prevents the Progression of Macrophage-Driven Atherosclerosis in Diabetic Apolipoprotein E-Null Mice |
title_sort | glucose-dependent insulinotropic polypeptide prevents the progression of macrophage-driven atherosclerosis in diabetic apolipoprotein e-null mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335006/ https://www.ncbi.nlm.nih.gov/pubmed/22536426 http://dx.doi.org/10.1371/journal.pone.0035683 |
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