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BH3-Only Molecule Bim Mediates β-Cell Death in IRS2 Deficiency
Irs2-deficient mice develop type 2–like diabetes due to a reduction in β-cell mass and a failure of pancreatic islets to undergo compensatory hyperplasia in response to insulin resistance. In order to define the molecular mechanisms, we knocked down Irs2 gene expression in mouse MIN6 insulinoma cell...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171655/ https://www.ncbi.nlm.nih.gov/pubmed/24760140 http://dx.doi.org/10.2337/db13-1814 |
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author | Ren, Decheng Sun, Juan Mao, Liqun Ye, Honggang Polonsky, Kenneth S. |
author_facet | Ren, Decheng Sun, Juan Mao, Liqun Ye, Honggang Polonsky, Kenneth S. |
author_sort | Ren, Decheng |
collection | PubMed |
description | Irs2-deficient mice develop type 2–like diabetes due to a reduction in β-cell mass and a failure of pancreatic islets to undergo compensatory hyperplasia in response to insulin resistance. In order to define the molecular mechanisms, we knocked down Irs2 gene expression in mouse MIN6 insulinoma cells. Insulin receptor substrate 2 (IRS2) suppression induced apoptotic cell death, which was associated with an increase in expression of the BH3-only molecule Bim. Knockdown (KD) of Bim reduced apoptotic β-cell death induced by IRS2 suppression. In Irs2-deficient mice, Bim ablation restored β-cell mass, decreased the number of TUNEL-positive cells, and restored normal glucose tolerance after glucose challenge. FoxO1 mediates Bim upregulation induced by IRS2 suppression, and FoxO1 KD partially inhibits β-cell death induced by IRS2 suppression. These results suggest that Bim plays an important role in mediating the increase in β-cell apoptosis and the reduction in β-cell mass that occurs in IRS2-deficient diabetes. |
format | Online Article Text |
id | pubmed-4171655 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-41716552015-10-01 BH3-Only Molecule Bim Mediates β-Cell Death in IRS2 Deficiency Ren, Decheng Sun, Juan Mao, Liqun Ye, Honggang Polonsky, Kenneth S. Diabetes Islet Studies Irs2-deficient mice develop type 2–like diabetes due to a reduction in β-cell mass and a failure of pancreatic islets to undergo compensatory hyperplasia in response to insulin resistance. In order to define the molecular mechanisms, we knocked down Irs2 gene expression in mouse MIN6 insulinoma cells. Insulin receptor substrate 2 (IRS2) suppression induced apoptotic cell death, which was associated with an increase in expression of the BH3-only molecule Bim. Knockdown (KD) of Bim reduced apoptotic β-cell death induced by IRS2 suppression. In Irs2-deficient mice, Bim ablation restored β-cell mass, decreased the number of TUNEL-positive cells, and restored normal glucose tolerance after glucose challenge. FoxO1 mediates Bim upregulation induced by IRS2 suppression, and FoxO1 KD partially inhibits β-cell death induced by IRS2 suppression. These results suggest that Bim plays an important role in mediating the increase in β-cell apoptosis and the reduction in β-cell mass that occurs in IRS2-deficient diabetes. American Diabetes Association 2014-10 2014-09-15 /pmc/articles/PMC4171655/ /pubmed/24760140 http://dx.doi.org/10.2337/db13-1814 Text en © 2014 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. |
spellingShingle | Islet Studies Ren, Decheng Sun, Juan Mao, Liqun Ye, Honggang Polonsky, Kenneth S. BH3-Only Molecule Bim Mediates β-Cell Death in IRS2 Deficiency |
title | BH3-Only Molecule Bim Mediates β-Cell Death in IRS2 Deficiency |
title_full | BH3-Only Molecule Bim Mediates β-Cell Death in IRS2 Deficiency |
title_fullStr | BH3-Only Molecule Bim Mediates β-Cell Death in IRS2 Deficiency |
title_full_unstemmed | BH3-Only Molecule Bim Mediates β-Cell Death in IRS2 Deficiency |
title_short | BH3-Only Molecule Bim Mediates β-Cell Death in IRS2 Deficiency |
title_sort | bh3-only molecule bim mediates β-cell death in irs2 deficiency |
topic | Islet Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171655/ https://www.ncbi.nlm.nih.gov/pubmed/24760140 http://dx.doi.org/10.2337/db13-1814 |
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