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A Role for von Hippel-Lindau Protein in Pancreatic β-Cell Function
OBJECTIVE—The Vhlh gene codes for the von Hippel-Lindau protein (VHL), a tumor suppressor that is a key player in the cellular response to oxygen sensing. In humans, a germline mutation in the VHL gene leads to the von Hippel-Lindau disease, a familial syndrome characterized by benign and malignant...
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Formato: | Texto |
Lenguaje: | English |
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American Diabetes Association
2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628617/ https://www.ncbi.nlm.nih.gov/pubmed/19033400 http://dx.doi.org/10.2337/db08-0749 |
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author | Puri, Sapna Cano, David A. Hebrok, Matthias |
author_facet | Puri, Sapna Cano, David A. Hebrok, Matthias |
author_sort | Puri, Sapna |
collection | PubMed |
description | OBJECTIVE—The Vhlh gene codes for the von Hippel-Lindau protein (VHL), a tumor suppressor that is a key player in the cellular response to oxygen sensing. In humans, a germline mutation in the VHL gene leads to the von Hippel-Lindau disease, a familial syndrome characterized by benign and malignant tumors of the kidney, central nervous system, and pancreas. RESEARCH DESIGN AND METHODS—We use Cre-lox recombination to eliminate Vhlh in adult mouse pancreatic β-cells. Morphology of mutant islets is assessed by immunofluorescence analysis. To determine the functional state of Vhlh(−/−) islets, insulin secretion is measured in vivo and in vitro, and quantitative PCR is used to identify changes in gene expression. RESULTS—Loss of VHL in β-cells leads to a severe glucose-intolerant phenotype in adult animals. Although VHL is not required for β-cell specification and development, it is critical for β-cell function. Insulin production is normal in β-cells lacking VHL; however, insulin secretion in the presence of high concentrations of glucose is impaired. Furthermore, the loss of VHL leads to dysregulation of glycolytic enzymes, pointing to a perturbation of the intracellular energy homeostasis. CONCLUSIONS—We show that loss of VHL in β-cells leads to defects in glucose homeostasis, indicating an important and previously unappreciated role for VHL in β-cell function. We believe that the β-cell–specific Vhlh-deficient mice might be a useful tool as a “genetic hypoxia” model, to unravel the possible link between hypoxia signaling and impairment of β-cell function. |
format | Text |
id | pubmed-2628617 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-26286172010-02-01 A Role for von Hippel-Lindau Protein in Pancreatic β-Cell Function Puri, Sapna Cano, David A. Hebrok, Matthias Diabetes Islet Studies OBJECTIVE—The Vhlh gene codes for the von Hippel-Lindau protein (VHL), a tumor suppressor that is a key player in the cellular response to oxygen sensing. In humans, a germline mutation in the VHL gene leads to the von Hippel-Lindau disease, a familial syndrome characterized by benign and malignant tumors of the kidney, central nervous system, and pancreas. RESEARCH DESIGN AND METHODS—We use Cre-lox recombination to eliminate Vhlh in adult mouse pancreatic β-cells. Morphology of mutant islets is assessed by immunofluorescence analysis. To determine the functional state of Vhlh(−/−) islets, insulin secretion is measured in vivo and in vitro, and quantitative PCR is used to identify changes in gene expression. RESULTS—Loss of VHL in β-cells leads to a severe glucose-intolerant phenotype in adult animals. Although VHL is not required for β-cell specification and development, it is critical for β-cell function. Insulin production is normal in β-cells lacking VHL; however, insulin secretion in the presence of high concentrations of glucose is impaired. Furthermore, the loss of VHL leads to dysregulation of glycolytic enzymes, pointing to a perturbation of the intracellular energy homeostasis. CONCLUSIONS—We show that loss of VHL in β-cells leads to defects in glucose homeostasis, indicating an important and previously unappreciated role for VHL in β-cell function. We believe that the β-cell–specific Vhlh-deficient mice might be a useful tool as a “genetic hypoxia” model, to unravel the possible link between hypoxia signaling and impairment of β-cell function. American Diabetes Association 2009-02 /pmc/articles/PMC2628617/ /pubmed/19033400 http://dx.doi.org/10.2337/db08-0749 Text en Copyright © 2009, 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 Puri, Sapna Cano, David A. Hebrok, Matthias A Role for von Hippel-Lindau Protein in Pancreatic β-Cell Function |
title | A Role for von Hippel-Lindau Protein in Pancreatic β-Cell Function |
title_full | A Role for von Hippel-Lindau Protein in Pancreatic β-Cell Function |
title_fullStr | A Role for von Hippel-Lindau Protein in Pancreatic β-Cell Function |
title_full_unstemmed | A Role for von Hippel-Lindau Protein in Pancreatic β-Cell Function |
title_short | A Role for von Hippel-Lindau Protein in Pancreatic β-Cell Function |
title_sort | role for von hippel-lindau protein in pancreatic β-cell function |
topic | Islet Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628617/ https://www.ncbi.nlm.nih.gov/pubmed/19033400 http://dx.doi.org/10.2337/db08-0749 |
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