期刊
DIABETES
卷 58, 期 2, 页码 433-441出版社
AMER DIABETES ASSOC
DOI: 10.2337/db08-0749
关键词
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资金
- Juvenile Diabetes Research Foundation
- Klein Family Foundation
- California Institute of Regenerative Medicine (CIRM)
- National Institutes of Health [DK60533]
- UCSF Diabetes and Endocrinology Research Center [P30 DK63720]
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 beta-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 beta-cells leads to a severe glucose-intolerant phenotype in adult animals. Although VHL is not required for beta-cell specification and development, it is critical for beta-cell function. Insulin production is normal in beta-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 beta-cells leads to defects in glucose homeostasis, indicating an important and previously unappreciated role for VHL in beta-cell function. We believe that the beta-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 beta-cell function. Diabetes 58:433-441, 2009
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