Vhl is required for normal pancreatic β cell function and the maintenance of β cell mass with age in mice

• Published in: Laboratory investigation 2011-04, Vol.91 (4), p.527-538
• Main Authors: Choi, Diana, Cai, Erica P, Schroer, Stephanie A, Wang, Linyuan, Woo, Minna
• Format: Article
• Language: English
• Subjects: 631/443/7; 631/67/581; 692/699/2743/137/773; Aging; angiogenesis; Animals; Biological and medical sciences; Biotechnology; diabetes mellitus; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Erythropoietin - pharmacology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Glucose - metabolism; Glucose Intolerance; Glucose Transporter Type 1 - metabolism; Glucose Transporter Type 2 - metabolism; GLUT2; Homeostasis; Humans; hypoxia-inducible factor; Hypoxia-Inducible Factor 1 - pharmacology; Insulin - genetics; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Neovascularization, Pathologic - etiology; Pathology; Promoter Regions, Genetic; Rats; Recombinant Proteins; research-article; Vascular Endothelial Growth Factor A - metabolism; von Hippel-Lindau; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; β-cell
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2010.207

Type 2 diabetes is hallmarked by insulin resistance and insufficient β-cell function. Islets of type 2 diabetes patients have been shown to have decreased hypoxia-inducible factor (HIF)-1α/β expression. Target genes of the HIF pathway are involved in angiogenesis, survival, proliferation, and energy metabolism, and von Hippel-Lindau protein (VHL) is a negative regulator of this pathway. We hypothesized that increased HIF-mediated gene transcription by VHL deletion in the β-cells would increase β-cell mass and function. We generated β-cell-specific VHL-knockout mice using the Cre-loxP recombination system driven by the rat insulin promoter to assess the role of VHL in glucose homeostasis and β-cell function. VHL deletion in the pancreatic β-cells led to impaired glucose tolerance due to defects in glucose-stimulated insulin secretion and β-cell mass with age. VHL-knockout islets had decreased GLUT2, but increased glucose transporter 1 and vascular endothelial growth factor expression. Furthermore, there were significant aberrations in islet morphology in the VHL-knockout mice, likely due to increased islet vasculature. Given that erythropoietin (EPO) is a target gene of the HIF pathway, which is not expressed in islets, we tested whether activating EPO signaling by systemic administration with recombinant human EPO (rHuEPO) can overcome the β-cell defects that occurred with VHL loss. We observed improved glucose tolerance and restoration of GLUT2 expression in VHL-deficient β-cells in response to rHuEPO. Contrary to our hypothesis, loss of VHL and increased transcription of HIF-target genes resulted in impaired β-cell function and mass, which can be overcome with exogenous EPO. Our results indicate a critical role for VHL in β-cell function and mass, and that EPO administration improved β-cell function making it a potential strategy for diabetes treatment.