| First Author | Choi D | Year | 2011 |
| Journal | Lab Invest | Volume | 91 |
| Issue | 4 | Pages | 527-38 |
| PubMed ID | 21242957 | Mgi Jnum | J:170625 |
| Mgi Id | MGI:4946990 | Doi | 10.1038/labinvest.2010.207 |
| Citation | Choi D, et al. (2011) Vhl is required for normal pancreatic beta cell function and the maintenance of beta cell mass with age in mice. Lab Invest 91(4):527-38 |
| abstractText | Type 2 diabetes is hallmarked by insulin resistance and insufficient beta-cell function. Islets of type 2 diabetes patients have been shown to have decreased hypoxia-inducible factor (HIF)-1alpha/beta 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 beta-cells would increase beta-cell mass and function. We generated beta-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 beta-cell function. VHL deletion in the pancreatic beta-cells led to impaired glucose tolerance due to defects in glucose-stimulated insulin secretion and beta-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 beta-cell defects that occurred with VHL loss. We observed improved glucose tolerance and restoration of GLUT2 expression in VHL-deficient beta-cells in response to rHuEPO. Contrary to our hypothesis, loss of VHL and increased transcription of HIF-target genes resulted in impaired beta-cell function and mass, which can be overcome with exogenous EPO. Our results indicate a critical role for VHL in beta-cell function and mass, and that EPO administration improved beta-cell function making it a potential strategy for diabetes treatment. |
