Vhl is required for normal pancreatic β cell function and the maintenance of β cell mass with age in mice.
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.
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Diana
D
Choi
Erica P
EP
Cai
Stephanie A
SA
Schroer
Linyuan
L
Wang
Minna
M
Woo
D000375:Aging; D000818:Animals; D004921:Erythropoietin / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000494:pharmacology; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000209:etiology; D011401:Promoter Regions, Genetic; D051381:Rats; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D051793:Hypoxia-Inducible Factor 1; D007328:Insulin; D011994:Recombinant Proteins; C495682:Slc2a2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse; D005947:Glucose