A Role for von Hippel-Lindau Protein in Pancreatic β-Cell Function

Puri, Sapna; Cano, David A.; Hebrok, Matthias

doi:10.2337/db08-0749

Cited by 86 publications

(97 citation statements)

References 49 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…45,46 Indeed, previous studies have shown that hypoxia impairs insulin secretion. 52,53 Thus, these studies along with our findings and others, 27,41,42 which all show impaired b-cell function with VHL loss, are in contrast to the results by Gunton et al, 12 which suggests that a reduction in HIF expression in the islets contributes to the b-cell dysfunction in type 2 diabetes. 12 In the same study, it was reported that knockdown of HIF-1a in Min6 cells leads to impaired glucose-stimulated insulin secretion.…”

Section: Discussioncontrasting

confidence: 55%

“…This is in keeping with other studies, which all show a defect in b-cell function as a result of VHL loss. 27,41,42 Importantly, however, these studies did not show a defect in b-cell mass. In contrast to these studies, we are the first to show that VHL has a critical role in b-cell growth that occurs with aging.…”

Section: Discussionmentioning

confidence: 73%

“…The mutant mice had decreased GLUT2 expression in their b-cells, which is in keeping with previously published studies. 27,41 Decreased expression of GLUT2 has been reported in several animal models of diabetes. 48,49 In addition, mice with GLUT2-deficient b-cells also have impaired insulin secretion, leading to diabetes development.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

Choi

Cai

Schroer

et al. 2011

Laboratory Investigation

View full text Add to dashboard Cite

Type 2 diabetes is hallmarked by insulin resistance and insufficient b-cell function. Islets of type 2 diabetes patients have been shown to have decreased hypoxia-inducible factor (HIF)-1a/b 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 b-cells would increase b-cell mass and function. We generated b-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 b-cell function. VHL deletion in the pancreatic b-cells led to impaired glucose tolerance due to defects in glucose-stimulated insulin secretion and b-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 b-cell defects that occurred with VHL loss. We observed improved glucose tolerance and restoration of GLUT2 expression in VHL-deficient b-cells in response to rHuEPO. Contrary to our hypothesis, loss of VHL and increased transcription of HIF-target genes resulted in impaired b-cell function and mass, which can be overcome with exogenous EPO. Our results indicate a critical role for VHL in b-cell function and mass, and that EPO administration improved b-cell function making it a potential strategy for diabetes treatment. KEYWORDS: angiogenesis; b-cell; diabetes mellitus; GLUT2; hypoxia-inducible factor; insulin secretion; von Hippel-Lindau Type 2 diabetes is a disease that is now considered epidemic, as it affects over 200 million people globally, and its prevalence continues to rise despite advances in treatment. 1,2 The two hallmark characteristics of type 2 diabetes are insulin resistance and b-cell dysfunction. 3,4 Under insulin-resistant conditions, b-cells undergo a compensation process by expanding b-cell mass and enhancing b-cell function. When b-cell compensation can adequately meet the insulin demands of the body, normoglycemia is maintained. 5-7 However, in susceptible individuals perhaps with genetic defects and/or environmental insults, the b-cells cannot meet the metabolic demands, ultimately resulting in type 2 diabetes. [8][9][10][11] A previous study by Gunton et al 12 reported results of gene expression profiling analyses on islets of humans with type 2 diabetes, and found a significant decrease in aryl-hydrocarbon-receptor nuclear translocator (ARNT)/hypoxiainducible factor-1b (HIF-1b) expression in these islets. 12 Concomitant with the decrease in ARNT expre...

show abstract

Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 73%

See 1 more Smart Citation

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

Choi

Cai

Schroer

et al. 2011

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…Conversely, increasing HIF-1α using iron chelation with DFO or DFS caused significant changes in gene expression, which differed from severe hypoxia or VHL deletion (46)(47)(48). DFS significantly improved glucose tolerance in mice receiving a highfat diet (HFD) but had no effect in β-Hif1a-null mice, demonstrating that β cell HIF-1α was required for its effect.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-inducible factor-1α regulates β cell function in mouse and human islets

et al. 2010

View full text Add to dashboard Cite

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1α protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1α is required for normal β cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D). Here we show that HIF-1α protein is present at low levels in mouse and human normoxic β cells and islets. Decreased levels of HIF-1α impaired glucosestimulated ATP generation and β cell function. C57BL/6 mice with β cell-specific Hif1a disruption (referred to herein as β-Hif1a-null mice) exhibited glucose intolerance, β cell dysfunction, and developed severe glucose intolerance on a high-fat diet. Increasing HIF-1α levels by inhibiting its degradation through iron chelation markedly improved insulin secretion and glucose tolerance in control mice fed a high-fat diet but not in β-Hif1a-null mice. Increasing HIF-1α levels markedly increased expression of ARNT and other genes in human T2D islets and improved their function. Further analysis indicated that HIF-1α was bound to the Arnt promoter in a mouse β cell line, suggesting direct regulation. Taken together, these findings suggest an important role for HIF-1α in β cell reserve and regulation of ARNT expression and demonstrate that HIF-1α is a potential therapeutic target for the β cell dysfunction of T2D. IntroductionThe transcription factor HIF-1α is important for a range of functions, including cellular responses to hypoxia and other stressors, angiogenesis, and fetal development (1-6). It has strong antiapoptotic effects (7-11) and is implicated in the pathogenesis of cardiovascular diseases and some cancers (12)(13)(14)(15)(16)(17)(18)(19)(20).HIF-1α is a member of the bHLH-PAS family (reviewed in refs. 2, 18, 21) and functions as an obligate dimer with other family members, including aryl hydrocarbon receptor (AhR) nuclear translocator (ARNT). We previously reported that ARNT was decreased in islets isolated from patients with type 2 diabetes (T2D) and that decreasing ARNT in Min6 cells or disrupting it in mouse β cells caused changes in gene expression and glucose-stimulated insulin secretion (GSIS) similar to those seen in islets isolated from humans with T2D (22). Recently, we reported a loss of ARNT expression in the livers of people with T2D, affecting dysregulation of gluconeogenesis (23). Though the specific ARNT partner which is important for its actions in β cells (or liver) is not known, candidates include AhR, HIF-1α, HIF-2α, HIF-3α, and circadian rhythm molecules, e.g., BMAL.

show abstract

“…Interestingly, however, we and others have reported that constitutive activation of HIF-1a, via deletion of VHL in b cells, also results in impaired glucose sensing and glucose stimulated insulin secretion. [13][14][15][16] While VHL signaling is complex and could have numerous effects in the b cell, these studies collectively suggest that both loss and constitutive activation of the HIF pathway leads to b cell dysfunction, however the specific role of HIF-2a, also known as endothelial PAS domain protein 1 (EPAS1), in regulating b cell function and glucose homeostasis is unknown.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis

Brunt

Shi

Schroer

et al. 2014

Islets

View full text Add to dashboard Cite

Keywords: Hypoxia inducible factor b cell glucose homeostasis diabetes mellitus pancreas Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; EPAS1, endothelial PAS domain protein 1; GLUT1 glucose transporter 1; GTT, glucose tolerance test; HFD, high fat diet; HIF, hypoxia inducible factor; HIF-1a, hypoxia inducible factor-1 a; HIF-1b, hypoxia inducible factor-1 b; HIF-2a, hypoxia inducible factor-2 a; i.p., intraperitoneal; ITT, insulin tolerance test; OE, overexpression; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau; WT, wild-type.Both type 1 and type 2 diabetes are associated with insufficient functional b-cell mass. Understanding intracellular signaling pathways associated with this decline is important in broadening our understanding of the disease and potential therapeutic strategies. The hypoxia inducible factor pathway (HIF) plays a critical role in cellular adaptation to hypoxic conditions. Activation of this pathway increases expression of numerous genes involved in multiple cellular processes and has been shown to impact the regulation of b-cell function. Previously, deletion of HIF-1a or HIF-1b in pancreatic b-cells, as well as constitutive activation of the HIF pathway in b-cells, was shown to result in glucose intolerance and impaired insulin secretion. The objective of this study was to delineate roles of HIF-2a overexpression in pancreatic b-cells in vivo. We overexpressed HIF-2a in pancreatic b-cells by employing the Cre-loxP system driven by the Pdx1 promoter to delete a stop codon. Our study revealed that pancreatic HIF-2a overexpression does not result in significant differences in glucose tolerance, insulin sensitivity or b-cell area compared to wild-type littermates under basal conditions or after high fat diet. Together, our study shows excess HIF-2a in the pancreatic b-cells does not play a significant role in b-cell function and glucose homeostasis.

show abstract

A Role for von Hippel-Lindau Protein in Pancreatic β-Cell Function

Cited by 86 publications

References 49 publications

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

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

Hypoxia-inducible factor-1α regulates β cell function in mouse and human islets

Overexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis

Contact Info

Product

Resources

About