The Effect of Hypoxia on Insulin and Glucagon Secretion in the Perfused Pancreas of the Rat

Narimiya, Manabu; Yamada, Hideaki; Matsuba, Ikuro; Ikeda, Yoshio; Tanese, Tomio; Abé, Masakazu

doi:10.1210/endo-111-3-1010

Cited by 21 publications

(15 citation statements)

References 15 publications

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“…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: 70%

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

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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...

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Section: Discussioncontrasting

confidence: 70%

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

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“…Previous work has demonstrated that hypoxia impairs insulin secretion (32)(33)(34). VHL inactivation, via HIF-1␣ stabilization, mimics certain aspects of the cellular response to hypoxia, and canonical target genes of the HIF complex, including Vegf and Glut1, are significantly upregulated in VHL-depleted islets.…”

Section: Discussionmentioning

confidence: 99%

“…in 29). Defects in ATP production have been linked to impairment of insulin secretion in response to glucose (27,33,35). Furthermore, mitochondrial mutations that result in decreased ATP production have been linked to diabetes in humans (36 -38).…”

Section: Discussionmentioning

confidence: 99%

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

2009

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OBJECTIVE-TheVhlh 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 useCre-lox recombination to eliminate Vhlh in adult mouse pancreatic ␤-cells. Morphology of mutant islets is assessed by immunofluorescence analysis. To determine the functional state of Vhlh Ϫ/Ϫ 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 ␤-cells leads to a severe glucoseintolerant phenotype in adult animals. Although VHL is not required for ␤-cell specification and development, it is critical for ␤-cell function. Insulin production is normal in ␤-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-Weshow that loss of VHL in ␤-cells leads to defects in glucose homeostasis, indicating an important and previously unappreciated role for VHL in ␤-cell function. We believe that the ␤-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 ␤-cell function. Diabetes 58:433-441, 2009 O xygen homeostasis is essential to cellular function, and low O 2 pressure (hypoxia) has a profound impact on cell metabolism and physiological processes. The von Hippel-Lindau tumor suppressor protein (VHL) is a key player in the cellular response to oxygen sensing. Hypoxia inducible factors (HIFs) are global regulators of oxygen homeostasis, allowing cellular adaptation to oxygen deprivation by transcriptionally modulating genes involved in cellular energy metabolism, angiogenesis, apoptosis, and proliferation, among other biological processes (rev. in 1-5).

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“…For example, oxygen‐deprived chondrocytes have been found to produce increased quantities of collagen type I, which leads to suboptimal cartilage properties (Lewis et al ., ; Murphy and Polak, ). Insulin secretion by pancreatic islet cells has been found to decrease as local oxygen content decreases (Narimiya et al ., ). Although cells generally reduce their metabolism in response to low oxygen (thus reducing oxygen requirements) by partially converting from aerobic to anaerobic metabolism (Koh et al ., ), this switch increases glucose requirements for energy and increases lactic acid production, which in turn decreases local pH and may cause tissue necrosis (Brown et al ., ).…”

Section: Hypoxia and Tissue Engineeringmentioning

confidence: 97%

Overcoming hypoxia to improve tissue-engineering approaches to regenerative medicine

Bland

Dréau

Burg

2012

J Tissue Eng Regen Med

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The current clinical successes of tissue engineering are limited primarily to low-metabolism, acellular, pre-vascularized or thin tissues. Mass transport has been identified as the primary culprit, limiting the delivery of nutrients (such as oxygen and glucose) and removal of wastes, from tissues deep within a cellular scaffold. While strategies to develop sufficient vasculature to overcome hypoxia in vitro are promising, inconsistencies between the in vitro and the in vivo environments may still negate the effectiveness of large-volume tissue-engineered scaffolds. While a common theme in tissue engineering is to maximize oxygen supply, studies suggest that moderate oxygenation of cellular scaffolds during in vitro conditioning is preferable to high oxygen levels. Aiming for moderate oxygen values to prevent hypoxia while still promoting angiogenesis may be obtained by tailoring in vitro culture conditions to the oxygen environment the scaffold will experience upon implantation. This review discusses the causes and effects of tissue-engineering hypoxia and the optimization of oxygenation for the minimization of in vivo hypoxia.

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The Effect of Hypoxia on Insulin and Glucagon Secretion in the Perfused Pancreas of the Rat

Cited by 21 publications

References 15 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

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

Overcoming hypoxia to improve tissue-engineering approaches to regenerative medicine

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