Islet Microvasculature in Islet Hyperplasia and Failure in a Model of Type 2 Diabetes

Li, Xianquan; Zhang, Lanjing; Meshinchi, Sasha; Dias-Leme, Claudia L.; Raffin, Diane; Johnson, Jeffery D.; Treutelaar, Mary K.; Burant, Charles F.

doi:10.2337/db06-0733

Cited by 134 publications

(152 citation statements)

References 57 publications

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“…Initially, the adaptive response of ␤ cells to insulin resistance involves both changes in mass and function that act to maintain normal glucose tolerance. In prediabetic ZDF rats, ␤-cell mass expansion is associated with the activation of certain hypoxia-inducible target genes (Li et al 2006). We also found that in ob/ob mice, which develop islet hyperplasia as a result of an adaptive response to spontaneous obesity due to leptin deficiency, certain HIF-target genes including Slc2a1, Pdk1, and Hif1␣ itself are activated (J. Zehetner and W. Krek, unpubl.).…”

Section: Pvhl-hif Regulates Insulin Secretion Genes and Development 3141mentioning

confidence: 78%

“…In this regard, gene expression analysis of prediabetic and diabetic Zucker diabetic fatty (ZDF) rats, which carry a mutation in the leptin receptor gene and serve as a model for ␤-cell mass adaptation and decompensation during progression of type 2 diabetes, revealed that certain hypoxia-inducible target genes become activated at the prediabetic stage, coinciding with adaptive ␤-cell mass expansion (Li et al 2006). The hypoxia-inducible genes that are activated include those whose products influence glycolysis, such as lactate dehydrogenase A (LDHA) that catalyzes the conversion of pyruvate to lactate, as well as angiogenesis, such as vascular endothelial growth factor (VEGF) that is known to be critical for ␤-cell function (Lammert et al 2003).…”

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confidence: 99%

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pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

Zehetner¹,

Danzer²,

Collins³

et al. 2008

Genes Dev.

108

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Insulin secretion from pancreatic ␤ cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1␣, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL-HIF1␣ pathway in the control of ␤-cell glucose utilization, insulin secretion, and glucose homeostasis. Conditional inactivation of Vhlh in ␤ cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca 2+ concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance. Importantly, combined deletion of Vhlh and Hif1␣ rescued these phenotypes, implying that they are the result of HIF1␣ activation. Together, these results identify pVHL and HIF1␣ as key regulators of insulin secretion from pancreatic ␤ cells. They further suggest that changes in the metabolic strategy of glucose metabolism in ␤ cells have profound effects on whole-body glucose homeostasis.[Keywords: HIF; VHL; glucose intolerance; islet; pancreas] Supplemental material is available at http://www.genesdev.org. Received July 14, 2008; revised version accepted September 5, 2008. During adulthood, cell type-specific growth that exceeds the normal physiological constraints is a common feature of adaptive processes of tissues to changes in metabolic homeostasis and underlies the development of many human diseases, including cancer, heart disease, and diabetes (De Boer et al. 2003;Bouwens and Rooman 2005). Adaptive cell mass expansion, whether neoplastic or nonneoplastic, creates a requirement for compensatory neovascularization to supply oxygen, metabolic substances, and growth/survival factors to the growing tissue (Marti 2005). Therefore, adaptive cell growth responses are generally accompanied, at least initially, by relative states of hypoxia as a result of a mismatch between oxygen demand caused by tissue expansion and oxygen supply provided by the vasculature. An immediate consequence of decreased tissue oxygen availability is that cells shift cellular fuel metabolism from mitochondrial respiration to glycolysis and activate an angiogenic program to increase oxygen delivery in order to overcome the imbalance between tissue mass and vascularization (Semenza 2001;Brahimi-Horn et al. 2007). In this way, tissue function is supported and further mass expansion can occur.At the molecular level, the central regulators of the cellular response to low-oxygen availability are the hypoxia-inducible transcription factors (HIF). HIF are heterodimeric transcription factors composed of HIF1␣, HIF2␣, or HI...

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Section: Pvhl-hif Regulates Insulin Secretion Genes and Development 3141mentioning

confidence: 78%

mentioning

confidence: 99%

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

Zehetner¹,

Danzer²,

Collins³

et al. 2008

Genes Dev.

108

View full text Add to dashboard Cite

show abstract

“…48,49 In addition, mice with GLUT2-deficient b-cells also have impaired insulin secretion, leading to diabetes development. 50 Therefore, defective glucose-sensing likely has a significant role in the impairment of b-cell function that is present in the VHL mutant mice. In addition to the changes observed within the VHL-deficient b-cells, there were significant alterations in islet architecture caused by increased vasculature likely due to Vegf upregulation, which may have influenced b-cell function.…”

Section: Discussionmentioning

confidence: 99%

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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“…Glucose stimulation of beta cell oxygen consumption generates intracellular hypoxia leading to activation of hypoxia-inducible factors (HIFs) and upregulation of HIF-target genes in rodent and human islets (reviewed in [1]). The presence of hypoxia in vivo in the islets of animal models of type 2 diabetes [3][4][5][6][7][8] supports a role for hypoxic stress in beta cell apoptosis. Moreover, severe hypoxia in islet grafts contributes to beta cell apoptosis in the early post-transplantation period [9,10].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

et al. 2016

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Aims/hypothesis Hypoxia may contribute to beta cell failure in type 2 diabetes and islet transplantation. The adaptive unfolded protein response (UPR) is required for endoplasmic reticulum (ER) homeostasis. Here we investigated whether or not hypoxia regulates the UPR in beta cells and the role the adaptive UPR plays during hypoxic stress. Methods Mouse islets and MIN6 cells were exposed to various oxygen (O 2 ) tensions. DNA-damage inducible transcript 3 (DDIT3), hypoxia-inducible transcription factor (HIF)1α and HSPA5 were knocked down using small interfering (si)RNA; Hspa5 was also overexpressed. db/db mice were used. Results Hypoxia-response genes were upregulated in vivo in the islets of diabetic, but not prediabetic, db/db mice. In isolated mouse islets and MIN6 cells, O 2 deprivation (1-5% vs 20%; 4-24 h) markedly reduced the expression of adaptive UPR genes, including Hspa5, Hsp90b1, Fkbp11 and spliced Xbp1. Coatomer protein complex genes (Copa, Cope, Copg [also known as Copg1], Copz1 and Copz2) and ER-to-Golgi protein trafficking were also reduced, whereas apoptotic genes (Ddit3, Atf3 and Trb3 [also known as Trib3]), c-Jun N-terminal kinase (JNK) phosphorylation and cell death were increased. Inhibition of JNK, but not HIF1α, restored adaptive UPR gene expression and ER-to-Golgi protein trafficking while protecting against apoptotic genes and cell death following hypoxia. DDIT3 knockdown delayed the loss of the adaptive UPR and partially protected against hypoxia-induced cell death. The latter response was prevented by HSPA5 knockdown. Finally, Hspa5 overexpression significantly protected against hypoxia-induced cell death. Conclusions/interpretation Hypoxia inhibits the adaptive UPR in beta cells via JNK and DDIT3 activation, but independently of HIF1α. Downregulation of the adaptive UPR contributes to reduced ER-to-Golgi protein trafficking and increased beta cell death during hypoxic stress.

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Islet Microvasculature in Islet Hyperplasia and Failure in a Model of Type 2 Diabetes

Cited by 134 publications

References 57 publications

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

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

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

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