scholarly journals The emerging role of FOXO transcription factors in pancreatic β cells

2007 ◽  
Vol 193 (2) ◽  
pp. 195-207 ◽  
Author(s):  
Dominique A Glauser ◽  
Werner Schlegel
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cell Mass ◽  
Endocrine Function ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Foxo Transcription Factors

FOXO transcription factors critically control fundamental cellular processes, including metabolism, cell differentiation, cell cycle arrest, DNA repair, and other reactions to cellular stress. FOXO factors sense the balance between stimuli promoting growth and differentiation versus stress stimuli signaling damage. Integrated through the FOXO system, these divergent stimuli decide on cell fate, a choice between proliferation, differentiation, or apoptosis. In pancreatic β cells, most recent evidence highlights complex FOXO-dependent responses to glucose, insulin, or other growth factors, which include regulatory feedback. In the short term, FOXO-dependent mechanisms help β cells to accomplish their endocrine function, and may increase their resistance to oxidative stress due to transient hyperglycemia. In the long term, FOXO-dependent responses lead to the adaptation of β cell mass, conditioning the future ability of the organism to produce insulin and cope with changes in fuel abundance. FOXO emerges as a key factor for the maintenance of a functional endocrine pancreas and represents an interesting element in the development of therapeutic approaches to treat diabetes. This review on the role of FOXO transcription factors in pancreatic β cells has three parts. In Part I, FOXO transcription factors will be presented in general: structure, molecular mechanisms of regulation, cellular functions, and physiological roles. Part II will focus on specific data about FOXO factors in pancreatic β cells. Lastly in Part III, it will be attempted to combine general and β cell-specific knowledge with the aim to envisage globally the role of FOXO factors in β cell-linked physiology and disease.

Autophagy in health and disease. 4. The role of pancreatic β-cell autophagy in health and diabetes

2010 ◽  
Vol 299 (1) ◽  
pp. C1-C6 ◽  
Author(s):  
Yoshio Fujitani ◽  
Takashi Ueno ◽  
Hirotaka Watada
Keyword(s):  
Cell Mass ◽  
Normal Function ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Ubiquitinated Proteins ◽  
Evolutionarily Conserved ◽  
Health And Disease ◽  
Cellular Stresses

Autophagy is an evolutionarily conserved machinery for degradation and recycling of various cytoplasmic components such as long-lived proteins and organelles. In pancreatic β-cells, as in most other cells, autophagy is also important for the low basal turnover of ubiquitinated proteins and damaged organelles under normal conditions. Insulin resistance results in upregulation of autophagic activity in β-cells. Induced autophagy in β-cells plays a pivotal role in the adaptive expansion of β-cell mass. Nevertheless, it is not clear whether autophagy is protective or detrimental in response to cellular stresses in β-cells. In this review, we describe the crucial roles of autophagy in normal function of β-cells and discuss how dysfunction of the autophagic machinery could lead to the development of diabetes mellitus.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research

2016 ◽  
Vol 174 (5) ◽  
pp. R225-R238 ◽  
Author(s):  
Jonàs Juan-Mateu ◽  
Olatz Villate ◽  
Décio L Eizirik
Keyword(s):  
Alternative Splicing ◽  
Cell Fate ◽  
Immune Cells ◽  
Regulatory Networks ◽  
Protein Isoforms ◽  
Diabetes Research ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic β cells are killed by infiltrating immune cells and by cytokines released by these cells. This takes place in the context of a dysregulated dialogue between invading immune cells and target β cells, but the intracellular signals that decide β cell fate remain to be clarified. Alternative splicing (AS) is a complex post-transcriptional regulatory mechanism affecting gene expression. It regulates the inclusion/exclusion of exons into mature mRNAs, allowing individual genes to produce multiple protein isoforms that expand the proteome diversity. Functionally related transcript populations are co-ordinately spliced by master splicing factors, defining regulatory networks that allow cells to rapidly adapt their transcriptome in response to intra and extracellular cues. There is a growing interest in the role of AS in autoimmune diseases, but little is known regarding its role in T1D. In this review, we discuss recent findings suggesting that splicing events occurring in both immune and pancreatic β cells contribute to the pathogenesis of T1D. Splicing switches in T cells and in lymph node stromal cells are involved in the modulation of the immune response against β cells, while β cells exposed to pro-inflammatory cytokines activate complex splicing networks that modulate β cell viability, expression of neoantigens and susceptibility to immune-induced stress. Unveiling the role of AS in β cell functional loss and death will increase our understanding of T1D pathogenesis and may open new avenues for disease prevention and therapy.

scholarly journals Nuclear Factor Y in Male Mouse pancreatic β-cells Plays a Crucial Role in Glucose Homeostasis by Regulating β-Cell Mass and Insulin Secretion

2021 ◽  
Author(s):  
Yin Liu ◽  
Siyuan He ◽  
Ruixue Zhou ◽  
Xueping Zhang ◽  
Shanshan Yang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Cell Mass ◽  
Physiological Role ◽  
Nuclear Factor ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Nuclear Factor Y

Pancreatic β-cell mass and insulin secretion are determined by the dynamic change of transcription factor expression levels in response to altered metabolic demand. Nuclear factor-Y (NF-Y) is an evolutionarily conserved transcription factor playing critical roles in multiple cellular processes. However, the physiological role of NF-Y in pancreatic β-cells is poorly understood. The present study was undertaken in a conditional knockout of <i>Nf-ya</i> specifically in pancreatic β-cells (<i>Nf-ya </i>βKO) to define the essential physiological role of NF-Y in β-cells. <i>Nf-ya </i>βKO mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell proliferation resulting in decreased β-cell mass was observed in these mice, which was associated with disturbed actin cytoskeleton. NF-Y-deficient β-cells also exhibited impaired insulin secretion with a reduced Ca<sup>2+</sup> influx in response to glucose, which was associated an inefficient glucose uptake into β-cells due to a decreased expression of glucose transporter 2 and a reduction in ATP production resulting from the disruption of mitochondrial integrity. This study is the first to show that NF-Y is critical for pancreatic islets homeostasis and function through regulation in β-cell proliferation, glucose uptake into β-cells, and mitochondrial energy metabolism. Modulating NF-Y expression in β-cells may therefore offer an attractive approach for therapeutic intervention.

scholarly journals Nuclear Factor Y in Male Mouse pancreatic β-cells Plays a Crucial Role in Glucose Homeostasis by Regulating β-Cell Mass and Insulin Secretion

2021 ◽  
Author(s):  
Yin Liu ◽  
Siyuan He ◽  
Ruixue Zhou ◽  
Xueping Zhang ◽  
Shanshan Yang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Cell Mass ◽  
Physiological Role ◽  
Nuclear Factor ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Nuclear Factor Y

Pancreatic β-cell mass and insulin secretion are determined by the dynamic change of transcription factor expression levels in response to altered metabolic demand. Nuclear factor-Y (NF-Y) is an evolutionarily conserved transcription factor playing critical roles in multiple cellular processes. However, the physiological role of NF-Y in pancreatic β-cells is poorly understood. The present study was undertaken in a conditional knockout of <i>Nf-ya</i> specifically in pancreatic β-cells (<i>Nf-ya </i>βKO) to define the essential physiological role of NF-Y in β-cells. <i>Nf-ya </i>βKO mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell proliferation resulting in decreased β-cell mass was observed in these mice, which was associated with disturbed actin cytoskeleton. NF-Y-deficient β-cells also exhibited impaired insulin secretion with a reduced Ca<sup>2+</sup> influx in response to glucose, which was associated an inefficient glucose uptake into β-cells due to a decreased expression of glucose transporter 2 and a reduction in ATP production resulting from the disruption of mitochondrial integrity. This study is the first to show that NF-Y is critical for pancreatic islets homeostasis and function through regulation in β-cell proliferation, glucose uptake into β-cells, and mitochondrial energy metabolism. Modulating NF-Y expression in β-cells may therefore offer an attractive approach for therapeutic intervention.

FoxO transcription factors in oxidative stress response and ageing – a new fork on the way to longevity?

2008 ◽  
Vol 389 (3) ◽  
pp. 279-283 ◽  
Author(s):  
Daniel G. Sedding
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Cellular Effects ◽  
Forkhead Box ◽  
Foxo Transcription Factors

Abstract Forkhead box O (FoxO) transcription factors are important downstream targets of the PI3K/Akt signaling pathway and crucial regulators of cell fate. This function of FoxOs relies on their ability to control diverse cellular functions, including proliferation, differentiation, apoptosis, DNA repair, defense against oxidative stress and ageing. FoxOs are regulated by a variety of different growth factors and hormones, and their activity is tightly controlled by post-translational modifications, including phosphorylation, acetylation, ubiquitination and interaction with different proteins and transcription factors. This brief review focuses on the molecular mechanisms, cellular effects and resulting organismal phenotypes generated by differentially regulated FoxO proteins and discusses our current understanding of the role of FoxOs in disease and ageing processes.

scholarly journals Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

2018 ◽  
Vol 236 (2) ◽  
pp. R109-R143 ◽  
Author(s):  
Mohammed Bensellam ◽  
Jean-Christophe Jonas ◽  
D Ross Laybutt
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Cell Mass ◽  
Embryonic Stem ◽  
Gene Clusters ◽  
Future Research ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dedifferentiation

Like all the cells of an organism, pancreatic β-cells originate from embryonic stem cells through a complex cellular process termed differentiation. Differentiation involves the coordinated and tightly controlled activation/repression of specific effectors and gene clusters in a time-dependent fashion thereby giving rise to particular morphological and functional cellular features. Interestingly, cellular differentiation is not a unidirectional process. Indeed, growing evidence suggests that under certain conditions, mature β-cells can lose, to various degrees, their differentiated phenotype and cellular identity and regress to a less differentiated or a precursor-like state. This concept is termed dedifferentiation and has been proposed, besides cell death, as a contributing factor to the loss of functional β-cell mass in diabetes. β-cell dedifferentiation involves: (1) the downregulation of β-cell-enriched genes, including key transcription factors, insulin, glucose metabolism genes, protein processing and secretory pathway genes; (2) the concomitant upregulation of genes suppressed or expressed at very low levels in normal β-cells, the β-cell forbidden genes; and (3) the likely upregulation of progenitor cell genes. These alterations lead to phenotypic reconfiguration of β-cells and ultimately defective insulin secretion. While the major role of glucotoxicity in β-cell dedifferentiation is well established, the precise mechanisms involved are still under investigation. This review highlights the identified molecular mechanisms implicated in β-cell dedifferentiation including oxidative stress, endoplasmic reticulum (ER) stress, inflammation and hypoxia. It discusses the role of Foxo1, Myc and inhibitor of differentiation proteins and underscores the emerging role of non-coding RNAs. Finally, it proposes a novel hypothesis of β-cell dedifferentiation as a potential adaptive mechanism to escape cell death under stress conditions.

Effects of atorvastatin on the regeneration of pancreatic β-cells after streptozotocin treatment in the neonatal rodent

2010 ◽  
Vol 299 (1) ◽  
pp. E92-E100 ◽  
Author(s):  
K. C. Marchand ◽  
E. J. Arany ◽  
D. J. Hill
Keyword(s):  
Endothelial Cells ◽  
Cell Injury ◽  
Cell Mass ◽  
Neonatal Rat ◽  
Neonatal Rats ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
And Control

To investigate the role of statins in β-cell regeneration a model of streptozotocin (STZ)-induced β-cell injury was used in the neonatal rat. We hypothesized that β-cell growth and regeneration would increase following treatment with atorvastatin and that this would be associated with intraislet vasculogenesis. Pregnant Wistar rats were gavaged with 20 or 40 mg/kg atorvastatin for 21 days commencing on gestation day 15. Atorvastatin was detected in the circulation of the offspring. On postnatal day 4, the pups were given either a control or STZ (70 mg/kg ip) injection. β-Cell mass had partially recovered by postnatal day 44 following STZ treatment, and atorvastatin (20 mg/kg) significantly increased β-cell mass in both STZ-treated and control animals. An increase in the numbers of small islets at postnatal day 44 was seen in STZ-treated animals following atorvastatin, suggestive of neogenesis, and glucose tolerance was improved. Treatment with atorvastatin caused an increase in the numbers of intraislet endothelial cells at postnatal day 14 and the percentage of endothelial cells undergoing DNA synthesis, suggesting that angiogenesis had preceded the increase in β-cell mass. The results indicate that functional β-cell mass was expanded with atorvastatin in both control and STZ-treated neonatal rats and suggests a novel effect of a statin in promoting islet plasticity.

Deletion of Fas in the pancreatic β-cells leads to enhanced insulin secretion

2009 ◽  
Vol 297 (6) ◽  
pp. E1304-E1312 ◽  
Author(s):  
Diana Choi ◽  
Anna Radziszewska ◽  
Stephanie A. Schroer ◽  
Nicole Liadis ◽  
Yunfeng Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Insulin Secretion ◽  
Essential Role ◽  
Fas Ligand ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Insulin Promoter

Fas/Fas ligand belongs to the tumor necrosis factor superfamily of receptors/ligands and is best known for its role in apoptosis. However, recent evidence supports its role in other cellular responses, including proliferation and survival. Although Fas has been implicated as an essential mediator of β-cell death in the pathogenesis of type 1 diabetes, the essential role of Fas specifically in pancreatic β-cells has been found to be controversial. Moreover, the role of Fas on β-cell homeostasis and function is not clear. The objective of this study is to determine the role of Fas specifically in β-cells under both physiological and diabetes models. Mice with Fas deletion specifically in the β-cells were generated using the Cre-loxP system. Cre-mediated Fas deletion was under the control of the rat insulin promoter. Absence of Fas in β-cells leads to complete protection against FasL-induced cell death. However, Fas is not essential in determining β-cell mass or susceptibility to streptozotocin- or HFD-induced diabetes. Importantly, Fas deletion in β-cells leads to increased p65 expression, enhanced glucose tolerance, and glucose-stimulated insulin secretion, with increased exocytosis as manifested by increased changes in membrane capacitance and increased expression of Syntaxin1A, VAMP2, and munc18a. Together, our study shows that Fas in the β-cells indeed plays an essential role in the canonical death receptor-mediated apoptosis but is not essential in regulating β-cell mass or diabetes development. However, β-cell Fas is critical in the regulation of glucose homeostasis through regulation of the exocytosis machinery.

scholarly journals NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas

2021 ◽  
Vol 22 (13) ◽  
pp. 6713
Author(s):  
Romana Bohuslavova ◽  
Ondrej Smolik ◽  
Jessica Malfatti ◽  
Zuzana Berkova ◽  
Zaneta Novakova ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Cell Mass ◽  
Neonatal Diabetes ◽  
Diabetes Research ◽  
Pancreas Development ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Islet Cell ◽  
Endocrine Differentiation

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.

scholarly journals Regulation of Insulin Secretion and β-Cell Mass by Activating Signal Cointegrator 2

2006 ◽  
Vol 26 (12) ◽  
pp. 4553-4563 ◽  
Author(s):  
Seon-Yong Yeom ◽  
Geun Hyang Kim ◽  
Chan Hee Kim ◽  
Heun Don Jung ◽  
So-Yeon Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Endocrine Cells ◽  
Potential Role ◽  
Cell Mass ◽  
Dominant Negative ◽  
Transcriptional Coactivator ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass

ABSTRACT Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes). In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic β-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2+/− mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2+/− mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2+/− islets. These results suggest that ASC-2 regulates insulin secretion and β-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.

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