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

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 Nf-ya specifically in pancreatic β-cells (Nf-ya βKO) to define the essential physiological role of NF-Y in β-cells. Nf-ya 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 Ca2+ 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.

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Nuclear factor Y in male mouse pancreatic β-cells plays a crucial role in glucose homeostasis by regulating β-cell mass and insulin secretion

Diabetes ◽

10.2337/db20-1238 ◽

2021 ◽

pp. db201238

Author(s):

Yin Liu ◽

Siyuan He ◽

Ruixue Zhou ◽

Xueping Zhang ◽

Shanshan Yang ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Homeostasis ◽

Crucial Role ◽

Male Mouse ◽

Cell Mass ◽

Nuclear Factor ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Nuclear Factor Y

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00217.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. E1304-E1312 ◽

Cited By ~ 15

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.

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Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

Scientific Reports ◽

10.1038/s41598-021-94725-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Brenda Strutt ◽

Sandra Szlapinski ◽

Thineesha Gnaneswaran ◽

Sarah Donegan ◽

Jessica Hill ◽

...

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Glucose Transporter ◽

Cell Mass ◽

Elevated Serum ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Glucose Transporter 2 ◽

Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

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

Molecular and Cellular Biology ◽

10.1128/mcb.01412-05 ◽

2006 ◽

Vol 26 (12) ◽

pp. 4553-4563 ◽

Cited By ~ 15

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

AJP Cell Physiology ◽

10.1152/ajpcell.00084.2010 ◽

2010 ◽

Vol 299 (1) ◽

pp. C1-C6 ◽

Cited By ~ 33

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.

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Trefoil Factor 2 Promotes Cell Proliferation in Pancreatic β-Cells through CXCR-4-Mediated ERK1/2 Phosphorylation

Endocrinology ◽

10.1210/en.2012-1814 ◽

2013 ◽

Vol 154 (1) ◽

pp. 54-64 ◽

Cited By ~ 14

Author(s):

Kazuki Orime ◽

Jun Shirakawa ◽

Yu Togashi ◽

Kazuki Tajima ◽

Hideaki Inoue ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Mass ◽

Brdu Incorporation ◽

Trefoil Factor ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Min6 Cells ◽

Trefoil Factor 2 ◽

Chemokine Receptor 4

Decreased β-cell mass is a hallmark of type 2 diabetes, and therapeutic approaches to increase the pancreatic β-cell mass have been expected. In recent years, gastrointestinal incretin peptides have been shown to exert a cell-proliferative effect in pancreatic β-cells. Trefoil factor 2 (TFF2), which is predominantly expressed in the surface epithelium of the stomach, plays a role in antiapoptosis, migration, and proliferation. The TFF family is expressed in pancreatic β-cells, whereas the role of TFF2 in pancreatic β-cells has been obscure. In this study, we investigated the mechanism by which TFF2 enhances pancreatic β-cell proliferation. The effects of TFF2 on cell proliferation were evaluated in INS-1 cells, MIN6 cells, and mouse islets using an adenovirus vector containing TFF2 or a recombinant TFF2 peptide. The forced expression of TFF2 led to an increase in bromodeoxyuridine (BrdU) incorporation in both INS-1 cells and islets, without any alteration in insulin secretion. TFF2 significantly increased the mRNA expression of cyclin A2, D1, D2, D3, and E1 in islets. TFF2 peptide increased ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. A MAPK kinase inhibitor (U0126) abrogated the TFF2 peptide-mediated proliferation of MIN6 cells. A CX-chemokine receptor-4 antagonist also prevented the TFF2 peptide-mediated increase in ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. These results indicated that TFF2 is involved in β-cell proliferation at least partially via CX-chemokine receptor-4-mediated ERK1/2 phosphorylation, suggesting TFF2 may be a novel target for inducing β-cell proliferation.

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β cell-specific deletion of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase causes overt diabetes due to reduction of β cell mass and impaired insulin secretion

10.2337/figshare.12771422.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Shoko Takei ◽

Shuichi Nagashima ◽

Akihito Takei ◽

Daisuke Yamamuro ◽

...

Keyword(s):

Insulin Secretion ◽

Coenzyme A ◽

Cell Mass ◽

Bzip Transcription Factor ◽

Β Cells ◽

Β Cell ◽

Embryonic Pancreas ◽

Endocrine Progenitors ◽

Coenzyme A Reductase

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins, which are used to prevent cardiovascular diseases, are associated with a modest increase in the risk of new-onset diabetes mellitus. To investigate the role of HMGCR in the development of β cells and glucose homeostasis, we deleted Hmgcr in a β cell-specific manner by using the Cre-loxP technique. Mice lacking Hmgcr in β cells (β-KO) exhibited hypoinsulinemic hyperglycemia as early as postnatal day 9 (P9) due to decreases in both β cell mass and insulin secretion. Ki67 positive cells were reduced in β-KO mice at P9, thus β cell mass reduction was caused by proliferation disorder immediately after birth. The mRNA expression of neurogenin3 (Ngn3), which is transiently expressed in endocrine progenitors of the embryonic pancreas, was maintained despite a striking reduction in the expression of β cell-associated genes, such as insulin, Pancreatic and duodenal homeobox 1 (Pdx1) and MAF BZIP transcription factor A (Mafa) in the islets from β-KO mice. Histological analyses revealed dysmorphic islets with markedly reduced numbers of β cells, some of which were also positive for glucagon. In conclusion, HMGCR plays critical roles not only in insulin secretion but also in the development of β cells in mice.

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The Plasticity of Pancreatic β-Cells

Metabolites ◽

10.3390/metabo11040218 ◽

2021 ◽

Vol 11 (4) ◽

pp. 218

Author(s):

Norikiyo Honzawa ◽

Kei Fujimoto

Keyword(s):

Insulin Secretion ◽

Progenitor Cells ◽

Islet Cells ◽

Cell Mass ◽

Pancreatic Β Cell ◽

Cell Plasticity ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Impaired Insulin

Type 2 diabetes is caused by impaired insulin secretion and/or insulin resistance. Loss of pancreatic β-cell mass detected in human diabetic patients has been considered to be a major cause of impaired insulin secretion. Additionally, apoptosis is found in pancreatic β-cells; β-cell mass loss is induced when cell death exceeds proliferation. Recently, however, β-cell dedifferentiation to pancreatic endocrine progenitor cells and β-cell transdifferentiation to α-cell was reported in human islets, which led to a new underlying molecular mechanism. Hyperglycemia inhibits nuclear translocation and expression of forkhead box-O1 (FoxO1) and induces the expression of neurogenin-3(Ngn3), which is required for the development and maintenance of pancreatic endocrine progenitor cells. This new hypothesis (Foxology) is attracting attention because it explains molecular mechanism(s) underlying β-cell plasticity. The lineage tracing technique revealed that the contribution of dedifferentiation is higher than that of β-cell apoptosis retaining to β-cell mass loss. In addition, islet cells transdifferentiate each other, such as transdifferentiation of pancreatic β-cell to α-cell and vice versa. Islet cells can exhibit plasticity, and they may have the ability to redifferentiate into any cell type. This review describes recent findings in the dedifferentiation and transdifferentiation of β-cells. We outline novel treatment(s) for diabetes targeting islet cell plasticity.

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Effects of metformin on compensatory pancreatic β-cell hyperplasia in mice fed a high-fat diet

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00447.2016 ◽

2017 ◽

Vol 313 (3) ◽

pp. E367-E380 ◽

Cited By ~ 8

Author(s):

Kazuki Tajima ◽

Jun Shirakawa ◽

Tomoko Okuyama ◽

Mayu Kyohara ◽

Shunsuke Yamazaki ◽

...

Keyword(s):

Insulin Resistance ◽

Cell Proliferation ◽

High Fat Diet ◽

Cell Mass ◽

Mammalian Target Of Rapamycin ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Cell Hyperplasia

Metformin has been widely used for the treatment of type 2 diabetes. However, the effect of metformin on pancreatic β-cells remains controversial. In this study, we investigated the impacts of treatment with metformin on pancreatic β-cells in a mouse model fed a high-fat diet (HFD), which triggers adaptive β-cell replication. An 8-wk treatment with metformin improved insulin resistance and suppressed the compensatory β-cell hyperplasia induced by HFD-feeding. In contrast, the increment in β-cell mass arising from 60 wk of HFD feeding was similar in mice treated with and those treated without metformin. Interestingly, metformin suppressed β-cell proliferation induced by 1 wk of HFD feeding without any changes in insulin resistance. Metformin directly suppressed glucose-induced β-cell proliferation in islets and INS-1 cells in accordance with a reduction in mammalian target of rapamycin phosphorylation. Taken together, metformin suppressed HFD-induced β-cell proliferation independent of the improvement of insulin resistance, partly via direct actions.

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