The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic β cell growth

Kitamura, Tadahiro; Nakae, Jun; Kitamura, Yoichi; Kido, Yoshiaki; Biggs, William H.; Wright, Christopher V.E.; White, Morris F.; Arden, Karen C.; Accili, Domenico

doi:10.1172/jci16857

Cited by 339 publications

(459 citation statements)

References 48 publications

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“…For example, in Irs2−/ − mice there is diminished β cell mass with impaired glucose tolerance [89,91]; in this model, superposition of haploinsufficiency of the Forkhead transcription factor Foxo1 causes activation of Pdx1 expression in duct cells, and the subsequent recovery of β cell mass [92]. In support of this observation, overexpression of Pdx1 alone in Irs2−/− animals promotes recovery of β cell mass and correction of glucose tolerance throughout life [93].…”

Section: Role Of Pdx1 In Adaptive β Cell Hyperplasia and β Cell Regenmentioning

confidence: 80%

“…Activation of Pdx1 in duct cells of the pancreas has also been observed following partial pancreatectomy in mice [85] and in insulin resistant Zucker fatty (ZF) rats [83]. Importantly in this regard, Pdx1 expression is often observed in proliferating duct cells [77,94,95], and such cells have been suggested to serve as substrate for β cell neogenesis, particularly in cases of adaptive hyperplasia or pancreas regeneration [92,[96][97][98][99]. A recent study suggests that Pdx1, in complex with TALE transcription factors, negatively regulates the duct-specific keratin 19 gene in mature duct cells [100].…”

Section: Role Of Pdx1 In Adaptive β Cell Hyperplasia and β Cell Regenmentioning

confidence: 99%

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A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

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Emerging evidence over the past decade indicates a central role for transcription factors in the embryonic development of pancreatic islets and the consequent maintenance of normal glucose homeostasis. Pancreatic and duodenal homeobox 1 (Pdx1) is the best studied and perhaps most important of these factors. Whereas deletion or inactivating mutations of the Pdx1 gene causes whole pancreas agenesis in both mice and humans, even haploinsufficiency of the gene or alterations in its expression in mature islet cells causes substantial impairments in glucose tolerance and the development of a late-onset form of diabetes known as maturity onset diabetes of the young. The study of Pdx1 has revealed crucial phenotypic interrelationships of the varied cell types within the pancreas, particularly as these impinge upon cellular differentiation in the embryo and neogenesis and regeneration in the adult. In this review, we describe the actions of Pdx1 in the developing and mature pancreas and attempt to unify these actions with its known roles in modulating transcriptional complex formation and chromatin structure at the molecular genetic level.

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Section: Role Of Pdx1 In Adaptive β Cell Hyperplasia and β Cell Regenmentioning

confidence: 80%

Section: Role Of Pdx1 In Adaptive β Cell Hyperplasia and β Cell Regenmentioning

confidence: 99%

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

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“…Although this may be due to insufficiency of the knockdown or the fetal stage at which the siRNA studies were carried out, our present data suggest a more important role for FOXO1 in cell differentiation during human fetal pancreas development. The most prominent role for FOXO1 in adult beta cells is negative transcriptional regulation of PDX-1 [4,7,33]. This mechanism is reversed by Akt-induced FOXO1 phosphorylation and nuclear export, thereby allowing FOXA2-induced PDX-1 expression [7,34].…”

Section: Discussionmentioning

confidence: 99%

“…Co-localisation of FOXO1 with transcription factors in the developing human fetal pancreas Several studies have demonstrated opposite nuclear vs cytoplasmic localisation of FOXO1 and PDX-1 in murine adult beta cells [7,8]. To better understand the subcellular distribution of FOXO1 and PDX-1 during human fetal pancreatic development, double immunofluorescence and morphometric analyses of FOXO1 in PDX-1 + cells throughout 8-21 weeks of human fetal pancreatic development were performed.…”

Section: Characterisation Of Foxo1 In the Developing Human Fetal Pancmentioning

confidence: 99%

“…In the mouse pancreas, FOXO1 competes with forkhead box A2 (FOXA2) for binding to the pancreatic and duodenal homeobox 1 (Pdx-1 [also known as Pdx1]) promoter, and, subsequently, acts as a negative regulator of PDX-1 production [7]. Moreover, under oxidative stress conditions, PDX-1 translocates to the cytoplasm of beta cells while FOXO1 moves into the nucleus, resulting in a restriction of beta cell growth and proliferation in order to prevent cellular damage [8].…”

Section: Introductionmentioning

confidence: 99%

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Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

et al. 2009

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Aims/hypothesis Recent studies have demonstrated that in adult murine beta cells the forkhead box O1 (FOXO1) transcription factor regulates proliferation and stress resistance. However, the role of FOXO1 during pancreatic development remains largely unknown. The present study aimed to characterise the expression of the FOXO1 transcription factor in the early to mid-gestation human fetal pancreas and to understand its role in islet cell development. Methods Human (8-21 week fetal age) pancreases were examined using immunohistological, quantitative RT-PCR and western blotting. Isolated human (18-21 week) fetal islet epithelial cell clusters were treated with insulin or glucose, or transfected with FOXO1 small interfering RNA (siRNA). Results Nuclear and cytoplasmic FOXO1 were widely produced during human fetal endocrine pancreatic development, co-localising in cells with the transcription factors pancreatic and duodenal homeobox 1 (PDX-1) and neurogenin 3 (NGN3) as well as cytokeratin 19 (CK19), insulin and glucagon. Treatment with exogenous insulin (50 nmol/l) induced the nuclear exclusion of FOXO1 in both cytokeratin 19 (CK19) + (p<0.01) and insulin + cells (p<0.05) in parallel with increased phospho-Akt (p<0.05) production. siRNA knockdown of FOXO1 significantly increased the number of NGN3 + (p<0.01) and NK6 homeobox 1 (NKX6-1) + (p<0.05) cells in parallel with increases in insulin gene expression (p<0.03) and C-peptide + cells (p<0.05) and reduced levels of hairy and enhancer of split 1 (HES1) (p<0.01). Conclusions/interpretation Our results indicate that FOXO1 may negatively regulate beta cell differentiation in the human fetal pancreas by controlling critical transcription factors, including NGN3 and NKX6-1. These data suggest that the manipulation of FOXO1 levels may be a useful tool for improving cell-based strategies for the treatment of diabetes.Keywords Human fetal pancreas . Human islet epithelial cell clusters . Islet transcription factors . Nuclear FOXO1 . FOXO1 siRNA Electronic supplementary material The online version of this article

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Chitooligosaccharide Biguanide Repairs Islet β‐Cell Dysfunction by Activating the IRS‐2/PI3K/Akt Signaling Pathway in Type 2 Diabetic Rats

Zou

Wang

Zhang

et al. 2019

Advanced Therapeutics

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Islet β cell failure is a critical metabolic disorder in the development of type 2 diabetes (T2DM), and the decreased viability and dysfunction of β cells accelerate diabetic pathogenesis in association with higher mortality. In this study, the therapeutic effects of chitooligosaccharide biguanide (COSG), which is similar in structure to metformin and has negligible side effects, on islet β-cell dysfunction and the possible mechanism are explored. Streptozocin-induced diabetic rats are administered COSG via daily intragastric gavage for 8 weeks. COSG significantly controlled body weight loss, attenuated glucose levels in blood and urine, and increased serum insulin. Histological examination of the pancreas reveals that COSG also alleviated pancreatic atrophy in T2DM rats. Furthermore, COSG stimulated insulin receptor substrate-2 (IRS-2) signaling in rat islet β cells, thereby mediating the activation of the phosphatidylinositol 3 kinase/protein kinase (PI3K/Akt) signaling pathway. In addition, COSG promoted downstream forkhead transcription factor O1 (FoxO1) nuclear output to potentially activate pancreas duodenum homeobox-1 (PDX-1)/glucose transporter type-2 (GLUT-2)/glucose kinase (GCK) pathway-regulated insulin secretion. COSG also inhibited the glycogen synthase kinase-3β (GSK-3β)/caspase-3 pathway to prevent cell apoptosis. The intrinsic protective effects of COSG on the impaired insulin signaling system to delay β-cell apoptosis, increase β-cell growth and proliferation, improve β-cell function and promote insulin secretion highlight the possibilities of COSG as a novel strategy for the prevention of T2DM.

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The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic β cell growth

Cited by 339 publications

References 48 publications

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

Chitooligosaccharide Biguanide Repairs Islet β‐Cell Dysfunction by Activating the IRS‐2/PI3K/Akt Signaling Pathway in Type 2 Diabetic Rats

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