Transcription Factor Glis3, a Novel Critical Player in the Regulation of Pancreatic β-Cell Development and Insulin Gene Expression

ABSTRACT In this study, we report that the Krüppel-like zinc finger transcription factor Gli-similar 3 (Glis3) is induced during the secondary transition of pancreatic development, a stage of cell lineage specification and extensive patterning, and that Glis3zf / zf mutant mice develop neonatal diabetes, evidenced by hyperglycemia and hypoinsulinemia. The Glis3zf / zf mutant mouse pancreas shows a dramatic loss of β and δ cells, contrasting a smaller relative loss of α, PP, and ε cells. In addition, Glis3zf / zf mutant mice develop ductal cysts, while no significant changes were observed in acini. Gene expression profiling and immunofluorescent staining demonstrated that the expression of pancreatic hormones and several transcription factors important in endocrine cell development, including Ngn3, MafA, and Pdx1, were significantly decreased in the developing pancreata of Glis3zf / zf mutant mice. The population of pancreatic progenitors appears not to be greatly affected in Glis3zf / zf mutant mice; however, the number of neurogenin 3 (Ngn3)-positive endocrine cell progenitors is significantly reduced. Our study indicates that Glis3 plays a key role in cell lineage specification, particularly in the development of mature pancreatic β cells. In addition, we provide evidence that Glis3 regulates insulin gene expression through two Glis-binding sites in its proximal promoter, indicating that Glis3 also regulates β-cell function.

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Naringin (4′,5,7-Trihydroxyflavanone 7-Rhamnoglucoside) Attenuates β-Cell Dysfunction in Diabetic Rats through Upregulation of PDX-1

Cells Tissues Organs ◽

10.1159/000496506 ◽

2018 ◽

Vol 206 (3) ◽

pp. 133-143 ◽

Cited By ~ 2

Author(s):

Manickam Subramanian ◽

Balaji Thotakura ◽

Swathi Priyadarshini Chandra Sekaran ◽

Ashok kumar Jyothi ◽

Indumathi Sundaramurthi

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Insulin Secretion ◽

Protein Expression ◽

Serum Insulin ◽

Diabetic Rats ◽

Insulin Gene ◽

Β Cells ◽

Β Cell ◽

Insulin Gene Expression

Background: Pancreatic duodenal homeobox-1 (PDX-1) is a key transcription factor which regulates Insulin gene expression and insulin secretion in adult β-cells and helps to maintain β-cells mass. Naringin, a flavanone, owing to its antioxidant property, is reported to have antidiabetic effects. Objectives: The present study tries to evaluate the role of naringin on the β-cell-specific transcription factor PDX-1 in diabetic rats. Methods: Diabetes was induced in male rats using streptozotocin and treated with naringin (100 mg/kg) orally for 4 and 8 weeks. Serum insulin level, Pdx-1 and Insulin gene expression, and PDX-1 protein expression were assessed in the rat pancreas. Histopathological and ultrastructural changes in the islet and β-cells were observed. Results: Naringin prevented leukocytic infiltration in the pancreas of diabetic rats and recouped the β-cells with adequate secretory granules. Naringin-treated diabetic rats showed significantly increased mRNA expression of Pdx-1 and Insulin genes, increased expression of transcription factor PDX-1, and higher serum insulin levels than the diabetic control animals. These changes were more pronounced in the 8-week naringin-treated diabetic animals. Conclusions: Naringin was found to be an effective antidiabetic agent which increased Insulin gene expression and insulin secretion by upregulating the PDX-1 gene and protein expression.

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Glucose Regulation of Insulin Gene Expression Requires the Recruitment of p300 by the β-Cell-Specific Transcription Factor Pdx-1

Molecular Endocrinology ◽

10.1210/me.2003-0463 ◽

2004 ◽

Vol 18 (9) ◽

pp. 2279-2290 ◽

Cited By ~ 80

Author(s):

Amber L. Mosley ◽

John A. Corbett ◽

Sabire Özcan

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Insulin Gene ◽

Glucose Regulation ◽

Β Cell ◽

Specific Transcription Factor ◽

Insulin Gene Expression

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NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation

Stem Cell Research & Therapy ◽

10.1186/s13287-020-01977-0 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Idil I. Aigha ◽

Essam M. Abdelalim

Keyword(s):

Transcription Factor ◽

Cell Function ◽

Disease Modeling ◽

Critical Role ◽

Cell Mass ◽

Cell Development ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Β Cell Function

Abstract Understanding the biology underlying the mechanisms and pathways regulating pancreatic β cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin-producing β cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive to β cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1−) results in an undesirable generation of non-functional polyhormonal β cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a means to increase β cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

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A cDNA from a mouse pancreatic β cell encoding a putative transcription factor of the insulin gene

Nucleic Acids Research ◽

10.1093/nar/18.5.1159 ◽

1990 ◽

Vol 18 (5) ◽

pp. 1159-1166 ◽

Cited By ~ 41

Author(s):

Michael D. Walker ◽

Cheol Won Park ◽

Ada Rosen ◽

Ami Aronheim

Keyword(s):

Transcription Factor ◽

Insulin Gene ◽

Pancreatic Β Cell ◽

Β Cell ◽

Putative Transcription Factor

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Endoplasmic Reticulum Stress-Induced Activation of Activating Transcription Factor 6 Decreases Insulin Gene Expression via Up-Regulation of Orphan Nuclear Receptor Small Heterodimer Partner

Endocrinology ◽

10.1210/en.2008-0015 ◽

2008 ◽

Vol 149 (8) ◽

pp. 3832-3841 ◽

Cited By ~ 71

Author(s):

Hye-Young Seo ◽

Yong Deuk Kim ◽

Kyeong-Min Lee ◽

Ae-Kyung Min ◽

Mi-Kyung Kim ◽

...

Keyword(s):

Gene Expression ◽

Er Stress ◽

Insulin Gene ◽

Orphan Nuclear Receptor ◽

Β Cell ◽

Cell Dysfunction ◽

Small Heterodimer Partner ◽

Insulin Gene Expression ◽

Long Evans ◽

Activating Transcription Factor

The highly developed endoplasmic reticulum (ER) structure of pancreatic β-cells is a key factor in β-cell function. Here we examined whether ER stress-induced activation of activating transcription factor (ATF)-6 impairs insulin gene expression via up-regulation of the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), which has been shown to play a role in β-cell dysfunction. We examined whether ER stress decreases insulin gene expression, and this process is mediated by ATF6. A small interfering RNA that targeted SHP was used to determine whether the effect of ATF6 on insulin gene expression is mediated by SHP. We also measured the expression level of ATF6 in pancreatic islets in Otsuka Long Evans Tokushima Fatty rats, a rodent model of type 2 diabetes. High glucose concentration (30 mmol/liter glucose) increased ER stress in INS-1 cells. ER stress induced by tunicamycin, thapsigargin, or dithiotreitol decreased insulin gene transcription. ATF6 inhibited insulin promoter activity, whereas X-box binding protein-1 and ATF4 did not. Adenovirus-mediated overexpression of active form of ATF6 in INS-1 cells impaired insulin gene expression and secretion. ATF6 also down-regulated pancreatic duodenal homeobox factor-1 and RIPE3b1/MafA gene expression and repressed the cooperative action of pancreatic duodenal homeobox factor-1, RIPE3b1/MafA, and β-cell E box transactivator 2 in stimulating insulin transcription. The ATF6-induced suppression of insulin gene expression was associated with up-regulation of SHP gene expression. Finally, we found that expression of ATF6 was increased in the pancreatic islets of diabetic Otsuka Long Evans Tokushima Fatty rats, compared with their lean, nondiabetic counterparts, Long-Evans Tokushima Otsuka rats. Collectively, this study shows that ER stress-induced activation of ATF6 plays an important role in the development of β-cell dysfunction.

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Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for β cell function

Journal of Molecular Endocrinology ◽

10.1530/jme-15-0132 ◽

2015 ◽

Vol 55 (1) ◽

pp. 21-29 ◽

Cited By ~ 7

Author(s):

S Lortz ◽

S Lenzen ◽

I Mehmeti

Keyword(s):

Gene Expression ◽

Hydrogen Peroxide ◽

Endoplasmic Reticulum ◽

Insulin Secretion ◽

Er Stress ◽

Insulin Gene ◽

Insulin Content ◽

Insulin Biosynthesis ◽

Β Cell ◽

Insulin Gene Expression

Oxidative folding of nascent proteins in the endoplasmic reticulum (ER), catalysed by one or more members of the protein disulfide isomerase family and the sulfhydryl oxidase ER oxidoreductin 1 (ERO1), is accompanied by generation of hydrogen peroxide (H2O2). Because of the high rate of insulin biosynthesis and the low expression of H2O2-inactivating enzymes in pancreatic β cells, it has been proposed that the luminal H2O2concentration might be very high. As the role of this H2O2in ER stress and proinsulin processing is still unsolved, an ER-targeted and luminal-active catalase variant, ER-Catalase N244, was expressed in insulin-secreting INS-1E cells. In these cells, the influence of ER-specific H2O2removal on cytokine-mediated cytotoxicity and ER stress, insulin gene expression, insulin content and secretion was analysed. The expression of ER-Catalase N244 reduced the toxicity of exogenously added H2O2significantly with a threefold increase of the EC50value for H2O2. However, the expression of cytokine-induced ER stress genes and viability after incubation with β cell toxic cytokines (IL1β alone or together with TNFα+IFNγ) was not affected by ER-Catalase N244. In control and ER-Catalase N244 expressing cells, insulin secretion and proinsulin content was identical, while removal of luminal H2O2reduced insulin gene expression and insulin content in ER-Catalase N244 expressing cells. These data show that ER-Catalase N244 reduced H2O2toxicity but did not provide protection against pro-inflammatory cytokine-mediated toxicity and ER stress. Insulin secretion was not affected by decreasing H2O2in the ER in spite of a reduced insulin transcription and processing.

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Protein calorie restriction has opposite effects on glucose metabolism and insulin gene expression in fetal and adult rat endocrine pancreas

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00242.2003 ◽

2004 ◽

Vol 286 (4) ◽

pp. E542-E550 ◽

Cited By ~ 16

Author(s):

M. A. Martín ◽

E. Fernández ◽

A. M. Pascual-Leone ◽

F. Escrivá ◽

C. Alvarez

Keyword(s):

Gene Expression ◽

Glucose Metabolism ◽

Food Restriction ◽

Cell Mass ◽

Insulin Gene ◽

Mrna Levels ◽

Β Cell ◽

Adult Age ◽

Insulin Gene Expression ◽

Insulin Mrna

We previously demonstrated that fetuses from undernourished pregnant rats exhibited increased β-cell mass and hyperinsulinemia, whereas keeping food restriction until adult age caused reduced β-cell mass, hypoinsulinemia, and decreased insulin secretion. Because these alterations can be related to insulin availability, we have now investigated early and long-term effects of protein calorie food restriction on insulin mRNA levels as well as the possible mechanisms that could modulate the endogenous insulin mRNA content. We used fetuses at 21.5 days of gestation proceeding from food-restricted rats during the last week of pregnancy and 70-day-old rats undernourished from day 14 of gestation until adult age and with respective controls. Insulin mRNA levels, glucose transporters, and total glycolysis and mitochondrial oxidative fluxes were evaluated. We additionally analyzed undernutrition effects on signals implicated in glucose-mediated insulin gene expression, especially pancreatic duodenal homeobox-1 (PDX-1), stress-activated protein kinase-2 (p38/SAPK2), and phosphatidylinositol 3-kinase. Undernourished fetuses showed increased insulin mRNA, oxidative glucose metabolism, and p38/SAPK2 levels, whereas undernutrition until adult age provoked a decrease in insulin gene expression, oxidative glucose metabolism, and PDX-1 levels. The results indicate that food restriction caused changes in insulin gene expression and content leading to alterations in glucose-stimulated insulin secretion. The molecular events, increased p38/SAPK2 levels in fetuses and decreased PDX-1 levels in adults, seem to be the responsible for the altered insulin mRNA expression. Moreover, because PDX-1 activation appears to be regulated by glucose-derived metabolite(s), the altered glucose oxidation caused by undernutrition could in some manner affect insulin mRNA expression.

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