Candidate plasticity gene 16 and jun dimerization protein 2 are involved in the suppression of insulin gene expression in rat pancreatic INS-1 β-cells

ABSTRACT Regulation of insulin gene expression by glucose in pancreatic β cells is largely dependent on a cis-regulatory element, termed RIPE3b/C1, in the insulin gene promoter. MafA, a member of the Maf family of basic leucine zipper (bZip) proteins, is a β-cell-specific transcriptional activator that binds to the C1 element. Based on increased C1-binding activity, MafA protein levels appear to be up-regulated in response to glucose, but the underlying molecular mechanism for this is not well understood. In this study, we show evidence supporting that the amino-terminal region of MafA is phosphorylated at multiple sites by glycogen synthase kinase 3 (GSK3) in β cells. Mutational analysis of MafA and pharmacological inhibition of GSK3 in MIN6 β cells strongly suggest that the rate of MafA protein degradation is regulated by glucose, that MafA is constitutively phosphorylated by GSK3, and that phosphorylation is a prerequisite for rapid degradation of MafA under low-glucose conditions. Our data suggest a new glucose-sensing signaling pathway in islet β cells that regulates insulin gene expression through the regulation of MafA protein stability.

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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 in pancreatic β-cells

Biochemical Journal ◽

10.1042/bj20081029 ◽

2008 ◽

Vol 415 (1) ◽

pp. 1-10 ◽

Cited By ~ 130

Author(s):

Sreenath S. Andrali ◽

Megan L. Sampley ◽

Nathan L. Vanderford ◽

Sabire Özcan

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Blood Glucose ◽

Insulin Gene ◽

Β Cells ◽

Β Cell ◽

Insulin Synthesis ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Insulin Gene Expression

Production and secretion of insulin from the β-cells of the pancreas is very crucial in maintaining normoglycaemia. This is achieved by tight regulation of insulin synthesis and exocytosis from the β-cells in response to changes in blood glucose levels. The synthesis of insulin is regulated by blood glucose levels at the transcriptional and post-transcriptional levels. Although many transcription factors have been implicated in the regulation of insulin gene transcription, three β-cell-specific transcriptional regulators, Pdx-1 (pancreatic and duodenal homeobox-1), NeuroD1 (neurogenic differentiation 1) and MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A), have been demonstrated to play a crucial role in glucose induction of insulin gene transcription and pancreatic β-cell function. These three transcription factors activate insulin gene expression in a co-ordinated and synergistic manner in response to increasing glucose levels. It has been shown that changes in glucose concentrations modulate the function of these β-cell transcription factors at multiple levels. These include changes in expression levels, subcellular localization, DNA-binding activity, transactivation capability and interaction with other proteins. Furthermore, all three transcription factors are able to induce insulin gene expression when expressed in non-β-cells, including liver and intestinal cells. The present review summarizes the recent findings on how glucose modulates the function of the β-cell transcription factors Pdx-1, NeuroD1 and MafA, and thereby tightly regulates insulin synthesis in accordance with blood glucose levels.

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Hedgehog Signaling Regulation of Homeodomain Protein Islet Duodenum Homeobox-1 Expression in Pancreatic β-Cells*

Endocrinology ◽

10.1210/endo.142.3.8007 ◽

2001 ◽

Vol 142 (3) ◽

pp. 1033-1040 ◽

Cited By ~ 26

Author(s):

Melissa K. Thomas ◽

Jee H. Lee ◽

Naina Rastalsky ◽

Joel F. Habener

Keyword(s):

Gene Expression ◽

Transcriptional Activation ◽

Gene Promoter ◽

Insulin Gene ◽

Reporter Construct ◽

Β Cells ◽

Pancreatic Β Cells ◽

Insulin Promoter ◽

Insulin Gene Expression ◽

Hh Signaling

Abstract Insulin gene expression in pancreatic β-cells is regulated by signals from developmental morphogen proteins known as hedgehogs (Hhs). By analyzing 5′-deletion insulin promoter-reporter constructs in transient transfections of clonal INS-1 β-cells, we located activating Hh-responsive regions within the rat insulin I promoter that include the glucose-response elements Far (E2) and Flat (A2/A3). Activation of Hh signaling in INS-1 cells by ectopic Hh expression increased (and inhibition of Hh signaling with the Hh-specific inhibitor cyclopamine decreased) transcriptional activation of a multimerized FarFlat enhancer-reporter construct. In DNA-binding studies, nuclear extracts from INS-1 cells activated by ectopic Hh expression increased (and extracts from INS-1 cells treated with cyclopamine decreased) protein binding to a radiolabeled FarFlat oligonucleotide probe. An antiserum directed against the transcription factor islet duodenum homeobox-1 (IDX-1), a regulator of pancreas development and activator of the insulin gene promoter, attenuated the binding activity of Hh-responsive protein complexes. Nuclear IDX-1 protein levels on Western blots were increased by ectopic Hh expression, thereby providing a mechanism for Hh-mediated regulation of the insulin promoter. Addition of cyclopamine to INS-1 cells decreased IDX-1 messenger RNA expression. In transient transfections of a− 4.5-kb mouse IDX-1 promoter-reporter construct, ectopic Hh expression increased (and cyclopamine administration decreased) transcriptional activation of the IDX-1 promoter in a dose-dependent manner. Thus, the IDX-1 gene is a direct regulatory target of Hh signaling in insulin-producing pancreatic β-cells. We propose that Hh signaling activates the insulin gene promoter indirectly via the direct activation of IDX-1 expression. Because IDX-1 gene expression is essential for insulin gene expression, pancreatic β-cell development, and normal glucose homeostasis, our findings that Hh signaling regulates IDX-1 expression in the endocrine pancreas suggest possible novel therapeutic approaches for diabetes mellitus.

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Blockage of ceramide metabolism exacerbates palmitate inhibition of pro-insulin gene expression in pancreatic β-cells

Molecular and Cellular Biochemistry ◽

10.1007/s11010-009-0362-4 ◽

2010 ◽

Vol 338 (1-2) ◽

pp. 283-290 ◽

Cited By ~ 29

Author(s):

Jun Guo ◽

YingYing Qian ◽

XiaoXue Xi ◽

XiaoHan Hu ◽

JianXi Zhu ◽

...

Keyword(s):

Gene Expression ◽

Insulin Gene ◽

Β Cells ◽

Pancreatic Β Cells ◽

Insulin Gene Expression

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Serum response factor expression is enriched in pancreatic β cells and regulates insulin gene expression

The FASEB Journal ◽

10.1096/fj.10-173757 ◽

2011 ◽

Vol 25 (8) ◽

pp. 2592-2603 ◽

Cited By ~ 9

Author(s):

Aloke Sarkar ◽

Mao Zhang ◽

Shi‐He Liu ◽

Swapna Sarkar ◽

F. Charles Brunicardi ◽

...

Keyword(s):

Gene Expression ◽

Serum Response Factor ◽

Insulin Gene ◽

Response Factor ◽

Β Cells ◽

Pancreatic Β Cells ◽

Factor Expression ◽

Insulin Gene Expression ◽

Serum Response

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PRMT4 is involved in insulin secretion via the methylation of histone H3 in pancreatic β cells

Journal of Molecular Endocrinology ◽

10.1530/jme-14-0325 ◽

2015 ◽

Vol 54 (3) ◽

pp. 315-324 ◽

Cited By ~ 8

Author(s):

Joong Kwan Kim ◽

Yongchul Lim ◽

Jung Ok Lee ◽

Young-Sun Lee ◽

Nam Hee Won ◽

...

Keyword(s):

Gene Expression ◽

Insulin Secretion ◽

High Glucose ◽

Histone H3 ◽

Insulin Gene ◽

Β Cells ◽

Pancreatic Β Cells ◽

Protein Arginine Methyltransferases ◽

Insulin Synthesis ◽

Insulin Gene Expression

The relationship between protein arginine methyltransferases (PRMTs) and insulin synthesis in β cells is not yet well understood. In the present study, we showed that PRMT4 expression was increased in INS-1 and HIT-T15 pancreatic β cells under high-glucose conditions. In addition, asymmetric dimethylation of Arg17 in histone H3 was significantly increased in both cell lines in the presence of glucose. The inhibition or knockdown of PRMT4 suppressed glucose-induced insulin gene expression in INS-1 cells by 81.6 and 79% respectively. Additionally, the overexpression of mutant PRMT4 also significantly repressed insulin gene expression. Consistently, insulin secretion induced in response to high levels of glucose was decreased by both PRMT4 inhibition and knockdown. Moreover, the inhibition of PRMT4 blocked high-glucose-induced insulin gene expression and insulin secretion in primary pancreatic islets. These results indicate that PRMT4 might be a key regulator of high-glucose-induced insulin secretion from pancreatic β cells via H3R17 methylation.

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β-Cell-protective effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid as a glutamate dehydrogenase activator in db/db mice

Journal of Endocrinology ◽

10.1530/joe-11-0340 ◽

2011 ◽

Vol 212 (3) ◽

pp. 307-315 ◽

Cited By ~ 13

Author(s):

Seung Jin Han ◽

Sung-E Choi ◽

Sang-A Yi ◽

Soo-Jin Lee ◽

Hae Jin Kim ◽

...

Keyword(s):

Gene Expression ◽

Cell Death ◽

Insulin Secretion ◽

Carboxylic Acid ◽

Glucose Tolerance ◽

Glutamate Dehydrogenase ◽

Insulin Gene ◽

Β Cells ◽

Β Cell ◽

Insulin Gene Expression

2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) is an activator of glutamate dehydrogenase (GDH), which is a mitochondrial enzyme with an important role in insulin secretion. We investigated the effect of BCH on the high-glucose (HG)-induced reduction in glucose-stimulated insulin secretion (GSIS), the HG/palmitate (PA)-induced reduction in insulin gene expression, and HG/PA-induced β-cell death. We also studied whether long-term treatment with BCH lowers blood glucose and improves β-cell integrity indb/dbmice. We evaluated GSIS, insulin gene expression, and DNA fragmentation in INS-1 cells exposed to HG or HG/PA in the presence or absence of BCH. Anin vivostudy was performed in which 7-week-old diabeticdb/dbmice were treated with BCH (0.7 g/kg,n=10) and placebo (n=10) every other day for 6 weeks. After treatment, an intraperitoneal glucose tolerance test and immunohistological examinations were performed. Treatment with BCH blocked HG-induced GSIS inhibition and the HG/PA-induced reduction in insulin gene expression in INS-1 cells. In addition, BCH significantly reduced HG/PA-induced INS-1 cell death and phospho-JNK level. BCH treatment improved glucose tolerance and insulin secretion indb/dbmice. BCH treatment also increased the ratio of insulin-positive β-cells to total islet area (P<0.05) and reduced the percentage of β-cells expressing cleaved caspase 3 (P<0.05). In conclusion, the GDH activator BCH improved glycemic control indb/dbmice. This anti-diabetic effect may be associated with improved insulin secretion, preserved islet architecture, and reduced β-cell apoptosis.

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