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

2018 ◽  
Vol 206 (3) ◽  
pp. 133-143 ◽  
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.

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

2011 ◽  
Vol 212 (3) ◽  
pp. 307-315 ◽  
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.

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

2015 ◽  
Vol 55 (1) ◽  
pp. 21-29 ◽  
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.

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

2010 ◽  
Vol 30 (7) ◽  
pp. 1864-1864
Author(s):  
Hong Soon Kang ◽  
Yong-Sik Kim ◽  
Gary ZeRuth ◽  
Ju Youn Beak ◽  
Kevin Gerrish ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Development ◽  
Insulin Gene ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Insulin Gene Expression

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

2009 ◽  
Vol 29 (24) ◽  
pp. 6366-6379 ◽  
Author(s):  
Hong Soon Kang ◽  
Yong-Sik Kim ◽  
Gary ZeRuth ◽  
Ju Youn Beak ◽  
Kevin Gerrish ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Endocrine Cell ◽  
Cell Lineage ◽  
Cell Development ◽  
Insulin Gene ◽  
Mutant Mice ◽  
Β Cell ◽  
Lineage Specification ◽  
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.

Glucose regulation of insulin gene expression in pancreatic β-cells

2008 ◽  
Vol 415 (1) ◽  
pp. 1-10 ◽  
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.

scholarly journals Regulation of islet function and gene expression by prolactin during pregnancy

2019 ◽  
Author(s):  
Vipul Shrivastava ◽  
Megan Lee ◽  
Marle Pretorius ◽  
Guneet Makkar ◽  
Carol Huang
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Serum Insulin ◽  
Prolactin Receptor ◽  
Cell Mass ◽  
Insulin Level ◽  
Β Cells ◽  
Β Cell

AbstractPancreatic islets adapt to insulin resistance of pregnancy by up regulating β-cell proliferation and increase insulin secretion. Previously, we found that prolactin receptor (Prlr) signaling is important for this process, as heterozygous prolactin receptor-null (Prlr+/−) mice are glucose intolerant, had a lower number of β cells and lower serum insulin levels than wild type mice during pregnancy. However, since Prlr expression is ubiquitous, to determine its β-cell specific effects, we generated a transgenic mouse with a floxed Prlr allele under the control of an inducible promoter, allowing conditional deletion of Prlr from β cells in adult mice. In this study, we found that β-cell-specific Prlr reduction resulted in elevated blood glucose during pregnancy. Similar to our previous finding in mouse with global Prlr reduction, β-cell-specific Prlr loss led to a lower β-cell mass and a lower in vivo insulin level during pregnancy. However, these islets do not have an intrinsic insulin secretion defect when tested in vitro. Interestingly, when we compared the islet gene expression profile, using islets isolated from mice with global versus β-cell-specific Prlr reduction, we found some important differences in genes that regulate apoptosis and insulin secretion. This suggests that Prlr has both cell-autonomous and non-cell-autonomous effect on β cells, beyond its regulation of pro-proliferative genes.

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

2015 ◽  
Vol 54 (3) ◽  
pp. 315-324 ◽  
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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