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 Development and Characteristics of Pancreatic Epsilon Cells

2019 ◽  
Vol 20 (8) ◽  
pp. 1867 ◽  
Author(s):  
Naoaki Sakata ◽  
Gumpei Yoshimatsu ◽  
Shohta Kodama
Keyword(s):  
Transcription Factors ◽  
Blood Glucose ◽  
Endocrine Cells ◽  
Current Evidence ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Ghrelin Gene ◽  
Pancreatic Endocrine Cells

Pancreatic endocrine cells expressing the ghrelin gene and producing the ghrelin hormone were first identified in 2002. These cells, named ε cells, were recognized as the fifth type of endocrine cells. Differentiation of ε cells is induced by various transcription factors, including Nk2 homeobox 2, paired box proteins Pax-4 and Pax6, and the aristaless-related homeobox. Ghrelin is generally considered to be a “hunger hormone” that stimulates the appetite and is produced mainly by the stomach. Although the population of ε cells is small in adults, they play important roles in regulating other endocrine cells, especially β cells, by releasing ghrelin. However, the roles of ghrelin in β cells are complex. Ghrelin contributes to increased blood glucose levels by suppressing insulin release from β cells and is also involved in the growth and proliferation of β cells and the prevention of β cell apoptosis. Despite increasing evidence and clarification of the mechanisms of ε cells over the last 20 years, many questions remain to be answered. In this review, we present the current evidence for the participation of ε cells in differentiation and clarify their characteristics by focusing on the roles of ghrelin.

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 Induction In Vivo in Severely Diabetic Male Mice by Changing the Circulating Levels and Pattern of the Ratios of Estradiol to Androgens

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 3829-3842 ◽  
Author(s):  
Akari Inada ◽  
Oogi Inada ◽  
Nobuharu L. Fujii ◽  
Kei Fujishima ◽  
Tetsuichiro Inai ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Male Mice ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Severe Diabetes ◽  
Cell Induction ◽  
Circulating Levels

Abstract Previously we have generated transgenic (Tg) mice developing severe diabetes early in life with a profound depletion of β-cells with β-cell-directed expression of inducible cAMP early repressor-Iγ. Only male mice continue to demonstrate hyperglycemia throughout life. To investigate this sexual dimorphism, we treated severely diabetic male Tg mice with orchiectomy (ORX) or 17β-estradiol (E2) pellet implantation alone or in combination with ORX and E2-implantation to change the circulating levels and patterns of the ratio of estradiol to androgens. In the Tg-ORX group, the blood-glucose levels decreased to a certain level within several weeks but never reached the female Tg-control level. In contrast, the Tg-ORX+E2 or Tg-E2 group showed a more rapid drop in blood glucose to the basal level with a substantial increase in β-cells, thus preventing the occurrence of severe diabetes in the male mice. The β-cells, not only within islet but also in and adjacent to ducts and scattered β-cell clusters, were strongly induced by 1 week after treatment, and the islet morphology dramatically changed. Enhanced β-cell induction in the ducts occurred concomitantly with markedly increased levels of pancreatic duodenal homeobox-1 and related transcription factors. The glucose-lowering and β-cell-increasing effects were independent of the age at which the treatment is started. These data provide evidence that the circulating level of E2 and the ratio of E2 to T greatly affect the blood glucose levels, the β-cell induction, and the islet morphology in diabetic male Tg mice. This novel mechanism offers great potential for developing strategies to increase the number of β-cells in vivo.

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.

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 Antidiabetes of Combination of Fractionated-extracts of Andrographispaniculata and Centellaasiatica in Neonatal Streptozotocin-induced Diabetic Rats

2020 ◽  
pp. 312-322
Author(s):  
Reni Ariesta ◽  
La Ode Muhammad Fitrawan ◽  
Agung Endro Nugroho ◽  
Suwidjiyo Pramono
Keyword(s):  
Blood Glucose ◽  
Diabetic Rats ◽  
Β Cells ◽  
Β Cell ◽  
Antioxidative Effect ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Pancreatic Insulin ◽  
Treatment Of Diabetes ◽  
Old Rats

Many medicinal plants are widely grown in South- and Southeast Asia countries. Some of them are traditionally used for treatment of diabetes mellitus such as Andrographispaniculata and Centellaasiatica. In the study, we provided fractionated-extracts of A. paniculata and C. asiatica to increase the concentration of their active compounds and eliminate unexpected substances. The aim of the study was to evaluate the antidiabetes effect of the combination of their fractionated-extracts in male neonatal streptozotocin (STZ)-induced diabetic rats. In the study, diabetes was injected intraperitoneally 90mg.kg-1 BWSTZ  to two day-old rats. At the age of three months, the rats were administered with the combination of both fractionated-extracts for 14 consecutive days. We evaluated antidiabetes with parameters of blood glucose levels, morphology of pancreatic islet, β-cell density as well as immunohistochemical pancreatic insulin. The levels of MDA, SOD and GPx were also determined about oxidative stress change after treatment with the combination. In the study, the combination succeeded to lower the blood glucose level in neonatal STZ-induced diabetic rats. Inline with fact, improvement of rat pancreatic islets and β cells density, as well as moderate restoration of pancreatic insulin, were observed after treatment with the combination. The substance could decrease the level of MDA, and increase the levels of SOD and GPx. In conclusion, the combination of fractionated-extracts of A. paniculata and C. asiatica exhibited potential antidiabetic effect to its antioxidative effect in male neonatal STZ-induced diabetes rats.

scholarly journals MON-613 The Expression of TBC1 Domain Family, Member 4 (TBC1D4) in Skeletal Muscles of Insulin-Resistant Mice in Response to Sulforaphane

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Nasser M Rizk ◽  
Amina Saleh ◽  
Abdelrahman ElGamal ◽  
Dina Elsayegh ◽  
Isin Cakir ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Skeletal Muscles ◽  
Glucose Disposal ◽  
Domain Family ◽  
Insulin Resistant ◽  
Glucose Levels ◽  
Blood Glucose Levels

Abstract The Expression of TBC1 Domain Family, member 4 (TBC1D4) in Skeletal Muscles of Insulin-Resistant Mice in Response to Sulforaphane. Background: Obesity is commonly accompanied by impaired glucose homeostasis. Decreased glucose transport to the peripheral tissues, mainly skeletal muscle, leads to reduced total glucose disposal and hyperglycemia. TBC1D4 gene is involved in the trafficking of GLUT4 to the outer cell membrane in skeletal muscle. Sulforaphane (SFN) has been suggested as a new potential anti-diabetic compound acting by reducing blood glucose levels through mechanisms not fully understood (1). The aim of this study is to investigate the effects SFN on TBC1D4 and GLUT4 gene expression in skeletal muscles of DIO mice, in order to elucidate the mechanism(s) through which SFN improves glucose homeostasis. Methodology: C57BL/6 mice (n=20) were fed with a high fat diet (60%) for 16 weeks to generate diet induced obese (DIO) mice with body weights between 45–50 gm. Thereafter, DIO mice received either SFN (5mg/kg BW) (n=10) or vehicle (n=10) as controls daily by intraperitoneal injections for four weeks. Glucose tolerance test (1g/kg BW, IP) and insulin sensitivity test (ITT) were conducted (1 IU insulin/ g BW, IP route) at the beginning and end of the third week of the injection. At the end of 4 weeks of the injection, samples of blood and skeletal muscles of both hindlimbs were collected. The expression levels of GLUT4 and TBC1D4 genes were analyzed by qRT-PCR. Blood was also used for glucose, adiponectin and insulin measurements. Results: SFN-treated DIO mice had significantly lower non-fasting blood glucose levels than vehicle-treated mice (194.16 ± 14.12 vs. 147.44 ± 20.31 mg/dL, vehicle vs. SFN, p value=0.0003). Furthermore, GTT results indicate that the blood glucose levels at 120 minutes after glucose infusion in was (199.83±34.53 mg/dl vs. 138.55±221.78 mg/dl) for vehicle vs. SFN with p=0.0011 respectively. ITT showed that SFN treatment did not enhance insulin sensitivity in DIO mice. Additionally, SFN treatment did not significantly change the expression of TBC1D4, and GLUT4 genes in skeletal muscles compared to vehicle treatment (p values &gt;0.05). Furthermore, SFN treatment did not significantly affect the systemic insulin (1.84±0.74 vs 1.54±0.55 ng/ml, p=0.436), or adiponectin (11.96 ±2.29 vs 14.4±3.33 ug/ml, p=0.551) levels in SFN vs. vehicle-treated DIO mice, respectively. Conclusion: SFN treatment improves glucose disposal in DIO mice, which is not linked to the gene expression of GLUT4 and TBC1D4 and its mechanism of glucose disposal in skeletal muscles. Furthermore, SFN treatment did not improve insulin level, and the insulin sensitizer hormone adiponectin as potential players for enhancing insulin sensitivity. 1. Axelsson AS, Tubbs E, Mecham B, Chacko S, Nenonen HA, Tang Y, et al. Sci Transl Med. 2017;9(394).

scholarly journals Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1

2011 ◽  
Vol 300 (2) ◽  
pp. E312-E320 ◽  
Author(s):  
Dan Wei ◽  
Rongya Tao ◽  
Yao Zhang ◽  
Morris F. White ◽  
X. Charlie Dong
Keyword(s):  
Gene Expression ◽  
Blood Glucose ◽  
Catalytic Domain ◽  
Wild Type Mouse ◽  
Diabetic Mouse ◽  
Luciferase Reporter ◽  
Wild Type ◽  
Hepatic Gluconeogenesis ◽  
Glucose Levels ◽  
Blood Glucose Levels

Protein deacetylase Sirt1 has been implicated in the regulation of hepatic gluconeogenesis; however, the mechanisms are not fully understood. To further elucidate how Sirt1 regulates gluconeogenesis, we took a loss-of-function approach by deleting the coding DNA sequence for the catalytic domain of the Sirt1 gene in the liver of a wild-type mouse (LKOSirt1) or a genetic diabetic mouse in which hepatic insulin receptor substrates 1 and 2 are deleted (DKOIrs1/2). Whereas LKOSirt1 mice exhibited normal levels of fasting and fed blood glucose, inactivation of Sirt1 in DKOIrs1/2 mice (TKOIrs1/2:Sirt1) reduced blood glucose levels and moderately improved systemic glucose tolerance. Pyruvate tolerance was also significantly improved in TKOIrs1/2:Sirt1 mice, suggesting that Sirt1 promotes hepatic gluconeogenesis in this diabetic mouse model. To understand why inactivation of hepatic Sirt1 does not alter blood glucose levels in the wild-type background, we searched for a potential cause and found that expression of small heterodimer partner (SHP, encoded by the Nr0b2 gene), an orphan nuclear receptor, which has been shown to suppress the activity of forkhead transcription factor FoxO1, was decreased in the liver of LKOSirt1 mice. Furthermore, our luciferase reporter assays and chromatin immunoprecipitation analysis revealed that the Nr0b2 gene is a target of FoxO1, which is also regulated by Sirt1. After the gene is upregulated, Nr0b2 can feed back and repress FoxO1- and Sirt1-activated G6pc and Pdk4 gene expression. Thus, our results suggest that Sirt1 can both positively and negatively regulate hepatic gluconeogenesis through FoxO1 and Nr0b2 and keep this physiological process in control.

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