TCF7L2 controls insulin gene expression and insulin secretion in mature pancreatic β-cells

Genetic studies have linked the risk of Type 2 diabetes with SNPs (single nucleotide polymorphisms) in the gene encoding the Wnt signalling-associated transcription factor, TCF7L2 (T-cell factor 7-like 2). The risk alleles have been associated with reduced glucose and GLP-1 (glucagon-like peptide 1)-stimulated insulin secretion. Recent evidence has suggested that inheritance of the at-risk T allele at SNP rs7903146 may increase the expression of TCF7L2 in adult human islets. However, the cellular mechanisms by which changes in TCF7L2 levels may affect insulin secretion are unclear. In the present paper, we describe the use of RNA silencing to investigate the role of TCF7L2 on insulin secretion and gene expression in rodent islets. We find that reduced TCF7L2 expression reduces glucose-simulated insulin secretion and insulin gene expression while slightly potentiating glucose stimulated changes in intracellular free Ca2+ concentrations.

Download Full-text

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.

Download Full-text

Leptin Suppression of Insulin Secretion and Gene Expression in Human Pancreatic Islets: Implications for the Development of Adipogenic Diabetes Mellitus1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.84.2.5460 ◽

1999 ◽

Vol 84 (2) ◽

pp. 670-676 ◽

Cited By ~ 2

Author(s):

Jochen Seufert ◽

Timothy J. Kieffer ◽

Colin A. Leech ◽

George G. Holz ◽

Wolfgang Moritz ◽

...

Keyword(s):

Gene Expression ◽

Insulin Secretion ◽

Pancreatic Islets ◽

Ribonucleic Acid ◽

Leptin Receptor ◽

Human Islets ◽

Β Cells ◽

Messenger Ribonucleic Acid ◽

Fluorescence Confocal Microscopy ◽

Glucagon Like Peptide 1

Previously we demonstrated the expression of the long form of the leptin receptor in rodent pancreatic β-cells and an inhibition of insulin secretion by leptin via activation of ATP-sensitive potassium channels. Here we examine pancreatic islets isolated from pancreata of human donors for their responses to leptin. The presence of leptin receptors on islet β-cells was demonstrated by double fluorescence confocal microscopy after binding of a fluorescent derivative of human leptin (Cy3-leptin). Leptin (6.25 nm) suppressed insulin secretion of normal islets by 20% at 5.6 mm glucose. Intracellular calcium responses to 16.7 mm glucose were rapidly reduced by leptin. Proinsulin messenger ribonucleic acid expression in islets was inhibited by leptin at 11.1 mm, but not at 5.6 mm glucose. Leptin also reduced proinsulin messenger ribonucleic acid levels that were increased in islets by treatment with 10 nm glucagon-like peptide-1 in the presence of either 5.6 or 11.1 mm glucose. These findings demonstrate direct suppressive effects of leptin on insulin-producingβ -cells in human islets at the levels of both stimulus-secretion coupling and gene expression. The findings also further indicate the existence of an adipoinsular axis in humans in which insulin stimulates leptin production in adipocytes and leptin inhibits the production of insulin in β-cells. We suggest that dysregulation of the adipoinsular axis in obese individuals due to defective leptin reception byβ -cells may result in chronic hyperinsulinemia and may contribute to the pathogenesis of adipogenic diabetes.

Download Full-text

Lack of preservation of insulin gene expression by a Glucagon-Like Peptide 1 agonist or a Dipeptidyl Peptidase 4 inhibitor in an in vivo model of glucolipotoxicity

Diabetes Research and Clinical Practice ◽

10.1016/j.diabres.2009.12.020 ◽

2010 ◽

Vol 87 (3) ◽

pp. 322-328 ◽

Cited By ~ 6

Author(s):

Ghislaine Fontés ◽

Derek K. Hagman ◽

Martin G. Latour ◽

Meriem Semache ◽

Vincent Poitout

Keyword(s):

Gene Expression ◽

Dipeptidyl Peptidase ◽

Insulin Gene ◽

In Vivo Model ◽

Dipeptidyl Peptidase 4 ◽

Dipeptidyl Peptidase 4 Inhibitor ◽

Insulin Gene Expression ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Download Full-text

Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells.

Journal of Clinical Investigation ◽

10.1172/jci119105 ◽

1996 ◽

Vol 98 (12) ◽

pp. 2786-2793 ◽

Cited By ~ 147

Author(s):

J B Redmon ◽

L K Olson ◽

M B Armstrong ◽

M J Greene ◽

R P Robertson

Keyword(s):

Gene Expression ◽

Insulin Secretion ◽

Human Insulin ◽

Insulin Gene ◽

Mrna Levels ◽

Human Insulin Gene ◽

Insulin Gene Expression ◽

Insulin Mrna

Download Full-text

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.

Download Full-text

Regulation and specificity of glucose-stimulated insulin gene expression in human islets of Langerhans

FEBS Letters ◽

10.1016/0014-5793(87)80523-9 ◽

1987 ◽

Vol 223 (1) ◽

pp. 131-137 ◽

Cited By ~ 23

Author(s):

Peter Hammonds ◽

Paul N. Schofield ◽

Stephen J.H. Ashcroft ◽

Robert Sutton ◽

Derek W.R. Gray

Keyword(s):

Gene Expression ◽

Islets Of Langerhans ◽

Human Islets ◽

Insulin Gene ◽

Human Islets Of Langerhans ◽

Insulin Gene Expression

Download Full-text

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.

Download Full-text

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.

Download Full-text