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https://www.readbyqxmd.com/read/28911206/identification-of-the-molecular-dysfunction-caused-by-glutamate-dehydrogenase-s445l-mutation-responsible-for-hyperinsulinism-hyperammonemia
#1
Mariagrazia Grimaldi, Melis Karaca, Livia Latini, Estelle Brioudes, Thomas Schalch, Pierre Maechler
Congenital hyperinsulinism/hyperammonemia (HI/HA) syndrome gives rise to unregulated protein-induced insulin secretion from pancreatic beta-cells, fasting hypoglycemia and elevated plasma ammonia levels. Mutations associated with HI/HA were identified in the Glud1 gene, encoding for glutamate dehydrogenase (GDH). We aimed at identifying the molecular causes of dysregulation in insulin secretion and ammonia production conferred by the most frequent HI/HA mutation Ser445Leu. Following transduction with adenoviruses carrying the human GDH-wild type or GDH-S445L-mutant gene, immunoblotting showed efficient expression of the transgenes in all the investigated cell types...
September 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28833790/pycnogenol-cytotoxicity-in-pancreatic-ins-1e-%C3%AE-cells-induced-by-calcium-dysregulation
#2
Jana Viskupicova, Petronela Zizkova, Lucia Rackova, Lubica Horakova
Natural standardized flavonoid extract from the bark of Pinus pinaster, Pycnogenol (Pyc), was recently found to decrease intensively the activity of sarcoplasmic reticulum Ca(2+) -ATPase of rabbit skeletal muscle (SERCA1). On the basis of this inhibitory effect in a cell-free system and similarities of SERCA1 to its other isoforms, proapoptotic properties of Pyc may be expected in cellular systems. Pycnogenol (40-100 μg/mL) induced a concentration-dependent decrease of the viability of pancreatic INS-1E β cells associated with induction of apoptosis...
August 18, 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28767692/insulin-receptor-signaling-and-glucagon-like-peptide-1-effects-on-pancreatic-beta-cells
#3
Nunzia Caporarello, Cristina Parrino, Vincenzo Trischitta, Lucia Frittitta
Glucagon-like peptide-1 (GLP-1) is a potent gluco-incretin hormone, which plays a central role on pancreatic beta cell proliferation, survival and insulin secreting activity and whose analogs are used for treating hyperglycemia in type 2 diabetes mellitus. Notably, abnormal insulin signaling affects all the above-mentioned aspects on pancreatic beta cells. The aim of our study was to investigate whether the protective effects of GLP1-1 on beta cells are affected by altered insulin receptor signaling. To this end, several effects of GLP-1 were studied in INS-1E rat beta cells transfected either with an inhibitor of insulin receptor function (i...
2017: PloS One
https://www.readbyqxmd.com/read/28751022/er-resident-antioxidative-gpx7-and-gpx8-enzyme-isoforms-protect-insulin-secreting-ins-1e-%C3%AE-cells-against-lipotoxicity-by-improving-the-er-antioxidative-capacity
#4
Ilir Mehmeti, Stephan Lortz, Edward Avezov, Anne Jörns, Sigurd Lenzen
Increased circulating levels of saturated fatty acids (FFAs) and glucose are considered to be major mediators of β-cell dysfunction and death in T2DM. Although it has been proposed that endoplasmic reticulum (ER) and oxidative stress play a crucial role in gluco/lipotoxicity, their interplay and relative contribution to β-cell dysfunction and apoptosis has not been fully elucidated. In addition it is still unclear how palmitate - the physiologically most abundant long-chain saturated FFA - elicits ER stress and which immediate signals commit β-cells to apoptosis...
July 24, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28724742/the-myokine-irisin-is-released-in-response-to-saturated-fatty-acids-and-promotes-pancreatic-beta-cell-survival-and-insulin-secretion
#5
Annalisa Natalicchio, Nicola Marrano, Giuseppina Biondi, Rosaria Spagnuolo, Rossella Labarbuta, Immacolata Porreca, Angelo Cignarelli, Marco Bugliani, Piero Marchetti, Sebastio Perrini, Luigi Laviola, Francesco Giorgino
This study explored the role of irisin as a new pancreatic beta-cell secretagogue and survival factor and its potential role in the communication between skeletal muscle and pancreatic beta-cells under lipotoxic conditions. Recombinant irisin stimulated insulin biosynthesis and glucose-stimulated insulin secretion (GSIS) in a PKA-dependent manner, and prevented saturated fatty acid-induced apoptosis in human and rat pancreatic beta-cells, as well as in human and murine pancreatic islets, via AKT/BCL2 signaling...
July 19, 2017: Diabetes
https://www.readbyqxmd.com/read/28685559/both-3-5-diiodo-l-thyronine-t2-and-t3-modulate-glucose-induced-insulin-secretion
#6
P Fallahi, S M Ferrari, E Santini, S Camastra, G Frenzilli, M Puccini, F Goglia, A Lanni, P Marchetti, A Antonelli
3,5-diiodo-L-thyronine (T2), a naturally existing iodothyronine, has biological effects on humans, but no information is available on its action on pancreatic b-cells. We evaluated its effect vs triiodothyronine (T3), on glucose-induced insulin secretion in INS-1e cells, a rat insulinoma line, and on human islets. INS-1e were incubated in the presence/absence of T2 or T3 (0.1 nmol/L-10 μmol/L), and glucose (3.3, 7.5, 11.0, and 20 mmol/L). Insulin release and content (at 11.0 and 20 mmol/L glucose) were significantly (p less than 0...
April 2017: Journal of Biological Regulators and Homeostatic Agents
https://www.readbyqxmd.com/read/28665109/role-of-site-specific-asparagine-deamidation-in-islet-amyloid-polypeptide-amyloidogenesis-key-contributions-of-residues-14-and-21
#7
Phuong Trang Nguyen, Ximena Zottig, Mathew Sebastiao, Steve Bourgault
Deamidation of an asparagine residue is a spontaneous non-enzymatic post-translational modification that results in the conversion of asparagine into a mixture of aspartic acid and isoaspartic acid. This chemical conversion modulates protein conformation and physicochemical properties, which could lead to protein misfolding and aggregation. In this study, we investigated the effects of site-specific Asn deamidation on the amyloidogenicity of the aggregation-prone peptide islet amyloid polypeptide (IAPP). IAPP is a 37-residue peptidic hormone whose deposition as insoluble amyloid fibrils is closely associated with type 2 diabetes...
July 25, 2017: Biochemistry
https://www.readbyqxmd.com/read/28527697/antibiotics-induce-mitonuclear-protein-imbalance-but-fail-to-inhibit-respiration-and-nutrient-activation-in-pancreatic-%C3%AE-cells
#8
Jaime Santo-Domingo, Isabelle Chareyron, Charlotte Broenimann, Steve Lassueur, Andreas Wiederkehr
Chloramphenicol and several other antibiotics targeting bacterial ribosomes inhibit mitochondrial protein translation. Inhibition of mitochondrial protein synthesis leads to mitonuclear protein imbalance and reduced respiratory rates as confirmed here in HeLa and PC12 cells. Unexpectedly, respiration in INS-1E insulinoma cells and primary human islets was unaltered in the presence of chloramphenicol. Resting respiratory rates and glucose stimulated acceleration of respiration were also not lowered when a range of antibiotics including, thiamphenicol, streptomycin, gentamycin and doxycycline known to interfere with bacterial protein synthesis were tested...
August 15, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28510423/phycocyanin-functionalized-selenium-nanoparticles-reverse-palmitic-acid-induced-pancreatic-%C3%AE-cell-apoptosis-by-enhancing-cellular-uptake-and-blocking-reactive-oxygen-species-ros-mediated-mitochondria-dysfunction
#9
Chang Liu, Yuanting Fu, Chang-E Li, Tianfeng Chen, Xiaoling Li
Accumulation of palmitic acid (PA) in human bodies could cause damage to pancreatic β cells and lead to chronic diseases by generation of reactive oxygen species (ROS). Therefore, it is of great significance to search for nutrition-available agents with antioxidant activity to protect pancreatic islet cells against PA-induced damage. Phycocyanin (PC) and selenium (Se) have been reported to have excellent antioxidant activity. In this study, PC-functionalized selenium nanoparticles (PC-SeNPs) were synthesized to investigate the in vitro protective effects on INS-1E rat insulinoma β cells against PA-induced cell death...
June 7, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28502980/w2476-ameliorates-%C3%AE-cell-dysfunction-and-exerts-therapeutic-effects-in-mouse-models-of-diabetes-via-modulation-of-the-thioredoxin-interacting-protein-signaling-pathway
#10
Ting Li, Guang-Yao Lin, Li Zhong, Yan Zhou, Jia Wang, Yue Zhu, Yang Feng, Xiao-Qing Cai, Qing Liu, Olivier Nosjean, Jean A Boutin, Pierre Renard, De-Hua Yang, Ming-Wei Wang
Recent evidence shows that high glucose levels recruit carbohydrate response element-binding protein, which binds the promoter of thioredoxin-interacting protein (txnip), thereby regulating its expression in β-cells. Overexpression of txnip not only induces β-cell apoptosis but also reduces insulin production. Thus, the discovery of compounds that either inhibit TXNIP activity or suppress its expression was the focus of the present study. INS-1E cells stably transfected with either a txnip proximal glucose response element connected to a luciferase reporter plasmid (BG73) or full-length txnip promoter connected to a luciferase reporter plasmid (CL108) were used in primary and secondary high-throughput screening campaigns, respectively...
July 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28449948/sunitinib-specifically-augments-glucose-induced-insulin-secretion
#11
Stefan Z Lutz, Axel Ullrich, Hans-Ulrich Häring, Susanne Ullrich, Felicia Gerst
The tyrosine kinase inhibitor sunitinib is used for the treatment of numerous cancers in humans. In diabetic patients, sunitinib lowers blood glucose levels and improves glycaemic control. This study aims to analyse whether sunitinib has specific and direct effects on insulin secreting β-cells. Regulation of insulin secretion, of cellular cAMP levels and activation of signalling pathways were examined upon exposure of rat insulinoma INS-1E cells to sunitinib under specific stimulatory and inhibitory conditions...
April 24, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28438776/the-immunoproteasome-is-induced-by-cytokines-and-regulates-apoptosis-in-human-islets
#12
Morten Lundh, Marco Bugliani, Tina Dahlby, Danny Hung-Chieh Chou, Bridget Wagner, Seyed Mojtaba Ghiasi, Vincenzo De Tata, Zhifei Chen, Marianne Nissan Lund, Michael J Davies, Piero Marchetti, Thomas Mandrup-Poulsen
In addition to degrading misfolded and damaged proteins, the proteasome regulates the fate of cells in response to stress. The role of the proteasome in pro-inflammatory cytokine-induced human beta-cell apoptosis is unknown. Using INS-1, INS-1E and human islets exposed to combinations of IFNγ, IL-1β and TNFα with or without addition of small molecules, we assessed the role of the immunoproteasome in pancreatic beta-cell demise. Here, we show that cytokines induce the expression and activity of the immuno-proteasome in INS-1E cells and human islets...
June 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28432305/systematic-synergy-of-glucose-and-glp-1-to-stimulate-insulin-secretion-revealed-by-quantitative-phosphoproteomics
#13
Jia-Shu Tang, Qing-Run Li, Jia-Ming Li, Jia-Rui Wu, Rong Zeng
GLP-1 synergizes with glucose in regulating pancreatic β-cell function, including facilitating β-cell survival and insulin secretion. Though it has been widely accepted that phosphorylation is extremely important in regulating β-cell functions, our knowledge to the global mechanism is still limited. Here we performed a quantitative phosphoproteomics study to systematically present the synergistic regulation of INS-1E cell phosphoproteome mediated by glucose and GLP-1. We generated the largest pancreatic β-cell phosphoproteome by identifying 25,327 accurately localized phosphorylation sites on 5,389 proteins...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28404787/novel-atp-synthase-independent-mechanism-coupling-mitochondrial-activation-to-exocytosis-in-insulin-secreting-cells
#14
Umberto De Marchi, Aurelie Hermant, Jonathan Thevenet, Yann Ratinaud, Jaime Santo-Domingo, Denis Barron, Andreas Wiederkehr
Pancreatic beta-cells sense glucose promoting insulin secretion. Glucose sensing requires the sequential stimulation of glycolysis, mitochondrial metabolism and Ca(2+) entry. To elucidate how mitochondrial activation in beta-cells contributes to insulin secretion, we have compared the effects of glucose and the mitochondrial substrate methylsuccinate in INS-1E insulin secreting cells, at the respective concentrations they maximally activate mitochondrial respiration. Both substrates induced insulin secretion with distinct respiratory profiles, mitochondrial hyperpolarization, NADH production and ATP/ADP ratios...
April 12, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28390953/pannexin-2-deficiency-sensitizes-pancreatic-%C3%AE-cells-to-cytokine-induced-apoptosis-in%C3%A2-vitro-and-impairs-glucose-tolerance-in%C3%A2-vivo
#15
Lukas A Berchtold, Michela Miani, Thi A Diep, Andreas N Madsen, Valentina Cigliola, Maikel Colli, Jelena M Krivokapic, Flemming Pociot, Decio L Eizirik, Paolo Meda, Birgitte Holst, Nils Billestrup, Joachim Størling
Pannexins (Panx's) are membrane proteins involved in a variety of biological processes, including cell death signaling and immune functions. The role and functions of Panx's in pancreatic β-cells remain to be clarified. Here, we show Panx1 and Panx2 expression in isolated islets, primary β-cells, and β-cell lines. The expression of Panx2, but not Panx1, was downregulated by interleukin-1β (IL-1β) plus interferon-γ (IFNγ), two pro-inflammatory cytokines suggested to contribute to β-cell demise in type 1 diabetes (T1D)...
April 5, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28359774/trpv4-regulates-insulin-mrna-expression-and-ins-1e-cell-death-via-erk1-2-and-no-dependent-mechanisms
#16
M Billert, M Skrzypski, M Sassek, D Szczepankiewicz, T Wojciechowicz, S Mergler, M Z Strowski, K W Nowak
TRPV4 is a Ca(2+)-permeable, nonselective cation channel. Recently, TRPV4 was implicated in controlling peripheral insulin sensitivity, insulin secretion and apoptosis of pancreatic beta cells. Here, we characterize the role and potential mechanisms of TRPV4 in regulating insulin mRNA expression and cell death in insulin producing INS-1E cells and rat pancreatic islets. TRPV4 protein production was downregulated by siRNA. Intracellular calcium level was measured using Fluo-3 AM. Gene expression was studied by real-time PCR...
March 27, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28342877/quantitative-visualization-of-synchronized-insulin-secretion-from-3d-cultured-cells
#17
Takahiro Suzuki, Takao Kanamori, Satoshi Inouye
Quantitative visualization of synchronized insulin secretion was performed in an isolated rat pancreatic islet and a spheroid of rat pancreatic beta cell line using a method of video-rate bioluminescence imaging. Video-rate images of insulin secretion from 3D-cultured cells were obtained by expressing the fusion protein of insulin and Gaussia luciferase (Insulin-GLase). A subclonal rat INS-1E cell line stably expressing Insulin-GLase, named iGL, was established and a cluster of iGL cells showed oscillatory insulin secretion that was completely synchronized in response to high glucose...
May 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28286763/bisphenol-a-is-more-potent-than-phthalate-metabolites-in-reducing-pancreatic-%C3%AE-cell-function
#18
Nina Mickelson Weldingh, Lena Jørgensen-Kaur, Rune Becher, Jørn A Holme, Johanna Bodin, Unni C Nygaard, Anette Kocbach Bølling
Bisphenol A (BPA) and phthalates are common environmental contaminants that have been proposed to influence incidence and development of types 1 and 2 diabetes. Thus, effects of BPA and three phthalate metabolites (monoisobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and mono-(2-ethylhexyl) phthalate (MEHP)) were studied in the pancreatic β-cell line INS-1E, after 2-72 h of exposure to 5-500 μM. Three endpoints relevant to accelerated development of types 1 or 2 diabetes were investigated: β-cell viability, glucose-induced insulin secretion, and β-cell susceptibility to cytokine-induced cell death...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28222054/ucp2-expression-is-increased-in-pancreas-from-brain-dead-donors-and-involved-in-cytokine-induced-%C3%AE-cells-apoptosis
#19
Leticia A Brondani, Tatiana H Rech, Gabriela Boelter, Andrea C Bauer, Cristiane B Leitão, Décio L Eizirik, Daisy Crispim
BACKGROUND: Systemic inflammation associated with brain death (BD) decreases islet yield and quality, negatively affecting outcomes of human islet transplantation. A recent study from our group showed an increased expression of uncoupling protein-2 (UCP2) in pancreas from rats with BD as compared with controls. UCP2 is located in the mitochondrial inner membrane and regulates production of reactive oxygen species and glucose-stimulated insulin secretion. It has been suggested that UCP2 also plays a role in β cell apoptosis, but these findings remain controversial...
March 2017: Transplantation
https://www.readbyqxmd.com/read/28216051/morin-activates-the-nrf2-are-pathway-and-reduces-oxidative-stress-induced-dna-damage-in-pancreatic-beta-cells
#20
Pachamuthu Vanitha, Sankareswaran Senthilkumar, Sireesh Dornadula, Sundaramurthy Anandhakumar, Palanisamy Rajaguru, Kunka Mohanram Ramkumar
Oxidative stress is an important factor contributing to the pathogenesis of diabetes and its complications. In our earlier study, we demonstrated the antidiabetic efficacy of morin by regulating key enzymes of carbohydrate metabolism in diabetic rats. The present study was designed to assess the antigenotoxic potential of morin in pancreatic β-cells, using the COMET assay. To explore its potential mechanisms of action, three genotoxic agents, H2O2 which induces DNA damage by the generation of reactive oxygen species, streptozotocin (STZ) by RNS and Methyl methanesulfonate (MMS) by DNA alkylation was used...
April 15, 2017: European Journal of Pharmacology
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