scholarly journals Phagocytic NADPH Oxidase Links ARNO-Arf6 Signaling Pathway in Glucose-Stimulated Insulin Secretion from the Pancreatic �-Cell

2012 ◽  
Vol 30 (6) ◽  
pp. 1351-1362 ◽  
Author(s):  
Bhavaani Jayaram ◽  
Anjaneyulu Kowluru
Keyword(s):  
Insulin Secretion ◽  
Nadph Oxidase ◽  
Signaling Pathway ◽  
Pancreatic Cell ◽  
Glucose Stimulated Insulin Secretion

scholarly journals Protective Effect of 2-Dodecyl-6-Methoxycyclohexa-2, 5-Diene-1, 4-Dione, Isolated from Averrhoa Carambola L., Against Palmitic Acid-Induced Inflammation and Apoptosis in Min6 Cells by Inhibiting the TLR4-MyD88-NF-κB Signaling Pathway

2016 ◽  
Vol 39 (5) ◽  
pp. 1705-1715 ◽  
Author(s):  
Qiuqiao Xie ◽  
Shijun Zhang ◽  
Chunxia Chen ◽  
Juman Li ◽  
Xiaojie Wei ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Inflammatory Response ◽  
Protective Effect ◽  
Cell Viability ◽  
Palmitic Acid ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Averrhoa Carambola ◽  
Min6 Cells ◽  
Glucose Stimulated Insulin Secretion

Background/Aims: Studies have demonstrated that 2-dodecyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione (DMDD), isolated from the roots of Averrhoa carambola L., has significant therapeutic potential for the treatment of diabetes. However, the protective effect of DMDD against pancreatic beta cell dysfunction has never been reported. We investigated whether DMDD protected against palmitic acid-induced dysfunction in pancreatic β-cell line Min6 cells by attenuating the inflammatory response and apoptosis and to shed light on its possible mechanism. Methods: Cell viability was assessed by CCK-8. Glucose-stimulated insulin secretion levels and inflammatory cytokines levels were examined by ELISA. Apoptosis was assessed by Annexin V-FITC/PI Flow cytometry assay, Hoechst 33342/PI double-staining assay, and Transmission electron microscopy assay. Relative quantitative real-time PCR and western blot were used to determine the expressions of genes and proteins. Results: Cell viability and glucose-stimulated insulin secretion levels were increased in DMDD-pretreated Min6 cells. DMDD inhibited inflammatory cytokines IL-6, TNF-α and MCP-1 generations in palmitic acid (PA)-induced Min6 cells. Moreover, DMDD protected against PA-induced Min6 cells apoptosis and the expression of Cleaved-Caspase-3, -8 and -9 were down-regulated and the Bcl-2/Bax ratio was increased in DMDD-pretreated Min6 cells. In addition, the expression of TLR4, MyD88 and NF-κB were down-regulated in DMDD-pretreated Min6 cells and TAK-242-pretreated group cells. Conclusions: DMDD protected Min6 cells against PA-induced dysfunction by attenuating the inflammatory response and apoptosis, and its mechanism of this protection was associated with inhibiting the TLR4-MyD88-NF-κB signaling pathway.

scholarly journals Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4

2020 ◽  
Author(s):  
Ada Admin ◽  
Lydie Plecitá-Hlavatá ◽  
Martin Jabůrek ◽  
Blanka Holendová ◽  
Jan Tauber ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Nadph Oxidase ◽  
B Cell ◽  
Redox Signaling ◽  
Acid Oxidation ◽  
Nadph Oxidase 4 ◽  
Peripheral Insulin Resistance ◽  
Branched Chain ◽  
Glucose Stimulated Insulin Secretion

NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islet (PI) b-cells by an as yet unknown mechanism. We found NADPH oxidase, isoform-4 (NOX4), to be the major producer of cytosolic H<sub>2</sub>O<sub>2</sub>, essential for GSIS, while the increase in ATP/ADP alone was insufficient. The fast GSIS phase was absent in PIs from NOX4-null, b-cell-specific knockout mice (NOX4bKO) (not NOX2KO), and NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H<sub>2</sub>O<sub>2</sub> rescued GSIS in PIs from NOX4bKO mice. NOX4 silencing suppressed Ca<sup>2+</sup> oscillations and the patch-clamped ATP-sensitive potassium channel (K<sub>ATP</sub>) opened more frequently at high glucose. Mitochondrial H<sub>2</sub>O<sub>2</sub>, decreasing upon GSIS, provided an alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxide by electron-transport flavoprotein:Q-oxidoreductase. Unlike GSIS, this ceased with mitochondrial antioxidant SkQ1. Both NOX4KO and NOX4bKO strains exhibited impaired glucose tolerance and peripheral insulin resistance. Thus the redox signaling previously suggested to cause b-cell-self-checking – hypothetically induces insulin resistance when absent. In conclusion, ATP plus H<sub>2</sub>O<sub>2</sub> elevations constitute an essential switch-on signal of insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (partly for fatty acids). Redox signaling could be impaired by cytosolic antioxidants, hence those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage.

scholarly journals Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4

2020 ◽  
Author(s):  
Ada Admin ◽  
Lydie Plecitá-Hlavatá ◽  
Martin Jabůrek ◽  
Blanka Holendová ◽  
Jan Tauber ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Nadph Oxidase ◽  
B Cell ◽  
Redox Signaling ◽  
Acid Oxidation ◽  
Nadph Oxidase 4 ◽  
Peripheral Insulin Resistance ◽  
Branched Chain ◽  
Glucose Stimulated Insulin Secretion

NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islet (PI) b-cells by an as yet unknown mechanism. We found NADPH oxidase, isoform-4 (NOX4), to be the major producer of cytosolic H<sub>2</sub>O<sub>2</sub>, essential for GSIS, while the increase in ATP/ADP alone was insufficient. The fast GSIS phase was absent in PIs from NOX4-null, b-cell-specific knockout mice (NOX4bKO) (not NOX2KO), and NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H<sub>2</sub>O<sub>2</sub> rescued GSIS in PIs from NOX4bKO mice. NOX4 silencing suppressed Ca<sup>2+</sup> oscillations and the patch-clamped ATP-sensitive potassium channel (K<sub>ATP</sub>) opened more frequently at high glucose. Mitochondrial H<sub>2</sub>O<sub>2</sub>, decreasing upon GSIS, provided an alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxide by electron-transport flavoprotein:Q-oxidoreductase. Unlike GSIS, this ceased with mitochondrial antioxidant SkQ1. Both NOX4KO and NOX4bKO strains exhibited impaired glucose tolerance and peripheral insulin resistance. Thus the redox signaling previously suggested to cause b-cell-self-checking – hypothetically induces insulin resistance when absent. In conclusion, ATP plus H<sub>2</sub>O<sub>2</sub> elevations constitute an essential switch-on signal of insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (partly for fatty acids). Redox signaling could be impaired by cytosolic antioxidants, hence those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage.

scholarly journals Bayesian metamodeling of complex biological systems across varying representations

2021 ◽  
Author(s):  
Barak Raveh ◽  
Liping Sun ◽  
Kate L White ◽  
Tanmoy Sanyal ◽  
Jeremy Tempkin ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Network Model ◽  
Insulin Response ◽  
Receptor Activation ◽  
Divide And Conquer ◽  
Coarse Grained ◽  
Mathematical Representation ◽  
Insulin Metabolism ◽  
Pancreatic Cell ◽  
Glucose Stimulated Insulin Secretion

Comprehensive modeling of a whole cell requires an integration of vast amounts of information on various aspects of the cell and its parts. To divide-and-conquer this task, we introduce Bayesian metamodeling, a general approach to modeling complex systems by integrating a collection of heterogeneous input models. Each input model can in principle be based on any type of data and can describe a different aspect of the modeled system using any mathematical representation, scale, and level of granularity. These input models are (i) converted to a standardized statistical representation relying on Probabilistic Graphical Models, (ii) coupled by modeling their mutual relations with the physical world, and (iii) finally harmonized with respect to each other. To illustrate Bayesian metamodeling, we provide a proof-of-principle metamodel of glucose-stimulated insulin secretion by human pancreatic β-cells. The input models include a coarse-grained spatiotemporal simulation of insulin vesicle trafficking, docking, and exocytosis; a molecular network model of glucose-stimulated insulin secretion signaling; a network model of insulin metabolism; a structural model of glucagon-like peptide-1 receptor activation; a linear model of a pancreatic cell population; and ordinary differential equations for systemic postprandial insulin response. Metamodeling benefits from decentralized computing, while often producing a more accurate, precise, and complete model that contextualizes input models as well as resolves conflicting information. We anticipate Bayesian metamodeling will facilitate collaborative science by providing a framework for sharing expertise, resources, data, and models, as exemplified by the Pancreatic β-Cell Consortium.

scholarly journals Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4

2020 ◽  
Author(s):  
Ada Admin ◽  
Lydie Plecitá-Hlavatá ◽  
Martin Jabůrek ◽  
Blanka Holendová ◽  
Jan Tauber ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Nadph Oxidase ◽  
B Cell ◽  
Redox Signaling ◽  
Acid Oxidation ◽  
Nadph Oxidase 4 ◽  
Peripheral Insulin Resistance ◽  
Branched Chain ◽  
Glucose Stimulated Insulin Secretion

NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islet (PI) b-cells by an as yet unknown mechanism. We found NADPH oxidase, isoform-4 (NOX4), to be the major producer of cytosolic H<sub>2</sub>O<sub>2</sub>, essential for GSIS, while the increase in ATP/ADP alone was insufficient. The fast GSIS phase was absent in PIs from NOX4-null, b-cell-specific knockout mice (NOX4bKO) (not NOX2KO), and NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H<sub>2</sub>O<sub>2</sub> rescued GSIS in PIs from NOX4bKO mice. NOX4 silencing suppressed Ca<sup>2+</sup> oscillations and the patch-clamped ATP-sensitive potassium channel (K<sub>ATP</sub>) opened more frequently at high glucose. Mitochondrial H<sub>2</sub>O<sub>2</sub>, decreasing upon GSIS, provided an alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxide by electron-transport flavoprotein:Q-oxidoreductase. Unlike GSIS, this ceased with mitochondrial antioxidant SkQ1. Both NOX4KO and NOX4bKO strains exhibited impaired glucose tolerance and peripheral insulin resistance. Thus the redox signaling previously suggested to cause b-cell-self-checking – hypothetically induces insulin resistance when absent. In conclusion, ATP plus H<sub>2</sub>O<sub>2</sub> elevations constitute an essential switch-on signal of insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (partly for fatty acids). Redox signaling could be impaired by cytosolic antioxidants, hence those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage.

scholarly journals Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4

2020 ◽  
Author(s):  
Ada Admin ◽  
Lydie Plecitá-Hlavatá ◽  
Martin Jabůrek ◽  
Blanka Holendová ◽  
Jan Tauber ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Nadph Oxidase ◽  
B Cell ◽  
Redox Signaling ◽  
Acid Oxidation ◽  
Nadph Oxidase 4 ◽  
Peripheral Insulin Resistance ◽  
Branched Chain ◽  
Glucose Stimulated Insulin Secretion

NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islet (PI) b-cells by an as yet unknown mechanism. We found NADPH oxidase, isoform-4 (NOX4), to be the major producer of cytosolic H<sub>2</sub>O<sub>2</sub>, essential for GSIS, while the increase in ATP/ADP alone was insufficient. The fast GSIS phase was absent in PIs from NOX4-null, b-cell-specific knockout mice (NOX4bKO) (not NOX2KO), and NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H<sub>2</sub>O<sub>2</sub> rescued GSIS in PIs from NOX4bKO mice. NOX4 silencing suppressed Ca<sup>2+</sup> oscillations and the patch-clamped ATP-sensitive potassium channel (K<sub>ATP</sub>) opened more frequently at high glucose. Mitochondrial H<sub>2</sub>O<sub>2</sub>, decreasing upon GSIS, provided an alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxide by electron-transport flavoprotein:Q-oxidoreductase. Unlike GSIS, this ceased with mitochondrial antioxidant SkQ1. Both NOX4KO and NOX4bKO strains exhibited impaired glucose tolerance and peripheral insulin resistance. Thus the redox signaling previously suggested to cause b-cell-self-checking – hypothetically induces insulin resistance when absent. In conclusion, ATP plus H<sub>2</sub>O<sub>2</sub> elevations constitute an essential switch-on signal of insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (partly for fatty acids). Redox signaling could be impaired by cytosolic antioxidants, hence those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage.

Coixol amplifies glucose-stimulated insulin secretion via cAMP mediated signaling pathway

2019 ◽  
Vol 858 ◽  
pp. 172514 ◽  
Author(s):  
Abdul Hameed ◽  
Rahman M. Hafizur ◽  
M. Israr Khan ◽  
Abira Jawed ◽  
Hao Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Signaling Pathway ◽  
Glucose Stimulated Insulin Secretion

scholarly journals Melatonin modifies basal and stimulated insulin secretion via NADPH oxidase

2016 ◽  
Vol 231 (3) ◽  
pp. 235-244 ◽  
Author(s):  
Daniel Simões ◽  
Patrícia Riva ◽  
Rodrigo Antonio Peliciari-Garcia ◽  
Vinicius Fernandes Cruzat ◽  
Maria Fernanda Graciano ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Nadph Oxidase ◽  
Pancreatic Islets ◽  
Membrane Receptors ◽  
Melatonin Treatment ◽  
Isolated Pancreatic Islets ◽  
Ros Homeostasis ◽  
Basal Insulin Secretion ◽  
Glucose Stimulated Insulin Secretion

Melatonin is a hormone synthesized in the pineal gland, which modulates several functions within the organism, including the synchronization of glucose metabolism and glucose-stimulated insulin secretion (GSIS). Melatonin can mediate different signaling pathways in pancreatic islets through two membrane receptors and via antioxidant or pro-oxidant enzymes modulation. NADPH oxidase (NOX) is a pro-oxidant enzyme responsible for the production of the reactive oxygen specie (ROS) superoxide, generated from molecular oxygen. In pancreatic islets, NOX-derived ROS can modulate glucose metabolism and regulate insulin secretion. Considering the roles of both melatonin and NOX in islets, the aim of this study was to evaluate the association of NOX and ROS production on glucose metabolism, basal and GSIS in pinealectomized rats (PINX) and in melatonin-treated isolated pancreatic islets. Our results showed that ROS content derived from NOX activity was increased in PINX at baseline (2.8 mM glucose), which was followed by a reduction in glucose metabolism and basal insulin secretion in this group. Under 16.7 mM glucose, an increase in both glucose metabolism and GSIS was observed in PINX islets, without changes in ROS content. In isolated pancreatic islets from control animals incubated with 2.8 mM glucose, melatonin treatment reduced ROS content, whereas in 16.7 mM glucose, melatonin reduced ROS and GSIS. In conclusion, our results demonstrate that both basal and stimulated insulin secretion can be regulated by melatonin through the maintenance of ROS homeostasis in pancreatic islets.

scholarly journals Bayesian metamodeling of complex biological systems across varying representations

2021 ◽  
Vol 118 (35) ◽  
pp. e2104559118 ◽  
Author(s):  
Barak Raveh ◽  
Liping Sun ◽  
Kate L. White ◽  
Tanmoy Sanyal ◽  
Jeremy Tempkin ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Network Model ◽  
Insulin Response ◽  
Receptor Activation ◽  
Divide And Conquer ◽  
Coarse Grained ◽  
Mathematical Representation ◽  
Insulin Metabolism ◽  
Pancreatic Cell ◽  
Glucose Stimulated Insulin Secretion

Comprehensive modeling of a whole cell requires an integration of vast amounts of information on various aspects of the cell and its parts. To divide and conquer this task, we introduce Bayesian metamodeling, a general approach to modeling complex systems by integrating a collection of heterogeneous input models. Each input model can in principle be based on any type of data and can describe a different aspect of the modeled system using any mathematical representation, scale, and level of granularity. These input models are 1) converted to a standardized statistical representation relying on probabilistic graphical models, 2) coupled by modeling their mutual relations with the physical world, and 3) finally harmonized with respect to each other. To illustrate Bayesian metamodeling, we provide a proof-of-principle metamodel of glucose-stimulated insulin secretion by human pancreatic β-cells. The input models include a coarse-grained spatiotemporal simulation of insulin vesicle trafficking, docking, and exocytosis; a molecular network model of glucose-stimulated insulin secretion signaling; a network model of insulin metabolism; a structural model of glucagon-like peptide-1 receptor activation; a linear model of a pancreatic cell population; and ordinary differential equations for systemic postprandial insulin response. Metamodeling benefits from decentralized computing, while often producing a more accurate, precise, and complete model that contextualizes input models as well as resolves conflicting information. We anticipate Bayesian metamodeling will facilitate collaborative science by providing a framework for sharing expertise, resources, data, and models, as exemplified by the Pancreatic β-Cell Consortium.

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