| 1. |
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| 2. |
- Anvari, Ebrahim, et al.
(författare)
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The H-1-Receptor Antagonist Cetirizine Protects Partially Against Cytokine- and Hydrogen Peroxide-Induced beta-TC6 Cell Death In Vitro
- 2014
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 43:4, s. 624-629
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Tidskriftsartikel (refereegranskat)abstract
- Objective It has been proposed that the histamine 1 (H-1) receptor not only promotes allergic reactions but also modulates autoimmune diseases, such as type 1 diabetes. In line with this, it has recently been reported that the H-1-receptor antagonist cetirizine can counteract the activation of signals/factors pertinent to the pathogenesis of type 1 diabetes and cytokine-induced beta-cell destruction. Therefore, the overall aim of this study was to determine whether H-1-receptor antagonists affect cytokine-induced beta-cell death and signaling in vitro. Methods The insulin-producing cell line beta-TC6 was exposed to the proinflammatory cytokines interleukin 1 beta(+) interferon gamma, or hydrogen peroxide. The H-1-receptor antagonists desloratadine and cetirizine were added to the cell cultures and cell viability; macrophage inhibitory factor levels, c-Jun N-terminal kinase phosphorylation, c-Jun expression, and beta-catenin levels were analyzed by flow cytometry, real-time polymerase chain reaction, and immunoblotting. Results Cetirizine protected partially against both cytokine- and hydrogen peroxide-induced cell death. This effect was paralleled by an inhibition of cytokine-induced c-Jun N-terminal kinase phosphorylation, c-Jun induction, and a restoration of macrophage inhibitory factor contents. Cetirizine also increased the beta-TC6 cell contents of beta-catenin at basal conditions. Conclusions Our results indicate a protective effect of a specific H-1-receptor antagonist.
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| 3. |
- Barbu, Andreea, et al.
(författare)
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Blood flow in endogenous and transplanted pancreatic islets in anesthetized rats : Effects of lactate and pyruvate
- 2012
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 41:8, s. 1263-1271
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The objective of this study was to evaluate the effects of exogenously administered lactate and pyruvate on blood perfusion in endogenous and transplanted islets. METHODS: Anesthetized Wistar-Furth rats were given lactate or pyruvate intravenously, and regional blood perfusion was studied 3 or 30 minutes later with a microsphere technique. Separate rats received a 30-minute infusion of pyruvate or lactate into the portal vein before blood flow measurements. We also administered these substances to islet-implanted rats 4 weeks after transplantation and measured graft blood flow with laser Doppler flowmetry. The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was analyzed. RESULTS: The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was markedly up-regulated in transplanted as compared with endogenous islets. Administration of pyruvate, but not lactate, increased mesenteric blood flow after 3 minutes. Pyruvate decreased mesenteric blood flow after 30 minutes, whereas lactate decreased only islet blood flow. These responses were absent in transplanted animals. A continuous intraportal infusion of lactate or pyruvate increased selectively islet blood flow but did not affect blood perfusion of transplanted islets. CONCLUSIONS: Lactate and pyruvate affect islet blood flow through effects mediated by interactions between the liver and the nervous system. Such a response can help adjust the release of islet hormones during excess substrate concentrations.
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| 4. |
- Barbu, Andreea, et al.
(författare)
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Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells and Is Overexpressed in the Endocrine Pancreatic Tissue of an MEN1 Mouse Model
- 2016
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 45:4, s. 533-540
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Progranulin (PGRN) promotes cell growth and cell cycle progression in several cell types and contributes to tumorigenesis in diverse cancers. We have recently reported PGRN expression in islets and tumors developed in an MEN1 transgenic mouse. Here we sought to investigate PGRN expression and regulation after exposure to hypoxia as well as its effects on pancreatic islet cells and neuroendocrine tumors (NETs) in MEN1 mice.METHODS: Gene and protein expression were analyzed by quantitative polymerase chain reaction, immunohistochemistry, and Western blot. We also investigated PGRN expression in samples from patients carrying pancreatic NETs associated or not with the multiple endocrine neoplasia 1 syndrome, using enzyme-linked immunosorbent assay and immunohistochemistry analysis.RESULTS: Progranulin is upregulated in tumors and islets of the MEN1 mouse as well as in the serum of patients with pancreatic NETs associated with glucagonoma syndrome. In normal mice islets and pancreatic tumors, PGRN expression was strongly potentiated by hypoxia. Progranulin promotes cell proliferation in islet cells and βTC-6 cells, a process paralleled by activation of the mitogen-activated protein kinase signaling cascade.CONCLUSIONS: Our findings identify PGRN as an effective inducer of pancreatic islet cell proliferation and a possible important factor for pancreatic endocrine tumor development.
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| 5. |
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| 6. |
- Blind, Per Jonas, et al.
(författare)
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Carboxylic ester hydrolase : a serum marker of acute pancreatitis
- 1987
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 2:5, s. 597-603
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Tidskriftsartikel (refereegranskat)abstract
- By use of an enzyme-linked immunosorbent assay we established serum reference values of carboxylic ester hydrolase, a pancreatic secretory lipolytic enzyme, and explored to see if a raised serum level is indicative of acute pancreatitis. Postoperative elevation of carboxylic ester hydrolase was observed in seven out of ten patients who underwent pancreatic surgery. Serum levels of carboxylic ester hydrolase and amylase were determined in 129 patients admitted due to abdominal emergency conditions. Amylase was elevated in 27 patients, and in 20 of these raised carboxylic ester hydrolase levels affirmed the diagnosis acute pancreatitis. In five out of the seven patients with elevated amylase alone no etiologic factor of acute pancreatitis was found. Another 11 patients had raised carboxylic ester hydrolase levels without concomitant elevation of amylase. In all these patients, a likely cause of pancreatic inflammation was identifiable. Hence, a raised carboxylic ester hydrolase level, even in presence of normal amylase, could be indicative of acute pancreatic inflammation.
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| 9. |
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| 11. |
- Ding, Jun-Li, et al.
(författare)
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Attenuation of Acute Pancreatitis by Peroxisome Proliferator-Activated Receptor-α in Rats: The Effect on Toll-Like Receptor Signaling Pathways
- 2013
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Ingår i: Pancreas. - : Lippincott, Williams and Wilkins. - 0885-3177 .- 1536-4828. ; 42:1, s. 114-122
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The peroxisome proliferator-activated receptor-α (PPAR-α) has attracted considerable attention for its anti-inflammatory properties; however, Toll-like receptor (TLR) pathways have an essential proinflammatory role in acute pancreatitis (AP). This study aimed to evaluate the attenuation of inflammation by PPAR-α and to investigate the interaction between PPAR-α and TLR pathways in AP.Methods: Acute pancreatitis was induced in rats by administration of cerulein. The PPAR-α agonist WY14643 and/or antagonist MK886 was administered. The severity of AP was determined by measuring serum amylase, lipase, Ca2+, pathological changes, myeloperoxidase activity, serum levels of interleukin (IL)-6, and intercellular adhesion molecule-1 (ICAM-1). The TLR2 and TLR4 messenger RNA (mRNA) and proteins were determined by real-time reverse transcriptase polymerase chain reaction and Western blotting, respectively. The mRNA expressions of target molecules of TLR pathways, including IL-6, IL-10, ICAM-1, and tumor necrosis factor α were also measured.Results: Treatment with WY14643 significantly decreased amylase, lipase, myeloperoxidase activity, pathological scores, IL-6, and ICAM-1 levels. The TLR2 and TLR4 mRNA and proteins were markedly decreased after treatment with WY14643, along with IL-6, ICAM-1, and tumor necrosis factor α mRNA levels. However, these effects were completely reversed by the coadministration of MK886.Conclusions: Activation of PPAR-α played a protective role in AP, partially mediated by modulation of TLR pathways.
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| 12. |
- Ericsson, Maja, et al.
(författare)
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Presence of Human Herpesvirus 6B in the Pancreas of Subjects With and Without Type 1 Diabetes
- 2017
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 46:10, s. 1341-1346
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aims of this study were to investigate the presence of human herpesvirus 6 (HHV6) A and B in human pancreata and to search for signs of active infection in this organ of subjects with and without type 1 diabetes (T1D). Methods: Pancreata from brain-dead organ donors with and without T1D were examined for the presence of HHV6 genomic sequences by polymerase chain reaction (PCR), transcripts by reverse transcriptase-PCR, and protein by immunohistochemistry. Quantitative PCR of isolated pancreatic islets and exocrine cell clusters was used to determine the intrapancreatic location of HHV6 DNA. Results: Human herpesvirus 6B genomic sequences were present in 1 of 2 donors who died of acute-onset T1D, 4 of 6 donors with long-standing T1D, and 9 of 12 nondiabetic donors. Higher copy numbers of HHV6B DNA were present in isolated islets than in exocrine tissue from the same donors. No signs of active HHV6 transcription were found. Human herpesvirus 6A was not present in any tested pancreas. Conclusions: The herein presented data demonstrate, for the first time, the presence of a latent HHV6B infection in the pancreas and islets of Langerhans. Whether this virus can contribute to disease in the pancreas remains to be determined.
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| 13. |
- Fan, BG, et al.
(författare)
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Photodynamic therapy for pancreatic cancer
- 2007
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Ingår i: Pancreas. - : Ovid Technologies (Wolters Kluwer Health). - 1536-4828 .- 0885-3177. ; 34:4, s. 385-389
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Tidskriftsartikel (refereegranskat)
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| 14. |
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| 15. |
- Frisk, Peter, et al.
(författare)
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Coxsackievirus B3 infection affects metal-binding/transporting proteins and trace elements in the pancreas in mice
- 2007
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Ingår i: Pancreas. - : Ovid Technologies (Wolters Kluwer Health). - 0885-3177 .- 1536-4828. ; 35:3, s. e37-e44
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The trigger of juvenile diabetes has been suggested to be an interaction between a virus and trace elements, where enteroviruses, including coxsackievirus B3 (CVB3), have been discussed as potential initiators. The aim of this study was to investigate the effects in the pancreas on gene expressions of metallothionein 1 (MT1), divalent metal transporter 1 (DMT1), and zinc transporter 5 (ZnT-5) and concomitant changes in iron (Fe), copper (Cu), and zinc (Zn) in serum and pancreas of Balb/c mice on days 3, 6, and 9 of CVB3 infection. Methods: Trace elements were measured through inductively coupled plasma-mass spectrometry, and CVB3, MT1, DMT1, and ZnT-5 were measured by reverse transcription/polymerase chain reaction. Results: Virus was found in the pancreas on all days, with a peak on day 3. Infection tended to increase Fe in both serum and the pancreas. The Cu/Zn ratio in the pancreas increased early in the infection because of a great decrease in Zn. In serum, the Cu/Zn ratio was not increased until day 9 of the disease. In the pancreas, MT1 decreased, whereas DMT1 tended to increase on day 6, and ZnT-5 increased progressively during the course of the disease. Conclusions: Virus-induced changes in trace elements, MT1, DMT1, and ZnT-5 in the pancreas may reflect early stages of the development of pancreatitis and prestages of diabetic disease.
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| 16. |
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| 17. |
- Gustavsson, Natalia, et al.
(författare)
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Pancreatic beta cells from db/db mice show cell-specific [Ca2+]i and NADH responses to glucose but not to alpha-ketoisocaproic acid.
- 2005
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 31:3, s. 242-250
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We recently showed that timing and magnitude of the glucose-induced cytoplasmic calcium [Ca2+]i response are reproducible and specific for the individual beta cell. We now wanted to identify which step(s) of stimulus-secretion coupling determine the cell specificity of the [Ca2+]i response and whether cell specificity is lost in beta-cells from diabetic animals. Besides glucose, we studied the effects of glyceraldehyde, a glycolytic intermediate, and alpha-ketoisocaproic acid (KIC), a mitochondrial substrate. METHODS: Early [Ca2+]i changes were studied stimulations in fura-2-labeled dispersed beta cells from lean, ob/ob, and db/db mice. Lag time and peak height were compared during 2 consecutive stimulations with the same stimulator. Nicotinamide adenine dinucleotide (NADH) responses to glucose and KIC were studied as a measure of metabolic flux. RESULTS: Both glyceraldehyde and KIC induced cell-specific temporal responses in lean mouse beta cells with a correlation between lag times for [Ca2+]i rise during the first and second stimulation. Beta cells from ob/ob and db/db mice showed cell-specific temporal [Ca2+]i responses to glucose and glyceraldehyde but not to KIC. Glucose induced cell-specific NADH responses in all 3 models, but KIC did so only in lean mouse [beta] cells. CONCLUSIONS: A cell-specific response may be induced at several steps of beta-cell stimulus-secretion coupling. Mitochondrial metabolism generates a cell-specific response in normal beta cells but not in db/db and ob/ob mouse beta cells.
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| 18. |
- Gylfe, Erik, et al.
(författare)
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The Neurotransmitter ATP Triggers Ca2+ Responses Promoting Coordination of Pancreatic Islet Oscillations
- 2012
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 41:2, s. 258-263
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Pulsatile insulin release into the portal vein is critically dependent on entrainment of the islets in the pancreas into a common oscillatory phase. Because the pulses reflect periodic variations of the cytoplasmic Ca2+ concentration ([Ca2+](i)), we studied whether the neurotransmitters adenosine triphosphate (ATP) and acetylcholine promote synchronization of [Ca2+](i) oscillations between islets lacking contact. Methods: Medium-sized and small mouse islets and cell aggregates were used for measuring [Ca2+](i) with the indicator fura-2. Results: Exposure to acetylcholine resulted in an initial [Ca2+](i) peak followed by disappearance of the [Ca2+](i) oscillations induced by 11-mmol/L glucose. The effect of ATP was often restricted to an elusive [Ca2+](i) peak. The incidence of distinct [Ca2+](i) responses to ATP increased under conditions (accelerated superfusion, small islets, or cell aggregates) intended to counteract purinoceptor desensitization owing to intercellular accumulation of ATP. Attempts to imitate neural activity by brief (15 seconds) exposure to ATP or acetylcholine resulted in temporary synchronization of the glucose-induced [Ca2+](i) oscillations between islets lacking contact. Conclusions: The data support the idea that purinergic signaling has a key role for coordinating the oscillatory activity of the islets in the pancreas, reinforcing previous arguments for the involvement of nonadrenergic, noncholinergic neurons.
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| 19. |
- Hellman, Bo, et al.
(författare)
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Sulfonylurea blockade of KATP channels unmasks a distinct type of glucose-induced Ca2+ decrease in pancreatic β-cells
- 2017
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 46:4, s. 467-475
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: This study aimed to explore how sulfonylurea blockade of K-ATP channels affects the early Ca2+ signals for glucose generation of insulin release. Methods: Cytoplasmic Ca2+ was measured with ratiometric microfluorometry in isolated mouse islets loaded with Fura-PE3. Results: After sulfonylurea blockade of the K-ATP channels (50 mu M-1 mM tolbutamide or 1 mu M-1 mM gliclazide), increase of glucose from 3 to 20 mM resulted in suppression of elevated Ca2+ during a 3- to 5-minute period. The Ca2+ decrease was shorter after inhibition of the Na/K pump with ouabain (10 and 100 mu M) but prolonged when the alpha(2A) adrenoceptors were activated with clonidine (1 and 10 nM) or epinephrine (10 nM). Inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase pump with 10 mu M cyclopiazonic acid counteracted the action of 10 nM clonidine, making the Ca2+ decrease shorter than in controls. Extended superfusion of islets with a medium containing 20 mM glucose and 1 mM tolbutamide sometimes resulted in delayed appearance of Ca2+ oscillations mediated by periodic interruption of elevated Ca2+. Conclusions: Increase of glucose generates prompt suppression of cytoplasmic Ca2+ in beta-cells lacking functional KATP channels. Activation of alpha(2A) adrenoceptors markedly prolongs the period of glucose-induced Ca2+ decrease, an effect counteracted by cyclopiazonic acid.
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| 20. |
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| 22. |
- Ivanics, Tommy, et al.
(författare)
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Small Cell Carcinoma of the Pancreas
- 2016
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Ingår i: Pancreas. - : Ovid Technologies (Wolters Kluwer Health). - 0885-3177 .- 1536-4828. ; 45:10, s. 1461-1466
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Tidskriftsartikel (refereegranskat)
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| 23. |
- Krishnan, Kalaiselvan, et al.
(författare)
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Calcium Signaling in a Genetically Engineered Human Pancreatic beta-Cell Line
- 2015
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 44:5, s. 773-777
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The use of primary human -cells for studying Ca2+ signaling is limited by the scarcity of human pancreatic islets. Rodent insulinoma cell lines are widely used, but it is difficult to extrapolate results obtained from rodent cells to human. Recently, a genetically engineered human -cell line EndoC-BH1 has been developed. We have examined whether the EndoC-BH1 cells could be used as a model for studying Ca2+ signaling in the -cells. Methods We used microscope-based fluorometry to measure cytoplasmic-free Ca2+ concentration from fura-2-loaded single EndoC-BH1 cells cultured on glass cover slips. Ca2+ responses to different agonists of insulin secretion were studied. Insulin secretion was measured by radioimmunoassay. Results EndoC-BH1 cells secreted insulin in response to glucose in a dose-dependent manner, and the secretion was enhanced by GLP-1 (glucagon-like peptide 1). Glucose, potassium chloride, carbachol, l-arginine, and tolbutamide increased cytoplasmic-free Ca2+ concentration in the EndoC-BH1 cells. We found that GLP-1 was essential for Ca2+ response to glucose and tolbutamide. Conclusions We concluded that the EndoC-BH1 cells can be used as model cells to study Ca2+ signaling and stimulus-secretion coupling in the human -cells.
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| 24. |
- Krishnan, Kalaiselvan, et al.
(författare)
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Calcium signaling in a genetically engineered human pancreatic β-cell line
- 2015
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 44:5, s. 773-777
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The use of primary human β-cells for studying Ca2+ signalingis limited by the scarcity of human pancreatic islets. Rodent insulinomacell lines are widely used, but it is difficult to extrapolate results obtainedfrom rodent cells to human. Recently, a genetically engineered humanβ-cell line EndoC-BH1 has been developed. We have examined whetherthe EndoC-BH1 cells could be used as a model for studying Ca2+ signalingin the β-cells.Methods: We used microscope-based fluorometry to measure cytoplasmicfreeCa2+ concentration from fura-2–loaded single EndoC-BH1 cellscultured on glass cover slips. Ca2+ responses to different agonists of insulinsecretion were studied. Insulin secretion was measured by radioimmunoassay.Results: EndoC-BH1 cells secreted insulin in response to glucose ina dose-dependent manner, and the secretion was enhanced by GLP-1(glucagon-like peptide 1). Glucose, potassium chloride, carbachol, L-arginine,and tolbutamide increased cytoplasmic-free Ca2+ concentration in theEndoC-BH1 cells. We found that GLP-1 was essential for Ca2+ responseto glucose and tolbutamide.Conclusions: We concluded that the EndoC-BH1 cells can be used asmodel cells to study Ca2+ signaling and stimulus-secretion coupling inthe human β-cells.
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| 25. |
- Krishnan, Kalaiselvan, et al.
(författare)
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Role of Transient Receptor Potential Melastatin-like Subtype 5 Channel in Insulin Secretion From Rat beta-Cells
- 2014
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 43:4, s. 597-604
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Tidskriftsartikel (refereegranskat)abstract
- Objective Several studies have reported that the transient receptor potential melastatin-like subtype 5 (TRPM5) channel, a Ca2+-activated monovalent cation channel, is involved in the stimulus-secretion coupling in the mouse pancreatic beta-cells. We have studied the role of the TRPM5 channel in regulating insulin secretion and cytoplasmic free Ca2+ concentration ([Ca2+](i)) in the rat beta-cells by using triphenylphosphine oxide, a selective inhibitor of the channel. Methods Insulin secretion from islets from Sprague-Dawley rats was measured in batch incubations. Cytoplasmic free Ca2+ concentration was measured from single beta-cells by fura-2-based microfluorometry. Results Triphenylphosphine oxide did not alter insulin secretion and [Ca2+](i) response triggered by KCl or fructose. It inhibited insulin secretion in response to glucose, l-arginine, and glucagon-like peptide 1. It also inhibited glucose-induced insulin secretion by mechanisms that are independent of the adenosine triphosphate-sensitive potassium channels and [Ca2+](i) increase. Conclusions Our results suggest that in the rat islets, TRPM5 is involved in mediating insulin secretion by glucose and l-arginine and in potentiating the glucose-induced insulin secretion by glucagon-like peptide 1.
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