Glucose Induces Anion Conductance and Cytosol-To-Membrane Transposition of ICln in INS-1E Rat Insulinoma Cells

Jakab, Martin; Grundbichler, Michael; Benický, Július; Ravasio, Andrea; Chwatal, Sabine; Schmidt, Sabine; Štrbák, Vladimír; Fürst, Johannes; Paulmichl, Markus; Ritter, Markus

doi:10.1159/000095131

Cited by 31 publications

(27 citation statements)

References 43 publications

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“…However, the unexpected effect of carbenoxolone can be explained by that this compound has been described as a potent inhibitor of volume-regulated anionic channels also known as VRACs [16]. There is an accumulating body of evidence that the VRAC is involved in the nutrient-sensing mechanism of the pancreatic beta cell, as both glucose [17,18] and fatty acids [18] have been shown to cause VRAC activation. While the molecular identity of the VRAC is still unknown, it has been suggested as a critical component in an alternate route for depolarization of the pancreatic beta cell [19], a route that is independent of metabolic coupling and subsequent activation of K ATP channels.…”

Section: Discussionmentioning

confidence: 99%

High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y13 receptor

Tan

Voss

Svensson

et al. 2012

Purinergic Signalling

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While high levels of glucose and saturated fatty acids are known to have detrimental effects on beta cell function and survival, the signalling pathways mediating these effects are not entirely known. In a previous study, we found that ADP regulates beta cell insulin secretion and beta cell apoptosis. Using MIN6c4 cells as a model system, we investigated if autocrine/paracrine mechanisms of ADP and purinergic receptors are involved in this process. High glucose (16.7 mmol/l) and palmitate (100 μmol/l) rapidly and potently elevated the extracellular ATP levels, while mannitol was without effect. Both tolbutamide and diazoxide were without effect, while the calcium channel blocker nifedipine, the volume-regulated anion channels (VRAC) inhibitor NPPB, and the pannexin inhibitor carbenoxolone could inhibit both effects. Similarly, silencing the MDR1 gene also blocked nutrient-generated ATP release. These results indicate that calcium channels and VRAC might be involved in the ATP release mechanism. Furthermore, high glucose and palmitate inhibited cAMP production, reduced cell proliferation in MIN6c4 and increased activated Caspase-3 cells in mouse islets and in MIN6c4 cells. The P2Y 13 -specific antagonist MRS2211 antagonized all these effects. Further studies showed that blocking the P2Y 13 receptor resulted in enhanced CREB, Bad and IRS-1 phosphorylation, which are known to be involved in beta cell survival and insulin secretion. These findings provide further support for the concept that P2Y 13 plays an important role in beta cell apoptosis and suggest that autocrine/ paracrine mechanisms, related to ADP and P2Y 13 receptors, contribute to glucolipotoxicity.

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Section: Discussionmentioning

confidence: 99%

High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y13 receptor

Tan

Voss

Svensson

et al. 2012

Purinergic Signalling

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“…In contrast to hypotonic cell swelling, no significant RVD is evident during glucoseinduced cell swelling [66,67]. The fact that glucoseinduced insulin secretion is completely blocked at conditions when swelling-induced secretion is active (such as Ca 2+ depletion, MPA and BEL treatment) shows that swelling does not play important role in glucose-stimulated insulin release.…”

Section: +mentioning

confidence: 98%

“…It is of interest that rising of glucose concentration in the medium also increases rat pancreatic β [66] or insulinoma cell [67] volume. In contrast to hypotonic cell swelling, no significant RVD is evident during glucoseinduced cell swelling [66,67].…”

Section: +mentioning

confidence: 99%

Cell Swelling-Induced Signaling for Insulin Secretion Bypasses Steps Involving G Proteins and PLA2 and is N-ethylmaleimide Insensitive

Bačová

Orečná

Hafko

et al. 2007

Cell Physiol Biochem

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Background: This study was undertaken to examine putative mechanisms of calcium independent signal transduction pathway of cell swelling-induced insulin secretion. Methods: The role of phospholipase A₂, G proteins, and soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) in insulin secretion induced by 30% hypotonic medium was studied using isolated rat pancreatic islets. Results: In contrast to glucose stimulation, osmotically induced insulin secretion from pancreatic islets was not inhibited by 10 µmol/l bromoenol lactone, an iPLA₂ (Ca²⁺ independent phospholipase) inhibitor. Similarly, preincubation of islets for 20 hours with 25 µg/ml mycophenolic acid to inhibit GTP synthesis fully abolished glucose-induced insulin secretion but was without effect on hypotonicity stimulated insulin release. Glucose-induced insulin secretion was prevented by preincubation with 20 nmol/l tetanus toxin (TeTx), a metalloprotease inactivating soluble SNARE. Cell swelling-induced insulin secretion was inhibited by TeTx in the presence of calcium ions but not in calcium depleted medium. The presence of N-ethylmaleimide (NEM, 5 mmol/l, another inhibitor of SNARE proteins) in the medium resulted in high basal insulin secretion and lacking response to glucose stimulation. In contrast, high basal insulin secretion from NEM treated islets further increased after hypotonic stimulation. Conclusion: G proteins and iPLA₂ – putative mediators of Ca²⁺ independent signaling pathway participate in glucose but not in hypotonicity-induced insulin secretion. Hypotonicity-induced insulin secretion is sensitive to clostridial neurotoxin TeTx but is resistant to NEM.

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“…These currents are activated by cell swelling in response to glucose uptake or exposure to a hypotonic medium (referred to as ICl swell , ICl glucose or ICl islet ) and by intracellular ATP and other adenosine nucleotides [5][6][7][8][9][10]. In a previous work we provided evidence that ICl glucose and ICl swell are identical currents and found that glucose uptake induces a volume increase sufficient to activate the conductance in INS-1E rat insulinoma cells [11]. Importantly, Cl -efflux depolarizes the cell membrane which contributes to K ATP channel-independent triggering of insulin release upon cell swelling.…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Inhibits Electrical Activity and Insulin Release from Insulinoma Cells by Block of Voltage-Gated Ca2+ Channels and Swelling-Dependent Cl- Currents

Jakab

Lach²,

Bačová³

et al. 2008

Cell Physiol Biochem

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The phytostilbene resveratrol (RV) improves the metabolic state in animal models by increasing the insulin responsiveness of tissues and there is evidence that RV affects insulin secretion from native β-cells and insulinoma cells. In whole cell patch clamp experiments on clonal rat INS-1E cells we used high extracellular glucose (20 mM), extracellular hypotonicity (30%) or tolbutamide (100 μM) to elicit membrane depolarizations and electrical activity. Application of RV (50 μM) repolarized the cells, terminated electrical activity and prevented the hypotonicity-induced depolarization. These effects were fully reversible and intermittent application of RV restored tolbutamide-induced electrical activity after desensitization. Glucose-induced depolarization was counteracted by RV in presence of iberiotoxin (50 nM), showing that the RV effect does not depend on BK_Ca channel activation. RV dose-dependently inhibited K_ATP currents, L- and T-type Ca²⁺ currents and swelling-dependent Cl^- currents evoked by either hypotonicity or high extracellular glucose - ion conductances crucially involved in regulating the electrical activity of insulin secreting cells. We further show that RV blunts glucose-induced, but not basal insulin release. Our results indicate that RV counteracts/prevents stimulus-induced cell membrane depolarization and electrical activity by blocking voltage-gated Ca²⁺- and swelling-dependent Cl^- currents despite the inhibition of K_ATP currents.

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Glucose Induces Anion Conductance and Cytosol-To-Membrane Transposition of ICln in INS-1E Rat Insulinoma Cells

Cited by 31 publications

References 43 publications

High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y13 receptor

High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y13 receptor

Cell Swelling-Induced Signaling for Insulin Secretion Bypasses Steps Involving G Proteins and PLA<sub>2</sub> and is N-ethylmaleimide Insensitive

Resveratrol Inhibits Electrical Activity and Insulin Release from Insulinoma Cells by Block of Voltage-Gated Ca<sup>2+</sup> Channels and Swelling-Dependent Cl<sup>-</sup> Currents

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