Methylglyoxal Causes Swelling and Activation of a Volume-Sensitive Anion Conductance in Rat Pancreatic β-Cells

Best, Leonard; Miley, Hh.E; Brown, Petra; Cook, Lynda

doi:10.1007/s002329900472

Cited by 25 publications

(20 citation statements)

References 15 publications

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“…5B, C). This substance has previously been shown to cause b-cell swelling, a marked activation of the VSAC and electrical activity [12].…”

Section: Resultsmentioning

confidence: 99%

Study of a glucose-activated anion-selective channel in rat pancreatic β-cells

Best

2002

Pfl�gers Archiv European Journal of Physiology

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Cell-attached channel recordings were made of an inward channel current in isolated rat pancreatic beta-cells incubated in the presence of diazoxide to clamp the membrane potential close to the K(+) equilibrium potential. With 42 mM Cl(-) in the pipette solution, a channel of approximately 200 pS was observed in 20-40% of patches which conducted an inward current at a pipette potential of 0 mV. The channel was activated by a rise in glucose concentration over the range 5-20 mM. The channel was also activated by methylglyoxal, possibly due to its metabolism to D-lactate, but not by the non-metabolizable glucose analogue 3- O-methyl glucose. The channel was activated by hypotonic cell swelling and was sensitive to inhibition by the anion channel blockers 4,4'-dithiocyanatostilbene-2,2'-disulphonic acid, 5-nitro-2-(3-phenylpropylamino) benzoic acid and 4-hydroxytamoxifen. Current reversal occurred at a pipette potential of approximately -67 mV. Raising [Cl(-)] in the pipette solution to 142 mM shifted the reversal potential to -52 mV. It is suggested that the channel is the volume-sensitive anion channel previously described in insulin-secreting cells. Activation of the channel by glucose could be important in generating a depolarizing current leading to increased electrical activity and insulin release, particularly at higher concentrations of glucose where K(ATP) channel activity is minimal.

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“…5B, C). This substance has previously been shown to cause b-cell swelling, a marked activation of the VSAC and electrical activity [12].…”

Section: Resultsmentioning

confidence: 99%

Study of a glucose-activated anion-selective channel in rat pancreatic β-cells

Best

2002

Pfl�gers Archiv European Journal of Physiology

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“…The stimulatory action of D-glucose was found for concentrations above 5 mM and is most likely due to its metabolic conversion to L-lactate, which accumulates in significant quantities and causes cell swelling followed by current activation [301]. Besides providing a pathway for RVD, these channels, by giving rise to a depolarizing current upon glucose stimulation in a concentrations range where KATP channels are already maximally inhibited, would further increase the electrical activity of β-cells and insulin release [302].…”

Section: Metabolismmentioning

confidence: 99%

“…Whole-cell-, perforated patch-and cell-attached patch clamp studies on insulinoma cells and rat pancreatic β-cells revealed a swelling-and D-glucose-dependent Cl -conductance with properties of the outwardly rectifying swelling-dependent Cl -current described in other cell types [300][301][302]. The stimulatory action of D-glucose was found for concentrations above 5 mM and is most likely due to its metabolic conversion to L-lactate, which accumulates in significant quantities and causes cell swelling followed by current activation [301].…”

Section: Metabolismmentioning

confidence: 99%

Mechanisms Sensing and Modulating Signals Arising From Cell Swelling

Jakab

Fuerst

Gschwentner

et al. 2002

Cell Physiol Biochem

125

100

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Cell volume alterations are involved in numerous cellular events like epithelial transport, metabolic processes, hormone secretion, cell migration, proliferation and apoptosis. Above all it is a need for every cell to counteract osmotic cell swelling in order to avoid cell damage. The defence against excess cell swelling is accomplished by a reduction of the intracellular osmolarity by release of organic- or inorganic osmolytes from the cell or by synthesis of osmotically less active macromolecules from their specific subunits. De-spite the large amount of experimental data that has accumulated, the intracellular mechanisms underlying the sensing of cell volume perturbations and the activation of volume compensatory processes, commonly summarized as regulatory volume decrease (RVD), are still only partly revealed. Moving into this field opens a complex scenario of molecular rearrangements and interactions involving intracellular messengers such as calcium, phosphoinositides and inositolphosphates as well as phosphoryla-tion/dephosphorylation processes and cytoskeletal reorganization with marked cell type- and tissue specific variations. Even in one and the same cell type significant differences regarding the activated pathways during RVD may be evident. This makes it virtually im-possible to unambigously define common sensing- and sinaling pathways used by differ-ent cells to readjust their celll volume, even if all these pathways converge to the activa-tion of comparatively few sets of effectors serving for osmolyte extrusion, including ion channels and transporters. This review is aimed at providing an insight into the manifold cellular mechanisms and alterations occuring during cell swelling and RVD.

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“…An increased generation of glucose metabolites by sulphonylureas and the intracellular accumulation of these metabolites could explain the glucose-dependent beta cell swelling observed in response to tolbutamide, which, in turn, leads to VRAC activation (for discussion of this topic see [34]). Consistent with this possibility, we have previously demonstrated that methylglyoxal, which generates large quantities of D-lactate in islet cells [35], also causes beta cell swelling and VRAC activation [36]. The mechanism by which tolbutamide might influence glucose metabolism and, in particular, whether this effect involves SUR1, remain to be established.…”

Section: Discussionmentioning

confidence: 71%

“…However, under conditions of normoglycaemia and hyperglycaemia, when K ATP channel activity is minimal or absent, sulphonylureas exert an additional ionic effect consisting of a glucose-dependent activation of the VRAC, leading to a sustained depolarisation and electrical activity. The latter action is likely to underlie the reported stimulatory effect of these drugs on 36 Cl -efflux in pancreatic islets [37], and could be of considerable therapeutic relevance in the treatment of hyperglycaemia in type 2 diabetes.…”

Section: Discussionmentioning

confidence: 97%

Tolbutamide potentiates the volume-regulated anion channel current in rat pancreatic beta cells

2004

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Aims/hypothesis. Hypoglycaemic sulphonylureas are thought to stimulate insulin release by binding to a sulphonylurea receptor, closing K ATP channels and inducing electrical activity. However, the fact that these drugs stimulate insulin release at high glucose concentrations where K ATP channels are closed suggests additional ionic actions. The aim of this study was to test the hypothesis that sulphonylureas influence the current of the glucose-and volume-regulated anion channel. Methods. Electrical and ion-channel activity were recorded in isolated rat beta cells using the patchclamp technique. 86 Rb + efflux was measured using intact islets. Beta cell volume was measured using a video-imaging technique. Results. In the absence of glucose, tolbutamide (100 µmol/l) transiently depolarised the cells. In the presence of glucose (5 mmol/l), tolbutamide evoked a sustained period of electrical activity, whilst at 10 mmol/l glucose, the drug evoked a pronounced 'silent' depolarisation. In the absence of glucose, tolbutamide inhibited 86 Rb + efflux. However, at 10 mmol/l glucose, tolbutamide induced a transient stimulation of efflux. Tolbutamide potentiated the whole-cell volume-regulated anion conductance in a glucose-dependent manner with an EC 50 of 85 µmol/l. In single channel recordings, tolbutamide increased the channel-open probability. Tolbutamide caused beta cell swelling in the presence of glucose, but not in its absence. Conclusions/interpretation. Tolbutamide can induce beta cell electrical activity by potentiating the glucose-and volume-regulated anion channel current. This effect is probably not due to a direct effect of the drug on the channel, but could be secondary to a metabolic action in the beta cell.

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Methylglyoxal Causes Swelling and Activation of a Volume-Sensitive Anion Conductance in Rat Pancreatic β-Cells

Cited by 25 publications

References 15 publications

Study of a glucose-activated anion-selective channel in rat pancreatic β-cells

Study of a glucose-activated anion-selective channel in rat pancreatic β-cells

Mechanisms Sensing and Modulating Signals Arising From Cell Swelling

Tolbutamide potentiates the volume-regulated anion channel current in rat pancreatic beta cells

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