Chronic exposure to tolbutamide and glibenclamide impairs insulin secretion but not transcription of KATP channel components

Ball, Andrew J.; McCluskey, Jane T.; Flatt, Peter R.; McClenaghan, Neville H.

doi:10.1016/j.phrs.2003.12.001

Cited by 24 publications

(19 citation statements)

References 30 publications

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“…The glibenclamide concentration used in this study is similar to that of previous in vitro studies [23][24][25]. It is, however, significantly higher than that in patients (below 0.4 μmol/l) [26,27].…”

Section: Resultssupporting

confidence: 84%

Glibenclamide activates translation in rat pancreatic beta cells through calcium-dependent mTOR, PKA and MEK signalling pathways

et al. 2008

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Aims/hypothesis Prolonged exposure of rat beta cells to the insulin secretagogue glibenclamide has been found to induce a sustained increase in basal insulin synthesis. This effect was calcium-dependent and localised in cells that had been degranulated by the drug. Since it was blocked by the translation inhibitor cycloheximide, we examined whether sustained exposure to glibenclamide activates translational factors by calcium-dependent signalling pathways. Methods Purified rat beta cells were cultured with and without glibenclamide in the presence or absence of inhibitors of calcium-dependent signalling pathways before measurement of basal and stimulated protein and insulin synthesis, and assessment of abundance of (phosphorylated) translation factors.Results A 24 h exposure to glibenclamide induced activation of four translation factors, i.e. phosphorylation of eukaryotic initiation factor (eIF) 4e binding protein 1 and ribosomal protein S6 (rpS6), and dephosphorylation of eIF-2α and eukaryotic elongation factor 2. The rise in phospho-rpS6 intensity was localised to a subpopulation of beta cells with low insulin content. This activation of translational factors and the associated elevation of insulin synthesis were completely blocked by the calcium channel blocker verapamil and partially blocked by the mammalian target of rapamycin (mTOR) inhibitor rapamycin, the protein kinase A (PKA) inhibitor Rp-8-Br-cAMPs and the mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase (MEK) inhibitor U0126; a combination of inhibitors exhibited additive effects. Conclusions/interpretation Prolonged exposure to glibenclamide activates protein translation in pancreatic beta cells through the calcium-regulated mTOR, PKA and MEK signalling pathways. The observed intercellular differences in translation activation are proposed as underlying mechanism for functional heterogeneity in the pancreatic beta cell population.

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Section: Resultssupporting

confidence: 84%

Glibenclamide activates translation in rat pancreatic beta cells through calcium-dependent mTOR, PKA and MEK signalling pathways

et al. 2008

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“…Although both agents induce insulin secretion, only the GKA does so in a glucose-dependent and 'glucose-like' manner. Administration of sulphonylureas results in eventual loss of insulin secretory capacity (Ball et al 2004, Urban & Panten 2005, whereas in contrast, the experiments described in this study indicate that GKAs are able to stimulate the cellular mechanisms to increase insulin production, in addition to stimulating insulin secretion.…”

Section: Discussioncontrasting

confidence: 70%

Upregulation of β-cell genes and improved function in rodent islets following chronic glucokinase activation

Gill¹,

Brocklehurst²,

Brown³

et al. 2011

Journal of Molecular Endocrinology

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Glucokinase (GK) plays a critical role in controlling blood glucose; GK activators have been shown to stimulate insulin secretion acutely both in vitro and in vivo. Sustained stimulation of insulin secretion could potentially lead to b-cell exhaustion; this study examines the effect of chronic GK activation on b-cells. Gene expression and insulin secretion were measured in rodent islets treated in vitro with GKA71 for 72 h. Key b-cell gene expression was measured in rat, mouse and global GK heterozygous knockout mouse islets (gk del/wt ). Insulin secretion, after chronic exposure to GKA71, was measured in perifused rat islets. GKA71 acutely increased insulin secretion in rat islets in a glucose-dependent manner. Chronic culture of mouse islets with GKA71 in 5 mmol/l glucose significantly increased the expression of insulin, IAPP, GLUT2, PDX1 and PC1 and decreased the expression of C/EBPb compared with 5 mmol/l glucose alone. Similar increases were shown for insulin, GLUT2, IAPP and PC1 in chronically treated rat islets. Insulin mRNA was also increased in GKA71-treated gk del/wt islets. No changes in GK mRNA were observed. Glucose-stimulated insulin secretion was improved in perifused rat islets following chronic treatment with GKA71. This was associated with a greater insulin content and GK protein level. Chronic treatment of rodent islets with GKA71 showed an upregulation of key b-cell genes including insulin and an increase in insulin content and GK protein compared with glucose alone.

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“…This would suggest this might be a successful therapy over many years; in keeping with this, one patient who never received insulin has been successfully treated with sulfonylurea for 46 years [1]. Longer follow-up is required, as in type 2 diabetes secondary sulfonylurea failure typically occurs after 3 years [17,18].…”

Section: Discussionmentioning

confidence: 80%

Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene

et al. 2006

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Aims/hypothesis Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the K ATP channels in pancreatic beta cells are a common cause of neonatal diabetes. One-third of patients also have developmental delay, which probably results from mutated K ATP channels in muscle, nerve and brain. Sulfonylureas, which bind to the sulfonylurea receptor 1 subunit of the K ATP channel, can replace insulin injections in patients with KCNJ11 mutations. The aim of this study was to investigate the long-term outcome and impact on neurological features of sulfonylurea treatment.

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Chronic exposure to tolbutamide and glibenclamide impairs insulin secretion but not transcription of KATP channel components

Cited by 24 publications

References 30 publications

Glibenclamide activates translation in rat pancreatic beta cells through calcium-dependent mTOR, PKA and MEK signalling pathways

Glibenclamide activates translation in rat pancreatic beta cells through calcium-dependent mTOR, PKA and MEK signalling pathways

Upregulation of β-cell genes and improved function in rodent islets following chronic glucokinase activation

Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene

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