Tolbutamide stimulates exocytosis of glucagon by inhibition of a mitochondrial‐like ATP‐sensitive K<sup>+</sup> (K<sub>ATP</sub>) conductance in rat pancreatic A‐cells

Høy, Marianne; Olsen, Henrik Baare; Bokvist, Krister; Buschard, Karsten; Barg, Sebastian; Rorsman, Patrik; Gromada, Jesper

doi:10.1111/j.1469-7793.2000.00109.x

Cited by 30 publications

(11 citation statements)

References 25 publications

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“…As already remarked, the latter effect is likely to be the quantitatively more important one. Interestingly, the ability to stimulate exocytosis is not shared with repaglinide (present study) but the sulphonylureas tolbutamide and glibenclamide (28). A similar difference in the responses to nateglinide and repaglinide has previously also been observed in rat a-cells (25) and rat b-cells (26), where the former produced a more than threefold enhancement of Ca 2þ -dependent exocytosis and the latter did not affect the process at all.…”

Section: Discussionsupporting

confidence: 80%

Nateglinide, but not repaglinide, stimulates growth hormone release in rat pituitary cells by inhibition of K channels and stimulation of cyclic AMP-dependent exocytosis

Gromada

Bokvist²,

Høy³

et al. 2002

European Journal of Endocrinology

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Objective: GH causes insulin resistance, impairs glycemic control and increases the risk of vascular diabetic complications. Sulphonylureas stimulate GH secretion and this study was undertaken to investigate the possible stimulatory effect of repaglinide and nateglinide, two novel oral glucose regulators, on critical steps of the stimulus -secretion coupling in single rat somatotrophs. Methods: Patch-clamp techniques were used to record whole-cell ATP-sensitive K þ (K ATP ) and delayed outward K þ currents, membrane potential and Ca 2þ -dependent exocytosis. GH release was measured from perifused rat somatotrophs. Results: Both nateglinide and repaglinide dose-dependently suppressed K ATP channel activity with half-maximal inhibition being observed at 413 nM and 13 nM respectively. Both compounds induced action potential firing in the somatotrophs irrespective of whether GH-releasing hormone was present or not. The stimulation of electrical activity by nateglinide, but not repaglinide, was associated with an increased mean duration of the action potentials. The latter effect correlated with a reduction of the delayed outward K þ current, which accounts for action potential repolarization. The latter effect had a K d of 19 mM but was limited to 38% inhibition. When applied at concentrations similar to those required to block K ATP channels, nateglinide in addition potentiated Ca 2þ -evoked exocytosis 3.3-fold ðK d ¼ 3 mMÞ and stimulated GH release 4.5-fold. The latter effect was not shared by repaglinide. The stimulation of exocytosis by nateglinide was mimicked by cAMP and antagonized by the protein kinase A inhibitor Rp-cAMPS. Conclusion: Nateglinide stimulates GH release by inhibition of plasma membrane K þ channels, elevation of cytoplasmic cAMP levels and stimulation of Ca 2þ -dependent exocytosis. By contrast, the effect of repaglinide was confined to inhibition of the K ATP channels.

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Section: Discussionsupporting

confidence: 80%

Nateglinide, but not repaglinide, stimulates growth hormone release in rat pituitary cells by inhibition of K channels and stimulation of cyclic AMP-dependent exocytosis

Gromada

Bokvist²,

Høy³

et al. 2002

European Journal of Endocrinology

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“…This suggests that sulfonylureas do not induce, but rather stimulate (Ca 2π -dependent) exocytosis . Similar effects of sulfonylureas have been reported in pancreatic A-cells (Høy et al 2000) and clonal neuroendocrine PC12-cells (Taylor et al 1999), suggesting that the underlying mechanism is not restricted to B-cells and insulin secretion.…”

Section: Sulfonylureas Stimulate Insulin Releasesupporting

confidence: 71%

“…This may indeed be the case in A-cells, where intracellular application of certain K π -channel blockers interferes with exo-MiniReview cytosis (Høy et al 2000). However, exocytosis in the B-cell is unaffected by replacing intracellular K π with Cs π .…”

Section: Granular CL ª -Flux Through Clc-3 Channels Is Required For Imentioning

confidence: 96%

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Barg

2003

Pharmacology & Toxicology

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In pancreatic B-and A-cells, metabolic stimuli regulate biochemical and electrical processes that culminate in Ca 2π -influx and release of insulin or glucagon, respectively. Like in other (neuro)endocrine cells, Ca 2π -influx triggers the rapid exocytosis of hormone-containing secretory granules. Only a small fraction of granules (Ͻ1% in insulin-secreting B-cells) can be released immediately, while the remainder requires translocation to the plasma membrane and further ''priming'' for release by several ATP-and Ca 2π -dependent reactions. Such functional organization may account for systemic features such as the biphasic time course of glucose-stimulated insulin secretion. Since this release pattern is altered in type-2 diabetes mellitus, it is conceivable that disturbances in the exocytotic machinery underlie the disease. Here I will review recent data from our laboratory relevant for the understanding of these processes in insulin-secreting B-cells and glucagon-secreting A-cells and for the identification of novel targets for antidiabetic drug action. Two aspects are discussed in detail: 1) The importance of a tight interaction between L-type Ca 2π -channels and the exocytotic machinery for efficient secretion; and 2) the role of intragranular acidification for the priming of secretory granules and its regulation by a granular 65-kDa sulfonylurea-binding protein.

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“…Similar evidence has been obtained with rat alpha cells, which have much higher K ATP channel density [43] than mouse alpha cells [13,44]. Accordingly, tolbutamide stimulates the electrical activity [43] and exocytosis of glucagon [45] in isolated rat alpha cells, and Experiments were performed as illustrated in Fig. 4d.…”

Section: Discussionmentioning

confidence: 50%

Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells

2006

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Aims/hypothesis The mechanisms by which glucose regulates glucagon release are poorly understood. The present study aimed to clarify the direct effects of glucose on the glucagon-releasing alpha cells and those effects mediated by paracrine islet factors. Materials and methods Glucagon, insulin and somatostatin release were measured from incubated mouse pancreatic islets and the cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ) recorded in isolated mouse alpha cells. Results Glucose inhibited glucagon release with maximal effect at 7 mmol/l. Since this concentration corresponded to threshold stimulation of insulin secretion, it is unlikely that inhibition of glucagon secretion is mediated by beta cell factors. Although somatostatin secretion data seemed consistent with a role of this hormone in glucose-inhibited glucagon release, a somatostatin receptor type 2 antagonist stimulated glucagon release without diminishing the inhibitory effect of glucose. In islets exposed to tolbutamide plus 8 mmol/l K + , glucose inhibited glucagon secretion without stimulating the release of insulin and somatostatin, indicating a direct inhibitory effect on the alpha cells that was independent of ATP-sensitive K + channels. Glucose lowered [Ca 2+ ] i of individual alpha cells independently of somatostatin and beta cell factors (insulin, Zn 2+ and γ-aminobutyric acid). Glucose suppression of glucagon release was prevented by inhibitors of the sarco(endo)plasmic reticulum Ca 2+ -ATPase, which abolished the [Ca 2+ ] i -lowering effect of glucose on isolated alpha cells. Conclusions/interpretation Beta cell factors or somatostatin do not seem to mediate glucose inhibition of glucagon secretion. We instead propose that glucose has a direct inhibitory effect on mouse alpha cells by suppressing a depolarising Ca 2+ store-operated current.

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Tolbutamide stimulates exocytosis of glucagon by inhibition of a mitochondrial‐like ATP‐sensitive K⁺ (K_ATP) conductance in rat pancreatic A‐cells

Cited by 30 publications

References 25 publications

Nateglinide, but not repaglinide, stimulates growth hormone release in rat pituitary cells by inhibition of K channels and stimulation of cyclic AMP-dependent exocytosis

Nateglinide, but not repaglinide, stimulates growth hormone release in rat pituitary cells by inhibition of K channels and stimulation of cyclic AMP-dependent exocytosis

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells

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Tolbutamide stimulates exocytosis of glucagon by inhibition of a mitochondrial‐like ATP‐sensitive K+ (KATP) conductance in rat pancreatic A‐cells

Cited by 30 publications

References 25 publications

Nateglinide, but not repaglinide, stimulates growth hormone release in rat pituitary cells by inhibition of K channels and stimulation of cyclic AMP-dependent exocytosis

Nateglinide, but not repaglinide, stimulates growth hormone release in rat pituitary cells by inhibition of K channels and stimulation of cyclic AMP-dependent exocytosis

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells

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Tolbutamide stimulates exocytosis of glucagon by inhibition of a mitochondrial‐like ATP‐sensitive K⁺ (K_ATP) conductance in rat pancreatic A‐cells