Ion Channels and Insulin Secretion

Rajan, Arun S.; Aguilar‐Bryan, Lydia; Nelson, Daniel A.; Yaney, Gordon C.; Hsu, Walter H.; Kunze, Diana L.; Boyd, A. E.

doi:10.2337/diacare.13.3.340

Cited by 140 publications

(88 citation statements)

References 136 publications

(196 reference statements)

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“…3b trace 1), and the single channel conductance inferred from the unitary current amplitude as a function of voltage (I-V) relationship was 60 pS (Fig. 3c), as expected for I K ATP 6,7 . In 6 of 10 cells tested, application of 10-20 mM glucose had very little effect on channel activity ( Fig.…”

mentioning

confidence: 99%

“…The inhibitory action of glucose on I K ATP, as observed in the intact islet, is proposed to result from a glucose signalling system whereby uptake of glucose is mediated by a facilitative glucose transporter, intracellular glucose is converted to glucose-6-phosphate by glucokinase, and aerobic glycolysis generates ATP that is required to inhibit channel function 6,7 . In contrast, the best evidence available to date indicates that GLP-1 exerts its effects on β-cells by stimulating the production of cAMP 8,21,24 .…”

mentioning

confidence: 99%

“…Because I K ATP channels within the patch were inhibited by application of glucose and GLP-1 to the membrane outside the patch, a cytosolic signalling mechanism is implicated. Whether cAMP-dependent protein phosphorylation is responsible for the inhibition of I K ATP will require further analysis given that conflicting reports exist concerning how phosphorylation influences the activity of these channels [30][31][32] .The inhibitory action of glucose on I K ATP, as observed in the intact islet, is proposed to result from a glucose signalling system whereby uptake of glucose is mediated by a facilitative glucose transporter, intracellular glucose is converted to glucose-6-phosphate by glucokinase, and aerobic glycolysis generates ATP that is required to inhibit channel function 6,7 . In contrast, the best evidence available to date indicates that GLP-1 exerts its effects on β-cells by stimulating the production of cAMP 8,21,24 .…”

mentioning

confidence: 99%

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Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37)

Holz

Kühtreiber²,

Habener

1993

Nature

548

358

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Non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) is a disorder of glucose homeostasis characterized by hyperglycaemia, peripheral insulin resistance, impaired hepatic glucose metabolism, and diminished glucose-dependent secretion of insulin from pancreatic β-cells 1 . Glucagon-like-peptide-1(7-37) (GLP-1) 2 is an intestinally derived hormone that may be useful for the treatment of NIDDM because it acts in vivo to increase the level of circulating insulin, and thus lower the concentration of blood glucose 3,4 . This therapeutic effect may result from the ability of GLP-1 to compensate for a defect in the glucose signalling pathway that regulates insulin secretion from β-cells. In support of this concept we report here that GLP-1 confers glucose sensitivity to glucose-resistant β-cells, a phenomenon we term glucose competence. Induction of glucose competence by GLP-1 results from its synergistic interaction with glucose to inhibit metabolically regulated potassium channels that are also targeted for inhibition by sulphonylurea drugs commonly used in the treatment of NIDDM 5 . Glucose competence allows membrane depolarization, the generation of action potentials, and Ca 2+ influx, events that are known to trigger insulin secretion 6,7 .GLP-1 exerts diverse insulinotropic actions on β-cells that include stimulation of cyclic AMP formation 8 , insulin secretion 9 , insulin biosynthesis and proinsulin gene expression 10 . Because all insulinotropic actions of GLP-1 are dependent on simultaneous exposure of β-cells to glucose 10,11 , GLP-1 may act as a hormonal regulator, or modulator, of the β-cell glucose signalling system. To investigate this possibility, perforated-patch 12-14 and cellattached-patch 15 recordings were obtained from solitary β-cells isolated from dispersed rat islets of Langerhans and matained in short-term primary cell culture 16 . For unknown reasons, these single, isolated β-cells exhibit reduced sensitivity to glucose as measured by glucose-induced insulin secretion 17 , electrical activity 18 or calcium signalling 19 . When perforated-patch recordings were obtained from such cells under conditions in which the bathing solution contained no glucose, the depolarizing responses to 10 mM glucose were often ⩽10-15 mV in amplitude, and glucose did not always initiate repetitive spiking activity as is frequently observed in intact islets 6 (Fig. 1a trace 1). In addition, in the absence of glucose very little change in membrane potential was recorded in response to 10 nM GLP-1 (Fig. 1a left of trace 2). In marked contrast, a 30-35 mV depolarization accompanied by repetitive spiking activity was often observed when glucose and GLP-1 were applied simultaneously ( Fig. 1a right of trace 2). This synergistic interaction indicates that GLP-1 acts in a manner analogous to that of a modulatory transmitter. It enhances the reponsiveness of β-cells to glucose, yet is without effect in the absence of glucose. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe in...

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37)

Holz

Kühtreiber²,

Habener

1993

Nature

548

358

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“…Furthermore, this study suggests that the mechanism behind the insulinostatic effect of PYY involves inhibition of both the accumulation and the action of cyclic AMR It is known that the ATP-regulated K-channels are of importance in beta-cell signal transduction [13,14,21]. For example, glucose closes these channels which leads to depolarization and opening of voltage-dependent Ca 2 § channels and initiation of the exocytosis [14]. Some insulinostatic peptides, for example somatostatin, have been suggested to inhibit insulin secretion by opening these channels and there- by hyperpolarize the beta cell and lower the cytoplasmic Ca 2+ concentration [22].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms underlying the insulinostatic effect of peptide YY in mouse pancreatic islets

Nieuwenhuizen¹,

Karlsson²,

Fridolf³

et al. 1994

Diabetologia

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Summary Peptide YY is an insulinostatic peptide which is released into the circulation from the intestinal mucosa upon food intake. Peptide YY is also co-stored with glucagon in the secretory granules of the pancreatic alpha cells. We examined the mechanisms underlying the insulinostatic effect of peptide YY in isolated mouse pancreatic islets. We found that peptide YY (0.1 nmol/1-1 ~tmol/1) inhibited glucose (11.1 mmol/1)-stimulated insulin secretion from incubated isolated islets, with a maximal inhibition of approximately 70 % observed at a dose of 1 nmol/ 1 (p < 0.001). Also in perifused islets the peptide (1 nmol/1) inhibited insulin secretion in response to 11.1 mmol/1 glucose (p < 0.001). Furthermore, peptide YY inhibited glucose-stimulated cyclic AMP formation (by 67 %, p < 0.05), and insulin secretion stimulated by dibutyryl cyclic AMP (p < 0.01). In contrast, the peptide was without effect both on the cytoplasmic Ca 2 + concentration in dispersed mouse isletcell suspensions as measured by the FURA 2-AM technique, and on insulin release in isolated islets, when stimulated by the protein kinase C-activator 12-O-tetradecanoyl phorbol 13-acetate. Finally, in pre-labelled perifused islets, peptide YY caused a small and transient increase in the 86Rb+ efflux (p < 0.001), but only in the absence of extracellular Ca 2 +. We conclude that peptide YY inhibits glucosestimulated insulin secretion from isolated mouse islets by inhibiting two different steps in the cyclic AMP cascade, that is, both the accumulation and the action of the cyclic nucleotide. In contrast, the data suggest that protein kinase C, K + channels, the cytoplasmic Ca 2 + concentration or other processes directly regulating the exocytosis are not involved in the signal transduction underlying peptide YY-induced inhibition of insulin secretion. [Diabetologia (1994) [4,5]. Recently, PYY has been localized to the alpha cells in both the mouse and the rat pancreas [6,7], where it is co-stored with glucagon in the secretory granules [8]. The peptide has previously been demonstrated to inhibit stimulated insulin secretion under in vivo conditions in the rat [9], dog [10,11] and mouse [8], and in vitro in the perfused isolated rat pancreas and in isolatedrat islets [12]. This suggests that PYY participates in the regulation of insulin secretion.In the present study, we have examined possible mechanisms underlying the inhibitory effect of PYY

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“…To illustrate the usefulness of an integrated approach to the study of intracellular Ca 2+ signaling, we have selected the pancreatic β cell, a specialized endocrine cell that secretes the hormone insulin in a Ca 2+ -dependent fashion (reviewed by Ashcroft and Rorsman, 1989;Rajan et al, 1990;Boyd, 1992). β Cells are noteworthy because insulin secretion is a tightly regulated process that is subject to stimulatory and inhibitory modulation by a remarkably large number of nutrients (glucose, amino acids), hormones (glucagon-like peptides, arginine vasopressin, gastric inhibitory peptide), and neurotransmitters (norepinephrine, somatostatin, galanin).…”

Section: Pancreatic β Cell: a Model System For Analysis Of Ca 2+ mentioning

confidence: 99%

Application of Patch Clamp Methods to the Study of Calcium Currents and Calcium Channels

Leech

Holz

1994

Methods in Cell Biology

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Ion Channels and Insulin Secretion

Cited by 140 publications

References 136 publications

Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37)

Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37)

Mechanisms underlying the insulinostatic effect of peptide YY in mouse pancreatic islets

Application of Patch Clamp Methods to the Study of Calcium Currents and Calcium Channels

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