The Experts below are selected from a list of 120 Experts worldwide ranked by ideXlab platform
Jesper Gromada - One of the best experts on this subject based on the ideXlab platform.
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glucose stimulates Glucagon Release in single rat α cells by mechanisms that mirror the stimulus secretion coupling in β cells
Endocrinology, 2005Co-Authors: Hervor L Olsen, Claes B. Wollheim, Sten Theander, Krister Bokvist, Karsten Buschard, Jesper GromadaAbstract:In isolated rat pancreatic α-cells, glucose, arginine, and the sulfonylurea tolbutamide stimulated Glucagon Release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P < 0.05; n = 5) and doubled the free cytoplasmic Ca2+ concentration. In cell-attached recordings, azide opened KATP channels. The N-type Ca2+-channel blocker ω-conotoxin and the Na+-channel blocker tetrodotoxin inhibited glucose-induced Glucagon Release whereas tetraethylammonium, a blocker of delayed rectifying K+ channels, increased secretion. Glucagon Release increased monotonically with increasing K+ concentrations. ω-Conotoxin suppressed Glucagon Release to 15 mm K+, whereas a combination of ω-conotoxin and an L-type Ca2+-channel inhibitor was required to abrogate secretion in 50 mm K+. Recordings of cell capacitance revealed that glucose increased the exocytotic response ...
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Glucose Stimulates Glucagon Release in Single Rat α-Cells by Mechanisms that Mirror the Stimulus-Secretion Coupling in β-Cells
Endocrinology, 2005Co-Authors: Hervor L Olsen, Claes B. Wollheim, Sten Theander, Krister Bokvist, Karsten Buschard, Jesper GromadaAbstract:In isolated rat pancreatic alpha-cells, glucose, arginine, and the sulfonylurea tolbutamide stimulated Glucagon Release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P
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β cell secretory products activate α cell atp dependent potassium channels to inhibit Glucagon Release
Diabetes, 2005Co-Authors: Isobel Franklin, Jesper Gromada, Sten Theander, Asllan Gjinovci, Claes B. WollheimAbstract:Glucagon, secreted from islet alpha-cells, mobilizes liver glucose. During hyperglycemia, Glucagon secretion is inhibited by paracrine factors from other islet cells, but in type 1 and type 2 diabetic patients, this suppression is lost. We investigated the effects of beta-cell secretory products zinc and insulin on isolated rat alpha-cells, intact islets, and perfused pancreata. Islet Glucagon secretion was markedly zinc sensitive (IC(50) = 2.7 micromol/l) more than insulin Release (IC(50) = 10.7 micromol/l). Glucose, the mitochondrial substrate pyruvate, and the ATP-sensitive K(+) channel (K(ATP) channel) inhibitor tolbutamide stimulated isolated alpha-cell electrical activity and Glucagon secretion. Zinc opened K(ATP) channels and inhibited both electrical activity and pyruvate (but not arginine)-stimulated Glucagon secretion in alpha-cells. Insulin transiently increased K(ATP) channel activity, inhibited electrical activity and Glucagon secretion in alpha-cells, and inhibited pancreatic Glucagon output. Insulin receptor and K(ATP) channel subunit transcripts were more abundant in alpha- than beta-cells. Transcript for the Glucagon-like peptide 1 (GLP-1) receptor was not detected in alpha-cells nor did GLP-1 stimulate alpha-cell Glucagon Release. beta-Cell secretory products zinc and insulin therefore inhibit Glucagon secretion most probably by direct activation of K(ATP) channels, thereby masking an alpha-cell metabolism secretion coupling pathway similar to beta-cells.
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atp sensitive k channel dependent regulation of Glucagon Release and electrical activity by glucose in wild type and sur1 mouse α cells
Diabetes, 2004Co-Authors: Jesper Gromada, Krister Bokvist, Albert Salehi, Marianne Hoy, Perolof Berggren, Patrik RorsmanAbstract:Patch-clamp recordings and Glucagon Release measurements were combined to determine the role of plasma membrane ATP-sensitive K + channels (K ATP channels) in the control of Glucagon secretion from mouse pancreatic α-cells. In wild-type mouse islets, glucose produced a concentration-dependent (half-maximal inhibitory concentration [IC 50 ] = 2.5 mmol/l) reduction of Glucagon Release. Maximum inhibition (∼50%) was attained at glucose concentrations >5 mmol/l. The sulfonylureas tolbutamide (100 μmol/l) and glibenclamide (100 nmol/l) inhibited Glucagon secretion to the same extent as a maximally inhibitory concentration of glucose. In mice lacking functional K ATP channels (SUR1 −/− ), Glucagon secretion in the absence of glucose was lower than that observed in wild-type islets and both glucose (0–20 mmol/l) and the sulfonylureas failed to inhibit Glucagon secretion. Membrane potential recordings revealed that α-cells generate action potentials in the absence of glucose. Addition of glucose depolarized the α-cell by ∼7 mV and reduced spike height by 30% Application of tolbutamide likewise depolarized the α-cell (∼17 mV) and reduced action potential amplitude (43%). Whereas insulin secretion increased monotonically with increasing external K + concentrations (threshold 25 mmol/l), Glucagon secretion was paradoxically suppressed at intermediate concentrations (5.6–15 mmol/l), and stimulation was first detectable at >25 mmol/l K + . In α-cells isolated from SUR1 −/− mice, both tolbutamide and glucose failed to produce membrane depolarization. These effects correlated with the presence of a small (0.13 nS) sulfonylurea-sensitive conductance in wild-type but not in SUR1 −/− α-cells. Recordings of the free cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ) revealed that, whereas glucose lowered [Ca 2+ ] i to the same extent as application of tolbutamide, the Na + channel blocker tetrodotoxin, or the Ca 2+ channel blocker Co 2+ in wild-type α-cells, the sugar was far less effective on [Ca 2+ ] i in SUR1 −/− α-cells. We conclude that the K ATP channel is involved in the control of Glucagon secretion by regulating the membrane potential in the α-cell in a way reminiscent of that previously documented in insulin-releasing β-cells. However, because α-cells possess a different complement of voltage-gated ion channels involved in action potential generation than the β-cell, moderate membrane depolarization in α-cells is associated with reduced rather than increased electrical activity and secretion.
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atp sensitive k channel dependent regulation of Glucagon Release and electrical actiflty by glucose in wild type and sur1 mouse alpha cells
53 pp 181-189 (2004), 2004Co-Authors: Jesper Gromada, Krister Bokvist, Marianne Hoy, Albert S Salehi, P O Berggren, Patrik RorsmanAbstract:Patch-clamp recordings and Glucagon Release measurements were combined to determine the role of plasma membrane ATP-sensitive K+ channels (K-ATP channels) in the control of Glucagon secretion from mouse pancreatic alpha-cells. In wild-type mouse islets, glucose produced a concentration-dependent (half-maximal inhibitory concentration [IC50] = 2.5 mmol/l) reduction of Glucagon Release. Maximum inhibition (similar to50%) was attained at glucose concentrations >5 mmol/l. The sulfonylureas tolbutamide (100 mumol/l) and glibenclamide (100 nmol/l) inhibited Glucagon secretion to the same extent as a maximally inhibitory concentration of glucose. In mice lacking functional KATP channels (SUR1(-/-)), Glucagon secretion in the absence of glucose was lower than that observed in wild-type islets and both glucose (0-20 mmol/l) and the sulfonylureas failed to inhibit Glucagon secretion. Membrane potential recordings revealed that a-cells generate action potentials in the absence of glucose. Addition of glucose depolarized the alpha-cell by similar to7 mV and reduced spike height by 30% Application of tolbutamide likewise depolarized the alpha-cell (similar to17 mV) and reduced action potential amplitude (43%). Whereas insulin secretion increased monotonically with increasing external K+ concentrations (threshold 25 mmol/l), Glucagon secretion was paradoxically suppressed at intermediate concentrations (5.6-15 mmol/l), and stimulation was first detectable at > 25 mmol/l K+. In alpha-cells isolated from SUR1(-/-) mice, both tolbutamide and glucose failed to produce membrane depolarization. These effects correlated with the presence of a small (0.13 nS) sulfonylurea-sensitive conductance in wild-type but not in SUR1(-/-) a-cells. Recordings of the free cytoplasmic Ca2+ concentration ([Ca2+](i)) revealed that, whereas glucose lowered [Ca2+](i) to the same extent as application of tolbutamide, the Na+ channel blocker tetrodotoxin, or the Ca2+ channel blocker Co2+ in wild-type alpha-cells, the sugar was far less effective on [Ca2+](i) in SUR1(-/-) alpha-cells. We conclude that the K-ATP channel is involved in the control of Glucagon secretion by regulating the membrane potential in the alpha-cell in a way reminiscent of that previously documented in insulin-releasing beta-cells. However, because alpha-cells possess a different complement of voltage-gated ion channels involved in action potential generation than the beta-cell, moderate membrane depolarization in alpha-cells is associated with reduced rather than increased electrical activity and secretion. (Less)
W H Hsu - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of bradykinin-induced Glucagon Release in clonal alpha-cells In-R1-G9: involvement of Ca(2+)-dependent and -independent pathways.
Molecular and cellular endocrinology, 2002Co-Authors: S Yibchok-anun, H Cheng, E A Abu-basha, J Ding, M Ioudina, W H HsuAbstract:The mechanisms by which bradykinin (BK) increases Glucagon Release were investigated. BK (0.1-10 microM) increased [Ca(2+)](i) and Glucagon Release in clonal alpha-cells In-R1-G9. BK-induced Glucagon Release was lower in the absence than in the presence of extracellular Ca(2+), but it still increased Glucagon Release while [Ca(2+)](i) was stringently deprived. Depletion of intracellular Ca(2+) store with thapsigargin abolished both the BK-induced Ca(2+) peak and sustained plateau. Microinjection of heparin abolished BK-induced Ca(2+) Release. Pertussis toxin (PTX) did not block BK-induced [Ca(2+)](i) increase or Glucagon Release. U-73122 (8 microM), a phospholipase C (PLC) inhibitor, abolished BK-induced increases in [Ca(2+)](i), but only reduced BK-induced Glucagon Release by 40%. A phospholipase D (PLD) inhibitor zLYCK reduced BK-induced Glucagon Release by 60%. The combination of U-73122 and zLYCK abolished BK-induced Glucagon Release. Both SK&F 96365, a receptor-operated Ca(2+) channel (ROC) blocker and nimodipine, an L-type Ca(2+) channel blocker, reduced BK-induced [Ca(2+)](i) increase and Glucagon Release. These findings suggest that BK increase Glucagon Release through a PTX-insensitive G protein and both Ca(2+)-dependent and -independent pathways. The Ca(2+)-dependent pathway is attributable to PLC activation. PLC catalyzes IP(3) formation, inducing Ca(2+) Release from the endoplasmic reticulum, which, in turn, triggers Ca(2+) influx via both ROCs and L-type channels. PLD activation may be involved in Ca(2+)-dependent and/or -independent pathway.
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Glucose dependency of arginine vasopressin-induced insulin and Glucagon Release from the perfused rat pancreas.
Metabolism: clinical and experimental, 2002Co-Authors: Ehab A. Abu-basha, S Yibchok-anun, W H HsuAbstract:The purpose of this study was to investigate the glucose dependency of arginine vasopressin (AVP)-induced insulin, Glucagon, and somatostatin Release from the perfused rat pancreas. AVP (30 or 300 pmol/L) was tested in the presence of a glucose concentration of 0, 1.4, 5.5 (basal level), or 20 mmol/L. The rates of insulin Release at 0 and 1.4 mmol/L glucose were approximately 70% to 80% and 60% to 70% less, respectively, than that at the baseline level. AVP (30 or 300 pmol/L) failed to change insulin Release at 0 and 1.4 mmol/L glucose. At the basal glucose level, AVP (300 pmol/L) induced a biphasic insulin Release, a peak followed by a sustained phase. In addition, the combination of glucose (20 mmol/L) and AVP (300 pmol/L) induced a higher insulin peak and sustained phase than 20 mmol/L glucose alone. The rates of Glucagon Release at 0 and 1.4 mmol/L glucose were about 3- and 2-fold more, respectively, than that at the baseline level. At 0 and 1.4 mmol/L glucose, both 30 and 300 pmol/L AVP caused a higher Glucagon peak and sustained phase than 0 and 1.4 mmol/L glucose alone. At the basal glucose level, AVP (30 or 300 pmol/L) induced a biphasic Glucagon Release, a peak followed by a sustained phase. The rate of Glucagon Release at 20 mmol/L glucose was approximately 60% to 70% less than that at the baseline level. When AVP (300 pmol/L) was administered in 20 mmol/L glucose, it induced a transient Glucagon peak, which was 2.4-fold of the baseline level. At all glucose concentrations tested, AVP (30 or 300 pmol/L) failed to change somatostatin Release. These results suggested that (1) hypoglycemia directly increases Glucagon and decreases insulin Release; (2) AVP induces insulin and Glucagon Release by a direct action on beta and alpha cells, respectively; (3) AVP induces insulin and Glucagon Release in a glucose-dependent manner-the higher the glucose concentration, the greater the enhancement of AVP-induced insulin Release, whereas the lower the glucose concentration, the higher the enhancement of AVP-induced Glucagon Release; and (4) alpha cells are more sensitive to AVP than beta cells in hormone Release.
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Mechanisms of AVP-induced Glucagon Release in clonal α-cells In-R1-G9: involvement of Ca2+-dependent and -independent pathways
British journal of pharmacology, 2000Co-Authors: S Yibchok-anun, H Cheng, Ter-hsin Chen, W H HsuAbstract:1. The mechanisms underlying AVP-induced increase in [Ca(2+)](i) and Glucagon Release in clonal alpha-cells In-R1-G9 were investigated. 2. AVP increased [Ca(2+)](i) and Glucagon Release in a concentration-dependent manner. After the administration of AVP, Glucagon was Released within 30 s, quickly reached the maximum within 2 min, and maintained a steady-state concentration for at least 15 min. 3. In Ca(2+)-containing medium, AVP increased [Ca(2+)](i) in a biphasic pattern; a peak followed by a sustained plateau. In Ca(2+)-free medium, the Ca(2+) response to AVP became monophasic with lower amplitude and no plateau. Both the basal and AVP-induced Glucagon Releases were lower in the absence than in the presence of extracellular Ca(2+). When [Ca(2+)](i) was stringently deprived by BAPTA, a Ca(2+) chelator, AVP still significantly increased Glucagon Release. 4. Pretreatment with thapsigargin, a microsomal Ca(2+) ATPase inhibitor, abolished both the Ca(2+) peak and sustained plateau. 5.AVP increased intracellular concentration of IP(3). 6. U-73122 (8 microM), a phospholipase C inhibitor, abolished AVP-induced increases in [Ca(2+)](i), but only reduced AVP-induced Glucagon Release by 39%. 7. Pretreatment with nimodipine, an L-type Ca(2+) channel blocker failed to alter AVP-induced Glucagon Release or increase in [Ca(2+)](i). 8. The results suggest that AVP causes Glucagon Release through both Ca(2+)-dependent and -independent pathways. For the Ca(2+)-dependent pathway, the G(q) protein activates phospholipase C, which catalyzes the formation of IP(3). IP(3) induces Ca(2+) Release from the endoplasmic reticulum, which, in turn, triggers Ca(2+) influx. Both Ca(2+) Release and Ca(2+) influx may contribute to AVP-induced Glucagon Release.
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Characterization of receptors mediating AVP- and OT-induced Glucagon Release from the rat pancreas.
The American journal of physiology, 1999Co-Authors: S Yibchok-anun, H Cheng, Patricia A. Heine, W H HsuAbstract:We characterized the receptors that mediate arginine vasopressin (AVP)- and oxytocin (OT)-induced Glucagon Release by use of a number of antagonists in the perfused rat pancreas and the fluorescenc...
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Effects of arginine vasopressin and oxytocin on Glucagon Release from clonal α-cell line In-R1-G9: Involvement of V1b receptors
Life sciences, 1998Co-Authors: S Yibchok-anun, W H HsuAbstract:Abstract Receptor antagonists were used to determine which receptor mediates the effect of arginine vasopressin (AVP) and oxytocin (OT) on Glucagon Release from hamster Glucagonoma In-R1-G9 cells. Both AVP (10−9–10−6 M) and OT (10−8–10−5 M) increased Glucagon Release from In-R1-G9 cells in a concentration-dependent manner and AVP was ~30-fold more potent than OT in this aspect. The antagonists with potent V1b receptor blocking activity, CL-4-84 (10−9–10−6 M), dP[Tyr(Me)2]AVP and AO-2-44 (10−8–10−6 M), antagonized the effect of both AVP and OT in a concentration-dependent manner. Other receptor antagonists at 10−6 M failed to block the effect of AVP and OT; these included a highly selective OT-receptor antagonist, L-366,948 and a V 1a V 2 receptor antagonist WK-3–6. However, these antagonists at higher concentrations (10−5 and 10−4 M) caused inhibition of AVP- and OT-induced Glucagon Release. The order of antagonistic potency was estimated as CL-4-84 ≈ dP[Tyr(Me)2]AVP ≈ AO-2-44 > WK 3–6 > L366,948. d[D-3-Pal]VP (10−8–10−5 M), a V1b receptor agonist, also increased Glucagon Release in a concentration-dependent manner, which was antagonized by dP[Tyr(Me)2]AVP (10−8-10−6 M) and CL-4-84 (10−9–10−6 M), but not by WK-3–6 (10−6 M) or L-366,948 (10−6 M). Therefore, the stimulatory effects of both OT and AVP on Glucagon Release may be mediated by V1b receptors, but not by V1a, V2 or OT receptors.
Krister Bokvist - One of the best experts on this subject based on the ideXlab platform.
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glucose stimulates Glucagon Release in single rat α cells by mechanisms that mirror the stimulus secretion coupling in β cells
Endocrinology, 2005Co-Authors: Hervor L Olsen, Claes B. Wollheim, Sten Theander, Krister Bokvist, Karsten Buschard, Jesper GromadaAbstract:In isolated rat pancreatic α-cells, glucose, arginine, and the sulfonylurea tolbutamide stimulated Glucagon Release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P < 0.05; n = 5) and doubled the free cytoplasmic Ca2+ concentration. In cell-attached recordings, azide opened KATP channels. The N-type Ca2+-channel blocker ω-conotoxin and the Na+-channel blocker tetrodotoxin inhibited glucose-induced Glucagon Release whereas tetraethylammonium, a blocker of delayed rectifying K+ channels, increased secretion. Glucagon Release increased monotonically with increasing K+ concentrations. ω-Conotoxin suppressed Glucagon Release to 15 mm K+, whereas a combination of ω-conotoxin and an L-type Ca2+-channel inhibitor was required to abrogate secretion in 50 mm K+. Recordings of cell capacitance revealed that glucose increased the exocytotic response ...
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Glucose Stimulates Glucagon Release in Single Rat α-Cells by Mechanisms that Mirror the Stimulus-Secretion Coupling in β-Cells
Endocrinology, 2005Co-Authors: Hervor L Olsen, Claes B. Wollheim, Sten Theander, Krister Bokvist, Karsten Buschard, Jesper GromadaAbstract:In isolated rat pancreatic alpha-cells, glucose, arginine, and the sulfonylurea tolbutamide stimulated Glucagon Release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P
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atp sensitive k channel dependent regulation of Glucagon Release and electrical activity by glucose in wild type and sur1 mouse α cells
Diabetes, 2004Co-Authors: Jesper Gromada, Krister Bokvist, Albert Salehi, Marianne Hoy, Perolof Berggren, Patrik RorsmanAbstract:Patch-clamp recordings and Glucagon Release measurements were combined to determine the role of plasma membrane ATP-sensitive K + channels (K ATP channels) in the control of Glucagon secretion from mouse pancreatic α-cells. In wild-type mouse islets, glucose produced a concentration-dependent (half-maximal inhibitory concentration [IC 50 ] = 2.5 mmol/l) reduction of Glucagon Release. Maximum inhibition (∼50%) was attained at glucose concentrations >5 mmol/l. The sulfonylureas tolbutamide (100 μmol/l) and glibenclamide (100 nmol/l) inhibited Glucagon secretion to the same extent as a maximally inhibitory concentration of glucose. In mice lacking functional K ATP channels (SUR1 −/− ), Glucagon secretion in the absence of glucose was lower than that observed in wild-type islets and both glucose (0–20 mmol/l) and the sulfonylureas failed to inhibit Glucagon secretion. Membrane potential recordings revealed that α-cells generate action potentials in the absence of glucose. Addition of glucose depolarized the α-cell by ∼7 mV and reduced spike height by 30% Application of tolbutamide likewise depolarized the α-cell (∼17 mV) and reduced action potential amplitude (43%). Whereas insulin secretion increased monotonically with increasing external K + concentrations (threshold 25 mmol/l), Glucagon secretion was paradoxically suppressed at intermediate concentrations (5.6–15 mmol/l), and stimulation was first detectable at >25 mmol/l K + . In α-cells isolated from SUR1 −/− mice, both tolbutamide and glucose failed to produce membrane depolarization. These effects correlated with the presence of a small (0.13 nS) sulfonylurea-sensitive conductance in wild-type but not in SUR1 −/− α-cells. Recordings of the free cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ) revealed that, whereas glucose lowered [Ca 2+ ] i to the same extent as application of tolbutamide, the Na + channel blocker tetrodotoxin, or the Ca 2+ channel blocker Co 2+ in wild-type α-cells, the sugar was far less effective on [Ca 2+ ] i in SUR1 −/− α-cells. We conclude that the K ATP channel is involved in the control of Glucagon secretion by regulating the membrane potential in the α-cell in a way reminiscent of that previously documented in insulin-releasing β-cells. However, because α-cells possess a different complement of voltage-gated ion channels involved in action potential generation than the β-cell, moderate membrane depolarization in α-cells is associated with reduced rather than increased electrical activity and secretion.
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atp sensitive k channel dependent regulation of Glucagon Release and electrical actiflty by glucose in wild type and sur1 mouse alpha cells
53 pp 181-189 (2004), 2004Co-Authors: Jesper Gromada, Krister Bokvist, Marianne Hoy, Albert S Salehi, P O Berggren, Patrik RorsmanAbstract:Patch-clamp recordings and Glucagon Release measurements were combined to determine the role of plasma membrane ATP-sensitive K+ channels (K-ATP channels) in the control of Glucagon secretion from mouse pancreatic alpha-cells. In wild-type mouse islets, glucose produced a concentration-dependent (half-maximal inhibitory concentration [IC50] = 2.5 mmol/l) reduction of Glucagon Release. Maximum inhibition (similar to50%) was attained at glucose concentrations >5 mmol/l. The sulfonylureas tolbutamide (100 mumol/l) and glibenclamide (100 nmol/l) inhibited Glucagon secretion to the same extent as a maximally inhibitory concentration of glucose. In mice lacking functional KATP channels (SUR1(-/-)), Glucagon secretion in the absence of glucose was lower than that observed in wild-type islets and both glucose (0-20 mmol/l) and the sulfonylureas failed to inhibit Glucagon secretion. Membrane potential recordings revealed that a-cells generate action potentials in the absence of glucose. Addition of glucose depolarized the alpha-cell by similar to7 mV and reduced spike height by 30% Application of tolbutamide likewise depolarized the alpha-cell (similar to17 mV) and reduced action potential amplitude (43%). Whereas insulin secretion increased monotonically with increasing external K+ concentrations (threshold 25 mmol/l), Glucagon secretion was paradoxically suppressed at intermediate concentrations (5.6-15 mmol/l), and stimulation was first detectable at > 25 mmol/l K+. In alpha-cells isolated from SUR1(-/-) mice, both tolbutamide and glucose failed to produce membrane depolarization. These effects correlated with the presence of a small (0.13 nS) sulfonylurea-sensitive conductance in wild-type but not in SUR1(-/-) a-cells. Recordings of the free cytoplasmic Ca2+ concentration ([Ca2+](i)) revealed that, whereas glucose lowered [Ca2+](i) to the same extent as application of tolbutamide, the Na+ channel blocker tetrodotoxin, or the Ca2+ channel blocker Co2+ in wild-type alpha-cells, the sugar was far less effective on [Ca2+](i) in SUR1(-/-) alpha-cells. We conclude that the K-ATP channel is involved in the control of Glucagon secretion by regulating the membrane potential in the alpha-cell in a way reminiscent of that previously documented in insulin-releasing beta-cells. However, because alpha-cells possess a different complement of voltage-gated ion channels involved in action potential generation than the beta-cell, moderate membrane depolarization in alpha-cells is associated with reduced rather than increased electrical activity and secretion. (Less)
David H. Coy - One of the best experts on this subject based on the ideXlab platform.
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Intra-Islet Somatostatin Regulates Glucagon Release via Type 2 Somatostatin Receptors in Rats
Diabetes, 2003Co-Authors: Kenan Cejvan, David H. Coy, Suad EfendicAbstract:Exogenously administered somatostatin (SST) inhibits secretion of insulin and Glucagon. Furthermore, it is hypothesized that islet SST regulates Glucagon secretion by a local action. A number of studies utilizing SST antibodies have been performed to test this hypothesis, and their results have been conflicting. Five subtypes of SST receptor (SSTR1–5) mediate the effect of SST on target cells. In rodents, SST inhibits the Release of Glucagon, but not that of insulin, via SSTR2. A novel SSTR2-selective antagonist, DC-41-33, was synthesized recently. We have investigated the effects of this antagonist on arginine-stimulated Glucagon and insulin Release in batch incubations of isolated rat islets, perifused isolated rat islets, and isolated perfused rat pancreas. In batch incubations at 3.3 mmol/l glucose, DC-41-33 increased Glucagon Release in a dose-dependent manner. At the maximum dose tested (2 μmol/l), DC-41-33 enhanced the Glucagon response by 4.3- to 5-fold. Similarly, this compound increased arginine-induced Glucagon Release in perifused islets at 3.3 mmol/l glucose (2.8-fold) and perfused pancreas at 3.3 and 5.5 mmol/l glucose (2.5- and 2.3-fold, respectively). In the two latter experimental systems, DC-41-33 had no significant effect on insulin Release. In conclusion, our results strongly support the hypothesis that islet SST inhibits Glucagon secretion via a local action.
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Gliclazide directly inhibits arginine-induced Glucagon Release.
Diabetes, 2002Co-Authors: Kenan Cejvan, David H. Coy, Jens J. Holst, Erol Cerasi, Suad EfendicAbstract:Arginine-stimulated insulin and somatostatin Release is enhanced by the sulfonylurea gliclazide. In contrast, gliclazide inhibits the Glucagon response. The aim of the present study was to investigate whether this inhibition of Glucagon Release was mediated by a direct suppressive effect of gliclazide or was secondary to the paracrine effect of Released somatostatin. To eliminate the paracrine effects of somatostatin, we first perfused isolated rat pancreata with a medium supplemented with 23% of the standard calcium content. Second, we perifused isolated rat islets with a novel and highly specific antagonist of type 2 somatostatin receptor, DC-41-33 (2 μmol/l), which fully antagonizes the suppressive somatostatin effect on rat A cells. Gliclazide (30 μmol/l) inhibited Glucagon Release by 54% in the perfusion experiments, whereas the somatostatin response was nearly abolished. In islet perifusions with DC-41-33, arginine-induced Glucagon Release was inhibited by 66%. We therefore concluded that gliclazide inhibits Glucagon Release by a direct action on the pancreatic A cell.
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Specific Inhibition of Rat Pancreatic Insulin or Glucagon Release by Receptor-Selective Somatostatin Analogs
Biochemical and biophysical research communications, 1994Co-Authors: W.j. Rossowski, David H. CoyAbstract:Abstract A group of new peptide ligands displaying high selectivity for binding to somatostatin receptor subtypes 2, 3 or 5 have been used to characterize somatostatin receptor involvement in the inhibition of Glucagon secretion in rats. It was found that NC-8-12 and DC-25-100, which have high affinity for SSTR2 and much less affinity for the type 5 receptor, were by far the most potent inhibitors of Glucagon secretion with EC (50) s of 48 and 18 nmole, respectively, relative to somatostatin itself(EC 50 131 nmole). These two analogs were actually much less potent than somatostatin in inhibiting glucose-stimulated insulin Release. In contrast, DC-23-99 (a type 5 receptor selective analog), which was previously found to be a more potent inhibitor of insulin secretion than somatostatin, had considerably less potent (EC 50 410 nmole) effects on Glucagon Release. The SSTR3-specific ligands, DC-25-12 and DC-25-20, were not effective at the doses tested. The differing spectra of activities of these analogs suggest that inhibition of insulin and Glucagon secretion in rats is mediated by entirely different somatostatin receptor populations.
S Yibchok-anun - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of bradykinin-induced Glucagon Release in clonal alpha-cells In-R1-G9: involvement of Ca(2+)-dependent and -independent pathways.
Molecular and cellular endocrinology, 2002Co-Authors: S Yibchok-anun, H Cheng, E A Abu-basha, J Ding, M Ioudina, W H HsuAbstract:The mechanisms by which bradykinin (BK) increases Glucagon Release were investigated. BK (0.1-10 microM) increased [Ca(2+)](i) and Glucagon Release in clonal alpha-cells In-R1-G9. BK-induced Glucagon Release was lower in the absence than in the presence of extracellular Ca(2+), but it still increased Glucagon Release while [Ca(2+)](i) was stringently deprived. Depletion of intracellular Ca(2+) store with thapsigargin abolished both the BK-induced Ca(2+) peak and sustained plateau. Microinjection of heparin abolished BK-induced Ca(2+) Release. Pertussis toxin (PTX) did not block BK-induced [Ca(2+)](i) increase or Glucagon Release. U-73122 (8 microM), a phospholipase C (PLC) inhibitor, abolished BK-induced increases in [Ca(2+)](i), but only reduced BK-induced Glucagon Release by 40%. A phospholipase D (PLD) inhibitor zLYCK reduced BK-induced Glucagon Release by 60%. The combination of U-73122 and zLYCK abolished BK-induced Glucagon Release. Both SK&F 96365, a receptor-operated Ca(2+) channel (ROC) blocker and nimodipine, an L-type Ca(2+) channel blocker, reduced BK-induced [Ca(2+)](i) increase and Glucagon Release. These findings suggest that BK increase Glucagon Release through a PTX-insensitive G protein and both Ca(2+)-dependent and -independent pathways. The Ca(2+)-dependent pathway is attributable to PLC activation. PLC catalyzes IP(3) formation, inducing Ca(2+) Release from the endoplasmic reticulum, which, in turn, triggers Ca(2+) influx via both ROCs and L-type channels. PLD activation may be involved in Ca(2+)-dependent and/or -independent pathway.
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Glucose dependency of arginine vasopressin-induced insulin and Glucagon Release from the perfused rat pancreas.
Metabolism: clinical and experimental, 2002Co-Authors: Ehab A. Abu-basha, S Yibchok-anun, W H HsuAbstract:The purpose of this study was to investigate the glucose dependency of arginine vasopressin (AVP)-induced insulin, Glucagon, and somatostatin Release from the perfused rat pancreas. AVP (30 or 300 pmol/L) was tested in the presence of a glucose concentration of 0, 1.4, 5.5 (basal level), or 20 mmol/L. The rates of insulin Release at 0 and 1.4 mmol/L glucose were approximately 70% to 80% and 60% to 70% less, respectively, than that at the baseline level. AVP (30 or 300 pmol/L) failed to change insulin Release at 0 and 1.4 mmol/L glucose. At the basal glucose level, AVP (300 pmol/L) induced a biphasic insulin Release, a peak followed by a sustained phase. In addition, the combination of glucose (20 mmol/L) and AVP (300 pmol/L) induced a higher insulin peak and sustained phase than 20 mmol/L glucose alone. The rates of Glucagon Release at 0 and 1.4 mmol/L glucose were about 3- and 2-fold more, respectively, than that at the baseline level. At 0 and 1.4 mmol/L glucose, both 30 and 300 pmol/L AVP caused a higher Glucagon peak and sustained phase than 0 and 1.4 mmol/L glucose alone. At the basal glucose level, AVP (30 or 300 pmol/L) induced a biphasic Glucagon Release, a peak followed by a sustained phase. The rate of Glucagon Release at 20 mmol/L glucose was approximately 60% to 70% less than that at the baseline level. When AVP (300 pmol/L) was administered in 20 mmol/L glucose, it induced a transient Glucagon peak, which was 2.4-fold of the baseline level. At all glucose concentrations tested, AVP (30 or 300 pmol/L) failed to change somatostatin Release. These results suggested that (1) hypoglycemia directly increases Glucagon and decreases insulin Release; (2) AVP induces insulin and Glucagon Release by a direct action on beta and alpha cells, respectively; (3) AVP induces insulin and Glucagon Release in a glucose-dependent manner-the higher the glucose concentration, the greater the enhancement of AVP-induced insulin Release, whereas the lower the glucose concentration, the higher the enhancement of AVP-induced Glucagon Release; and (4) alpha cells are more sensitive to AVP than beta cells in hormone Release.
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Mechanisms of AVP-induced Glucagon Release in clonal α-cells In-R1-G9: involvement of Ca2+-dependent and -independent pathways
British journal of pharmacology, 2000Co-Authors: S Yibchok-anun, H Cheng, Ter-hsin Chen, W H HsuAbstract:1. The mechanisms underlying AVP-induced increase in [Ca(2+)](i) and Glucagon Release in clonal alpha-cells In-R1-G9 were investigated. 2. AVP increased [Ca(2+)](i) and Glucagon Release in a concentration-dependent manner. After the administration of AVP, Glucagon was Released within 30 s, quickly reached the maximum within 2 min, and maintained a steady-state concentration for at least 15 min. 3. In Ca(2+)-containing medium, AVP increased [Ca(2+)](i) in a biphasic pattern; a peak followed by a sustained plateau. In Ca(2+)-free medium, the Ca(2+) response to AVP became monophasic with lower amplitude and no plateau. Both the basal and AVP-induced Glucagon Releases were lower in the absence than in the presence of extracellular Ca(2+). When [Ca(2+)](i) was stringently deprived by BAPTA, a Ca(2+) chelator, AVP still significantly increased Glucagon Release. 4. Pretreatment with thapsigargin, a microsomal Ca(2+) ATPase inhibitor, abolished both the Ca(2+) peak and sustained plateau. 5.AVP increased intracellular concentration of IP(3). 6. U-73122 (8 microM), a phospholipase C inhibitor, abolished AVP-induced increases in [Ca(2+)](i), but only reduced AVP-induced Glucagon Release by 39%. 7. Pretreatment with nimodipine, an L-type Ca(2+) channel blocker failed to alter AVP-induced Glucagon Release or increase in [Ca(2+)](i). 8. The results suggest that AVP causes Glucagon Release through both Ca(2+)-dependent and -independent pathways. For the Ca(2+)-dependent pathway, the G(q) protein activates phospholipase C, which catalyzes the formation of IP(3). IP(3) induces Ca(2+) Release from the endoplasmic reticulum, which, in turn, triggers Ca(2+) influx. Both Ca(2+) Release and Ca(2+) influx may contribute to AVP-induced Glucagon Release.
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Characterization of receptors mediating AVP- and OT-induced Glucagon Release from the rat pancreas.
The American journal of physiology, 1999Co-Authors: S Yibchok-anun, H Cheng, Patricia A. Heine, W H HsuAbstract:We characterized the receptors that mediate arginine vasopressin (AVP)- and oxytocin (OT)-induced Glucagon Release by use of a number of antagonists in the perfused rat pancreas and the fluorescenc...
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Effects of arginine vasopressin and oxytocin on Glucagon Release from clonal α-cell line In-R1-G9: Involvement of V1b receptors
Life sciences, 1998Co-Authors: S Yibchok-anun, W H HsuAbstract:Abstract Receptor antagonists were used to determine which receptor mediates the effect of arginine vasopressin (AVP) and oxytocin (OT) on Glucagon Release from hamster Glucagonoma In-R1-G9 cells. Both AVP (10−9–10−6 M) and OT (10−8–10−5 M) increased Glucagon Release from In-R1-G9 cells in a concentration-dependent manner and AVP was ~30-fold more potent than OT in this aspect. The antagonists with potent V1b receptor blocking activity, CL-4-84 (10−9–10−6 M), dP[Tyr(Me)2]AVP and AO-2-44 (10−8–10−6 M), antagonized the effect of both AVP and OT in a concentration-dependent manner. Other receptor antagonists at 10−6 M failed to block the effect of AVP and OT; these included a highly selective OT-receptor antagonist, L-366,948 and a V 1a V 2 receptor antagonist WK-3–6. However, these antagonists at higher concentrations (10−5 and 10−4 M) caused inhibition of AVP- and OT-induced Glucagon Release. The order of antagonistic potency was estimated as CL-4-84 ≈ dP[Tyr(Me)2]AVP ≈ AO-2-44 > WK 3–6 > L366,948. d[D-3-Pal]VP (10−8–10−5 M), a V1b receptor agonist, also increased Glucagon Release in a concentration-dependent manner, which was antagonized by dP[Tyr(Me)2]AVP (10−8-10−6 M) and CL-4-84 (10−9–10−6 M), but not by WK-3–6 (10−6 M) or L-366,948 (10−6 M). Therefore, the stimulatory effects of both OT and AVP on Glucagon Release may be mediated by V1b receptors, but not by V1a, V2 or OT receptors.