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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

Gromada, J; Ma, Xiaosong LU ; Hoy, M; Bokvist, K; Salehi, S Albert LU ; Berggren, PO and Rorsman, P (2004) 5th Servier-IGIS Symposium In Diabetes 53. p.181-189
Abstract
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... (More)
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)
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organization
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Chapter in Book/Report/Conference proceeding
publication status
published
subject
in
Diabetes
volume
53
pages
181 - 189
publisher
American Diabetes Association
conference name
5th Servier-IGIS Symposium
external identifiers
  • wos:000225460000028
ISSN
0012-1797
language
English
LU publication?
yes
id
eb704748-8598-4312-96db-3275f935c095 (old id 259731)
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http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=15561909&dopt=AbstractPlus
date added to LUP
2007-08-02 13:50:09
date last changed
2016-04-16 04:47:57
@inproceedings{eb704748-8598-4312-96db-3275f935c095,
  abstract     = {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.},
  author       = {Gromada, J and Ma, Xiaosong and Hoy, M and Bokvist, K and Salehi, S Albert and Berggren, PO and Rorsman, P},
  booktitle    = {Diabetes},
  issn         = {0012-1797},
  language     = {eng},
  pages        = {181--189},
  publisher    = {American Diabetes Association},
  title        = {ATP-sensitive K+ channel-dependent regulation of glucagon release and electrical actiflty by glucose in wild-type and SUR1(-/-) mouse alpha-cells},
  volume       = {53},
  year         = {2004},
}