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
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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/259731
- author
- Gromada, J
; Ma, Xiaosong
LU
; Hoy, M
; Bokvist, K
; Salehi, S Albert
LU
; Berggren, PO
and Rorsman, P
- organization
- publishing date
- 2004
- type
- Chapter in Book/Report/Conference proceeding
- publication status
- published
- subject
- host publication
- Diabetes
- volume
- 53
- pages
- 181 - 189
- publisher
- American Diabetes Association
- conference name
- 5th Servier-IGIS Symposium
- conference location
- St Jean Cap Ferrat, France
- conference dates
- 2004-03-18 - 2004-03-20
- external identifiers
-
- wos:000225460000028
- ISSN
- 0012-1797
- language
- English
- LU publication?
- yes
- id
- eb704748-8598-4312-96db-3275f935c095 (old id 259731)
- alternative location
- http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=15561909&dopt=AbstractPlus
- date added to LUP
- 2016-04-01 16:44:00
- date last changed
- 2019-05-28 02:19:21
@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}},
url = {{http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=15561909&dopt=AbstractPlus}},
volume = {{53}},
year = {{2004}},
}