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A K-ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of langerhans

MacDonald, Patrick E.; De Marinis, Yang Zhang; Ramracheya, Reshma; Salehi, S Albert LU ; Ma, Xiaosong LU ; Johnson, Paul R. V.; Cox, Roger; Eliasson, Lena LU and Rorsman, Patrik LU (2007) In PLoS Biology 5(6). p.1236-1247
Abstract
Glucagon, secreted from pancreatic islet a cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring beta cells, or to an intrinsic glucose sensing by the a cells themselves. We examined hormone secretion and Ca2+ responses of a and b cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn (2+) signalling was blocked, but was reversed by low concentrations (1-20 mu M) of the ATP-sensitive K+ (K-ATP) channel opener diazoxide, which had no effect on insulin release or b cell responses. This effect was prevented by the K-ATP... (More)
Glucagon, secreted from pancreatic islet a cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring beta cells, or to an intrinsic glucose sensing by the a cells themselves. We examined hormone secretion and Ca2+ responses of a and b cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn (2+) signalling was blocked, but was reversed by low concentrations (1-20 mu M) of the ATP-sensitive K+ (K-ATP) channel opener diazoxide, which had no effect on insulin release or b cell responses. This effect was prevented by the K-ATP channel blocker tolbutamide (100 mu M). Higher diazoxide concentrations (>= 30 mu M) decreased glucagon and insulin secretion, and alpha-and beta-cell Ca2+ responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (< 1 mu M) stimulated glucagon secretion, whereas high concentrations (> 10 mu M) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the K-ATP channel, inhibition of voltage-gated Na+ (TTX) and N-type Ca2+ channels (omega-conotoxin), but not L-type Ca2+ channels (nifedipine), prevented glucagon secretion. Both the N-type Ca2+ channels and alpha-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an a-cell K-ATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Biology
volume
5
issue
6
pages
1236 - 1247
publisher
Public Library of Science
external identifiers
  • wos:000247173200009
  • scopus:38449088492
ISSN
1544-9173
DOI
10.1371/journal.pbio.0050143
language
English
LU publication?
yes
id
431bfe6b-fe5d-420c-94eb-46a0e08e9b36 (old id 648683)
date added to LUP
2007-12-18 09:20:28
date last changed
2017-11-19 04:11:57
@article{431bfe6b-fe5d-420c-94eb-46a0e08e9b36,
  abstract     = {Glucagon, secreted from pancreatic islet a cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring beta cells, or to an intrinsic glucose sensing by the a cells themselves. We examined hormone secretion and Ca2+ responses of a and b cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn (2+) signalling was blocked, but was reversed by low concentrations (1-20 mu M) of the ATP-sensitive K+ (K-ATP) channel opener diazoxide, which had no effect on insulin release or b cell responses. This effect was prevented by the K-ATP channel blocker tolbutamide (100 mu M). Higher diazoxide concentrations (&gt;= 30 mu M) decreased glucagon and insulin secretion, and alpha-and beta-cell Ca2+ responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (&lt; 1 mu M) stimulated glucagon secretion, whereas high concentrations (&gt; 10 mu M) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the K-ATP channel, inhibition of voltage-gated Na+ (TTX) and N-type Ca2+ channels (omega-conotoxin), but not L-type Ca2+ channels (nifedipine), prevented glucagon secretion. Both the N-type Ca2+ channels and alpha-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an a-cell K-ATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion.},
  author       = {MacDonald, Patrick E. and De Marinis, Yang Zhang and Ramracheya, Reshma and Salehi, S Albert and Ma, Xiaosong and Johnson, Paul R. V. and Cox, Roger and Eliasson, Lena and Rorsman, Patrik},
  issn         = {1544-9173},
  language     = {eng},
  number       = {6},
  pages        = {1236--1247},
  publisher    = {Public Library of Science},
  series       = {PLoS Biology},
  title        = {A K-ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of langerhans},
  url          = {http://dx.doi.org/10.1371/journal.pbio.0050143},
  volume       = {5},
  year         = {2007},
}