PMID- 30187652
OWN - NLM
STAT- MEDLINE
DCOM- 20190910
LR  - 20230928
IS  - 2051-817X (Electronic)
IS  - 2051-817X (Linking)
VI  - 6
IP  - 17
DP  - 2018 Sep
TI  - GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition 
      of P/Q-type Ca(2+) channels.
PG  - e13852
LID - 10.14814/phy2.13852 [doi]
LID - e13852
AB  - Glucagon is the body's main hyperglycemic hormone, and its secretion is 
      dysregulated in type 2 diabetes mellitus (T2DM). The incretin hormone 
      glucagon-like peptide-1 (GLP-1) is released from the gut and is used in T2DM 
      therapy. Uniquely, it both stimulates insulin and inhibits glucagon secretion and 
      thereby lowers plasma glucose levels. In this study, we have investigated the 
      action of GLP-1 on glucagon release from human pancreatic islets. 
      Immunocytochemistry revealed that only <0.5% of the alpha-cells possess detectable 
      GLP-1R immunoreactivity. Despite this, GLP-1 inhibited glucagon secretion by 
      50-70%. This was due to a direct effect on alpha-cells, rather than paracrine 
      signaling, because the inhibition was not reversed by the insulin receptor 
      antagonist S961 or the somatostatin receptor-2 antagonist CYN154806. The 
      inhibitory effect of GLP-1 on glucagon secretion was prevented by the 
      PKA-inhibitor Rp-cAMPS and mimicked by the adenylate cyclase activator forskolin. 
      Electrophysiological measurements revealed that GLP-1 decreased action potential 
      height and depolarized interspike membrane potential. Mathematical modeling 
      suggests both effects could result from inhibition of P/Q-type Ca(2+) channels. 
      In agreement with this, GLP-1 and omega-agatoxin (a blocker of P/Q-type channels) 
      inhibited glucagon secretion in islets depolarized by 70 mmol/L [K(+) ](o) , and 
      these effects were not additive. Intracellular application of cAMP inhibited 
      depolarization-evoked exocytosis in individual alpha-cells by a PKA-dependent 
      (Rp-cAMPS-sensitive) mechanism. We propose that inhibition of glucagon secretion 
      by GLP-1 involves activation of the few GLP-1 receptors present in the alpha-cell 
      membrane. The resulting small elevation of cAMP leads to PKA-dependent inhibition 
      of P/Q-type Ca(2+) channels and suppression of glucagon exocytosis.
CI  - (c) 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on 
      behalf of The Physiological Society and the American Physiological Society.
FAU - Ramracheya, Reshma
AU  - Ramracheya R
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, United Kingdom.
FAU - Chapman, Caroline
AU  - Chapman C
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, United Kingdom.
FAU - Chibalina, Margarita
AU  - Chibalina M
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, United Kingdom.
FAU - Dou, Haiqiang
AU  - Dou H
AD  - Institute of Neuroscience and Physiology, Metabolic Research Unit, University of 
      Goteborg, Goteborg, Sweden.
FAU - Miranda, Caroline
AU  - Miranda C
AD  - Institute of Neuroscience and Physiology, Metabolic Research Unit, University of 
      Goteborg, Goteborg, Sweden.
FAU - Gonzalez, Alejandro
AU  - Gonzalez A
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, United Kingdom.
FAU - Moritoh, Yusuke
AU  - Moritoh Y
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, United Kingdom.
FAU - Shigeto, Makoto
AU  - Shigeto M
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, United Kingdom.
FAU - Zhang, Quan
AU  - Zhang Q
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, United Kingdom.
FAU - Braun, Matthias
AU  - Braun M
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, United Kingdom.
FAU - Clark, Anne
AU  - Clark A
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, United Kingdom.
FAU - Johnson, Paul R
AU  - Johnson PR
AD  - Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, 
      Oxford, United Kingdom.
AD  - NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
FAU - Rorsman, Patrik
AU  - Rorsman P
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, United Kingdom.
AD  - Institute of Neuroscience and Physiology, Metabolic Research Unit, University of 
      Goteborg, Goteborg, Sweden.
AD  - NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
FAU - Briant, Linford J B
AU  - Briant LJB
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, United Kingdom.
AD  - Department of Computer Science, University of Oxford, Oxford, United Kingdom.
LA  - eng
GR  - 884655/WT_/Wellcome Trust/United Kingdom
GR  - 095531/Z/11/Z/WT_/Wellcome Trust/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
GR  - 201325/Z/16/Z/WT_/Wellcome Trust/United Kingdom
GR  - 089795/WT_/Wellcome Trust/United Kingdom
GR  - 095531/WT_/Wellcome Trust/United Kingdom
GR  - DUK_/Diabetes UK/United Kingdom
GR  - G0801995/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Physiol Rep
JT  - Physiological reports
JID - 101607800
RN  - 0 (Calcium Channel Blockers)
RN  - 0 (Calcium Channels, P-Type)
RN  - 0 (Calcium Channels, Q-Type)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
RN  - 9007-92-5 (Glucagon)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Calcium Channel Blockers/pharmacology
MH  - Calcium Channels, P-Type/*metabolism
MH  - Calcium Channels, Q-Type/*metabolism
MH  - Cells, Cultured
MH  - Exocytosis
MH  - Female
MH  - Glucagon/*metabolism
MH  - Glucagon-Like Peptide 1/*pharmacology
MH  - Glucagon-Secreting Cells/drug effects/*metabolism/physiology
MH  - Humans
MH  - Male
MH  - Membrane Potentials
MH  - Mice
MH  - Middle Aged
PMC - PMC6125244
OTO - NOTNLM
OT  - GLP-1, glucagon-like peptide 1
OT  - KATP, potassium ATP channel
OT  - SST, somatostatin
OT  - T2DM, Type 2 diabetes mellitus
OT  - cAMP, cyclic adenosine monophosphate
EDAT- 2018/09/07 06:00
MHDA- 2019/09/11 06:00
PMCR- 2018/09/05
CRDT- 2018/09/07 06:00
PHST- 2018/06/25 00:00 [received]
PHST- 2018/07/31 00:00 [revised]
PHST- 2018/08/07 00:00 [accepted]
PHST- 2018/09/07 06:00 [entrez]
PHST- 2018/09/07 06:00 [pubmed]
PHST- 2019/09/11 06:00 [medline]
PHST- 2018/09/05 00:00 [pmc-release]
AID - PHY213852 [pii]
AID - 10.14814/phy2.13852 [doi]
PST - ppublish
SO  - Physiol Rep. 2018 Sep;6(17):e13852. doi: 10.14814/phy2.13852.