PMID- 35304577
OWN - NLM
STAT- MEDLINE
DCOM- 20220405
LR  - 20230308
IS  - 2399-3642 (Electronic)
IS  - 2399-3642 (Linking)
VI  - 5
IP  - 1
DP  - 2022 Mar 18
TI  - Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion.
PG  - 238
LID - 10.1038/s42003-022-03170-w [doi]
LID - 238
AB  - Dysregulated glucagon secretion from pancreatic alpha-cells is a key feature of 
      type-1 and type-2 diabetes (T1D and T2D), yet our mechanistic understanding of 
      alpha-cell function is underdeveloped relative to insulin-secreting beta-cells. 
      Here we show that the enzyme acetyl-CoA-carboxylase 1 (ACC1), which couples 
      glucose metabolism to lipogenesis, plays a key role in the regulation of glucagon 
      secretion. Pharmacological inhibition of ACC1 in mouse islets or alphaTC9 cells 
      impaired glucagon secretion at low glucose (1 mmol/l). Likewise, deletion of ACC1 
      in alpha-cells in mice reduced glucagon secretion at low glucose in isolated 
      islets, and in response to fasting or insulin-induced hypoglycaemia in vivo. 
      Electrophysiological recordings identified impaired K(ATP) channel activity and 
      P/Q- and L-type calcium currents in alpha-cells lacking ACC1, explaining the loss 
      of glucose-sensing. ACC-dependent alterations in S-acylation of the K(ATP) 
      channel subunit, Kir6.2, were identified by acyl-biotin exchange assays. 
      Histological analysis identified that loss of ACC1 caused a reduction in 
      alpha-cell area of the pancreas, glucagon content and individual alpha-cell size, 
      further impairing secretory capacity. Loss of ACC1 also reduced the release of 
      glucagon-like peptide 1 (GLP-1) in primary gastrointestinal crypts. Together, 
      these data reveal a role for the ACC1-coupled pathway in proglucagon-expressing 
      nutrient-responsive endocrine cell function and systemic glucose homeostasis.
CI  - (c) 2022. The Author(s).
FAU - Veprik, Anna
AU  - Veprik A
AUID- ORCID: 0000-0002-3904-7151
AD  - Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
AD  - Novo Nordisk Research Centre Oxford, Oxford, UK.
FAU - Denwood, Geoffrey
AU  - Denwood G
AD  - The Oxford Centre for Diabetes, Endocrinology and Metabolism, University of 
      Oxford, Oxford, UK.
FAU - Liu, Dong
AU  - Liu D
AD  - Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
AD  - Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, 
      Scotland, UK.
FAU - Bany Bakar, Rula
AU  - Bany Bakar R
AUID- ORCID: 0000-0002-5643-0195
AD  - Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
FAU - Morfin, Valentin
AU  - Morfin V
AD  - Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, 
      Scotland, UK.
FAU - McHugh, Kara
AU  - McHugh K
AUID- ORCID: 0000-0002-2629-986X
AD  - School of Life Sciences, University of Dundee, Dundee, Scotland, UK.
FAU - Tebeka, Nchimunya N
AU  - Tebeka NN
AUID- ORCID: 0000-0003-3916-6107
AD  - Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
AD  - Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, 
      Scotland, UK.
FAU - Vetterli, Laurene
AU  - Vetterli L
AD  - Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
FAU - Yonova-Doing, Ekaterina
AU  - Yonova-Doing E
AD  - Novo Nordisk Research Centre Oxford, Oxford, UK.
FAU - Gribble, Fiona
AU  - Gribble F
AUID- ORCID: 0000-0002-4232-2898
AD  - Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of 
      Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
FAU - Reimann, Frank
AU  - Reimann F
AUID- ORCID: 0000-0001-9399-6377
AD  - Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of 
      Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
FAU - Hoehn, Kyle L
AU  - Hoehn KL
AUID- ORCID: 0000-0002-0214-3238
AD  - School of Biotechnology and Biomolecular Sciences, University of New South Wales, 
      Sydney, NSW, Australia.
FAU - Hemsley, Piers A
AU  - Hemsley PA
AUID- ORCID: 0000-0003-2950-0634
AD  - School of Life Sciences, University of Dundee, Dundee, Scotland, UK.
AD  - Cell and Molecular Sciences, The James Hutton Institute, Dundee, Scotland, UK.
FAU - Ahnfelt-Ronne, Jonas
AU  - Ahnfelt-Ronne J
AD  - Department of Pathology and Imaging, Novo Nordisk A/S, Malov, Denmark.
FAU - Rorsman, Patrik
AU  - Rorsman P
AUID- ORCID: 0000-0001-7578-0767
AD  - The Oxford Centre for Diabetes, Endocrinology and Metabolism, University of 
      Oxford, Oxford, UK.
FAU - Zhang, Quan
AU  - Zhang Q
AUID- ORCID: 0000-0002-3626-4855
AD  - The Oxford Centre for Diabetes, Endocrinology and Metabolism, University of 
      Oxford, Oxford, UK.
FAU - de Wet, Heidi
AU  - de Wet H
AUID- ORCID: 0000-0002-9871-6909
AD  - Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
FAU - Cantley, James
AU  - Cantley J
AUID- ORCID: 0000-0003-2509-1271
AD  - Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. 
      jcantley001@dundee.ac.uk.
AD  - Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, 
      Scotland, UK. jcantley001@dundee.ac.uk.
LA  - eng
GR  - MC_UU_12012/3/MRC_/Medical Research Council/United Kingdom
GR  - MR/V011979/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/T002107/1/MRC_/Medical Research Council/United Kingdom
GR  - BB/P020666/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - WT084210Z/07/Z/WT_/Wellcome Trust/United Kingdom
GR  - BB/T00875X/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - WT088357Z/09/Z/WT_/Wellcome Trust/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
DEP - 20220318
PL  - England
TA  - Commun Biol
JT  - Communications biology
JID - 101719179
RN  - 72-89-9 (Acetyl Coenzyme A)
RN  - 9007-92-5 (Glucagon)
RN  - EC 6.4.1.2 (ACC1 protein, mouse)
RN  - EC 6.4.1.2 (Acetyl-CoA Carboxylase)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Acetyl Coenzyme A/metabolism
MH  - Acetyl-CoA Carboxylase/metabolism
MH  - Animals
MH  - Glucagon
MH  - *Glucagon-Secreting Cells/metabolism
MH  - Glucose/metabolism
MH  - *Insulin-Secreting Cells/metabolism
MH  - Mice
PMC - PMC8933412
COIS- The authors declare the following competing interests: K.H. is a co-founder of 
      Continuum Biosciences, a company developing drugs for the treatment of metabolic 
      diseases; K.H. is an Editorial Board Member for Communications Biology but was 
      not involved in the editorial review of, nor the decision to publish this 
      article. All other authors declare that there is no duality of interest 
      associated with their contribution to this paper.
EDAT- 2022/03/20 06:00
MHDA- 2022/04/06 06:00
PMCR- 2022/03/18
CRDT- 2022/03/19 05:31
PHST- 2020/09/03 00:00 [received]
PHST- 2022/02/08 00:00 [accepted]
PHST- 2022/03/19 05:31 [entrez]
PHST- 2022/03/20 06:00 [pubmed]
PHST- 2022/04/06 06:00 [medline]
PHST- 2022/03/18 00:00 [pmc-release]
AID - 10.1038/s42003-022-03170-w [pii]
AID - 3170 [pii]
AID - 10.1038/s42003-022-03170-w [doi]
PST - epublish
SO  - Commun Biol. 2022 Mar 18;5(1):238. doi: 10.1038/s42003-022-03170-w.