Journal article
Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion
- Abstract:
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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 αTC9 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 KATP 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 KATP 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 2.2MB, Terms of use)
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- Publisher copy:
- 10.1038/s42003-022-03170-w
Authors
- Funder identifier:
- https://ror.org/00cwqg982
- Grant:
- BB/P020666/1
- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MC_UU_12012/3
- MR/T002107/1
- MR/V011979/1
- Publisher:
- Springer Nature
- Journal:
- Communications Biology More from this journal
- Volume:
- 5
- Issue:
- 1
- Article number:
- 238
- Publication date:
- 2022-03-18
- Acceptance date:
- 2022-02-08
- DOI:
- EISSN:
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2399-3642
- Pmid:
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35304577
- Language:
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English
- Keywords:
- Pubs id:
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1246996
- Local pid:
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pubs:1246996
- Deposit date:
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2025-03-17
- ARK identifier:
Terms of use
- Copyright holder:
- Veprik et al.
- Copyright date:
- 2022
- Rights statement:
- Copyright © 2022, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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