Acetyl-CoA-Carboxylase 1 (ACC1) plays a critical role in glucagon and glucagon-like peptide 1 (GLP-1) secretion and controls whole-body glucose homeostasis

Anna Veprik (Lead / Corresponding author), Laurène Vetterli, Rula Bany Bakar, Reshma Ramracheya, Patrik Rorsman, Fiona Gribble, Frank Reimann, Heidi de-Wet, James Cantley

Research output: Contribution to journalConference articlepeer-review

Abstract

Aims: One of the hallmarks of diabetes is dysregulated glucagon secretion from pancreatic alpha cells. Glucagon-Like Peptide 1 (GLP1) is secreted from gut enteroendocrine L cells, potentiating insulin secretion, and GLP-1 levels are reduced in Type 2 diabetes. Despite the important role of these cell types in glycaemic control, the mechanisms regulating their secretory function are not well defined.

We have previously identified that ACC1, the rate-limiting enzyme of de novo lipogenesis, plays a critical role in the growth and function of beta cells. The aim of the current project was to explore the role of ACC1 in pancreatic alpha and gut L-cell function.

Methods: ACC1 was ablated in alpha and L cells in vivo using a glucagon-driven Cre–Lox strategy, and in vitro using pharmacological inhibitors.

Results: Pharmacological inhibition of ACC impaired glucagon secretion from transformed alpha cells, primary mouse and human islets, as well as impairing GLP-1 secretion from transformed enteroendocrine cells and primary gut crypts. To investigate these mechanisms in vivo, we generated mice with ACC1 ablated in alpha and L cells (Glu-ACC1KO). Glu-ACC1KO mice were glucose intolerant, relative to littermate control mice, with lower fasting glucagon levels that were unresponsive to glucose administration. Correspondingly, the secretion of glucagon and GLP-1 from islets and gut crypts isolated from Glu-ACC1KO mice was severely impaired, relative to controls, and consistent with our in vitro ACC inhibitor data.

Summary: Our data reveals a critical role for ACC1 in controlling alpha and L-cell function and whole-body glucose homeostasis.
Original languageEnglish
Article numberA33
Pages (from-to)16-17
Number of pages2
JournalDiabetic Medicine
Volume36
Issue numberS1
Early online date5 Mar 2019
DOIs
Publication statusPublished - Mar 2019
EventDiabetes UK Professional Conference 2019 - ACC Liverpool, Liverpool, United Kingdom
Duration: 6 Mar 20198 Mar 2019

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