Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion

Anna Veprik, Geoffrey Denwood, Dong Liu, Rula Bany Bakar, Valentin Morfin, Kara McHugh, Nchimunya N. Tebeka, Laurène Vetterli, Ekaterina Yonova-Doing, Fiona Gribble, Frank Reimann, Kyle L. Hoehn, Piers A. Hemsley, Jonas Ahnfelt-Rønne, Patrik Rorsman, Quan Zhang, Heidi de Wet, James Cantley (Lead / Corresponding author)

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Abstract

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.

Original languageEnglish
Article number238
Number of pages13
JournalCommunications Biology
Volume5
Issue number1
DOIs
Publication statusPublished - 18 Mar 2022

Keywords

  • Homeostasis
  • Nutrient signalling
  • Type 2 diabetes

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