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- Title
Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion.
- Authors
Veprik, Anna; Denwood, Geoffrey; Liu, Dong; Bany Bakar, Rula; Morfin, Valentin; McHugh, Kara; Tebeka, Nchimunya N.; Vetterli, Laurène; Yonova-Doing, Ekaterina; Gribble, Fiona; Reimann, Frank; Hoehn, Kyle L.; Hemsley, Piers A.; Ahnfelt-Rønne, Jonas; Rorsman, Patrik; Zhang, Quan; de Wet, Heidi; Cantley, James
- 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. Veprik et al. show that Acetyl-CoA-carboxylase 1 (ACC1), an enzyme that couples glucose metabolism to lipogenesis, is involved in glucagon secretion and regulates S-acylation of critical glucose-sensing proteins. Loss of ACC1 in pancreatic alpha-cells negatively affects both size and number, as well as glucagon content, while in gut enteroendocrine cells leads to reduced release of glucagon-like peptide 1.
- Subjects
PANCREATIC beta cells; ENTEROENDOCRINE cells; GLUCAGON; GLUCAGON-like peptide 1; SECRETION; INSULIN; CELL physiology; TYPE 2 diabetes
- Publication
Communications Biology, 2022, Vol 5, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-03170-w