Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion.
Springer Science and Business Media LLC
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Veprik, A., Denwood, G., Liu, D., Bany Bakar, R., Morfin, V., McHugh, K., Tebeka, N. N., et al. (2022). Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion.. Commun Biol, 5 (1. ARTN 238), 238. https://doi.org/10.1038/s42003-022-03170-w
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.
Acetyl Coenzyme A, Acetyl-CoA Carboxylase, Animals, Glucagon, Glucagon-Secreting Cells, Glucose, Insulin-Secreting Cells, Mice
Medical Research Council (MC_UU_12012/3)
External DOI: https://doi.org/10.1038/s42003-022-03170-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336592
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/