biostudies-literatureJia JNatural Science Foundation of Fujian ProvinceNatural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)2473https://www.ebi.ac.uk/biostudies/studies/S-EPMC11903786biostudies-literatureUnknown16(1)Blockade of the glucagon receptor (GCGR) has been shown to improve glycemic control. However, this therapeutic approach also brings side effects, such as α-cell hyperplasia and hyperglucagonemia, and the mechanisms underlying these side effects remain elusive. Here, we conduct single-cell transcriptomic sequencing of islets from male GCGR knockout (GCGR-KO) mice. Our analysis confirms the elevated expression of Gcg in GCGR-KO mice, along with enhanced glucagon secretion at single-cell level. Notably, Vgf (nerve growth factor inducible) is specifically upregulated in α cells of GCGR-KO mice. Inhibition of VGF impairs the formation of glucagon immature secretory granules and compromises glucagon maturation, lead to reduced α-cell hypersecretion of glucagon. We further demonstrate that activaNature communicationsBlockade of glucagon receptor induces α-cell hypersecretion by hyperaminoacidemia in mice.PMC119037862023I0002Jin QKang QJiang FWong FSBai XLi MJia JfalseBlockade of glucagon receptor induces α-cell hypersecretion by hyperaminoacidemia in mice.Blockade of the glucagon receptor (GCGR) has been shown to improve glycemic control. However, this therapeutic approach also brings side effects, such as α-cell hyperplasia and hyperglucagonemia, and the mechanisms underlying these side effects remain elusive. Here, we conduct single-cell transcriptomic sequencing of islets from male GCGR knockout (GCGR-KO) mice. Our analysis confirms the elevated expression of Gcg in GCGR-KO mice, along with enhanced glucagon secretion at single-cell level. Notably, Vgf (nerve growth factor inducible) is specifically upregulated in α cells of GCGR-KO mice. Inhibition of VGF impairs the formation of glucagon immature secretory granules and compromises glucagon maturation, lead to reduced α-cell hypersecretion of glucagon. We further demonstrate that activa2025-01-01T00:00:00Z2025 Mar2025-04-21T16:55:03.162Z2025-04-21T16:55:03.162ZS-EPMC119037864007506610.1038/s41467-025-57786-7