Blockade of glucagon receptor induces α-cell hypersecretion by hyperaminoacidemia in mice

Jianxin Jia, Xuanxuan Bai, Qi Kang, Fuquan Jiang, F. Susan Wong, Quanwen Jin () and Mingyu Li ()
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Jianxin Jia: Xiamen University
Xuanxuan Bai: Xiamen University
Qi Kang: Xiamen University
Fuquan Jiang: Xiamen University
F. Susan Wong: Cardiff University School of Medicine
Quanwen Jin: Xiamen University
Mingyu Li: Xiamen University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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 activation of both mTOR-STAT3 and ERK-CREB pathways, induced by elevated circulation amino acids, is responsible for upregulation of Vgf and Gcg expression following glucagon receptor blockade. Thus, our findings elucidate parts of the molecular mechanism underlying hyperglucagonemia in GCGR blockade.

Date: 2025
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DOI: 10.1038/s41467-025-57786-7

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