2. Academic Validation
  3. Blockade of glucagon receptor induces α-cell hypersecretion by hyperaminoacidemia in mice

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

  • Nat Commun. 2025 Mar 12;16(1):2473. doi: 10.1038/s41467-025-57786-7.
Jianxin Jia 1 2,  Xuanxuan Bai 1 3,  Qi Kang 1 2,  Fuquan Jiang 2,  F Susan Wong 4,  Quanwen Jin 5,  Mingyu Li 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences and School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
  • 2 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
  • 3 School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 4 Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
  • 5 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences and School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China. jinquanwen@xmu.edu.cn.
  • 6 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences and School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China. limingyu@xmu.edu.cn.
  • 7 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China. limingyu@xmu.edu.cn.
PMID: 40075066 DOI: 10.1038/s41467-025-57786-7
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.

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