Crispr-Cas9 mediated complete deletion of glucagon receptor in mice display hyperglucagonemia and α-cell hyperplasia

Yuan, Hang; Kang, Qi; Li, Zhehui; Bai, Xuanxuan; Jia, Jianxin; Han, Daxiong; Wu, Xi-Jie; Li, Mingyu

doi:10.1016/j.bbrc.2022.12.079

Cited by 2 publications

(2 citation statements)

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“…Many studies have revealed that GCGR blockade led to α-cell hyperplasia 7,16,17,[24][25][26][27] . However, none of the studies investigated glucagon secretion at the single cell level in the GCGR-de cient α cell.…”

Section: Discussionmentioning

confidence: 99%

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Disruption of glucagon receptor induces single α-cell hypersecretion through upregulation of VGF

Jia,

Kang,

Bai

et al. 2024

Preprint

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Antagonism of the glucagon receptor (GCGR) improves glycemic control both in rodent diabetes models and humans with diabetes. However, GCGR antagonism, as well as GCGR-deficiency in animal models, cause side effects of α-cell hyperplasia and hyperglucagonemia, which limit its clinical applications. The cause of these side effects has been unclear. In this study, we performed single-cell transcriptomic sequencing of α cells from glucagon receptor knockout (GCGR-KO) mice. We confirmed that α cells increased proliferation, and increased the expression of Glucagon and Slc38a5. We also found that the interaction of α cells with other endocrine cells increased, and insulin- and somatostatin-mediated inhibition of glucagon secretion was blunted. Importantly, we demonstrated that the GCGR-KO mouse not only had induced α-cell hyperplasia but also increased glucagon secretion at the single-cell level. Interestingly, GCGR-KO mouse dramatically and specifically increased VGF in α cells. Suppression of VGF reduced the α cell hypersecretion both ex vivo and in vivo. Moreover, inhibition of VGF impaired the formation of immature proglucagon secretory granules in the trans‑Golgi network, and reduced glucagon peptide maturation. These results demonstrated the basis for hyperglucagonemia in the GCGR-deficient animal, and will be beneficial for optimization of clinical application of GCGR antagonism for diabetes treatment.

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Section: Discussionmentioning

confidence: 99%

“…The WT and Glucagon receptor knockout (GCGR-KO) mice 24 were bred and maintained in individuallyventilated cages (IVC) (≤ 5 animals per cage) in SPF conditions at the Xiamen University experimental animal center. They were allowed free access to conventional chow diet and water, with a 12/12h daynight lighting cycle.…”

Section: Animalsmentioning

confidence: 99%