Glucagon-receptor-antagonism-mediated β-cell regeneration as an effective anti-diabetic therapy

• Published in: Cell reports (Cambridge) Vol. 39; no. 9; p. 110872
• Main Authors: Xi, Yannan, Song, Benbo, Ngan, Iris, Solloway, Mark J., Humphrey, Mark, Wang, Yan, Mondal, Kalyani, Wu, Hao, Liu, Wenhui, Lindhout, Darrin A., Li, Diana, Matern, Hugo, Kekatpure, Avantika, Haldankar, Raj, Kaplan, Daniel D., Yang, Hong, Pedersen, Ophelia, Chen, Anna, Zhou, Mei, Winans, Bethany, Guo, Wei, Kutach, Alan, Fanget, Marie, Fox, Michael, Tang, Jie, Zha, Jiping, Younis, Husam, Shen, David, DePaoli, Alex, Tian, Hui, Liu, Zhonghao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.05.2022
• Subjects: anti-diabetic therapy; anti-glucagon receptor; antibody therapy; autoimmune diabetes; beta-cell regeneration; glucagon receptor; type 1 diabetes; α- to β-cell transdifferentiation; β-cell proliferation; β-cell proliferation; α- to β-cell transdifferentiation; anti-diabetic therapy; type 1 diabetes; autoimmune diabetes; CP: Metabolism; glucagon receptor; anti-glucagon receptor; beta-cell regeneration; antibody therapy
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110872

Type 1 diabetes mellitus (T1D) is a chronic disease with potentially severe complications, and β-cell deficiency underlies this disease. Despite active research, no therapy to date has been able to induce β-cell regeneration in humans. Here, we discover the β-cell regenerative effects of glucagon receptor antibody (anti-GcgR). Treatment with anti-GcgR in mouse models of β-cell deficiency leads to reversal of hyperglycemia, increase in plasma insulin levels, and restoration of β-cell mass. We demonstrate that both β-cell proliferation and α- to β-cell transdifferentiation contribute to anti-GcgR-induced β-cell regeneration. Interestingly, anti-GcgR-induced α-cell hyperplasia can be uncoupled from β-cell regeneration after antibody clearance from the body. Importantly, we are able to show that anti-GcgR-induced β-cell regeneration is also observed in non-human primates. Furthermore, anti-GcgR and anti-CD3 combination therapy reverses diabetes and increases β-cell mass in a mouse model of autoimmune diabetes. [Display omitted] •Glucagon receptor blockade in β-cell-deficient mice leads to robust β-cell regeneration•Regenerated β cells induced by anti-GcgR persist even after antibody washout•β-cell replication and α- to β-cell transdifferentiation as two underlying mechanisms•β-cell regenerative effects observed in non-human primates and model of type 1 diabetes β-cell regeneration is highly sought as a potential anti-diabetes therapy. Xi et al. demonstrate that chronic treatment with anti-glucagon receptor antibody can lead to robust β-cell regeneration in multiple preclinical models. Both β-cell replication and α- to β-cell transdifferentiation contribute to this effect.