Glucagon-receptor-antagonism-mediated β-cell regeneration as an effective anti-diabetic therapy
Yannan Xi, Benbo Song, Iris Ngan, Mark J. Solloway, Mark Humphrey, Yan Wang, Kalyani Mondal, Hao Wu, Wenhui Liu, Darrin A. Lindhout, Diana Li, Hugo Matern, Avantika Kekatpure, Raj Haldankar, Daniel D. Kaplan, Hong Yang, Ophelia Pedersen, Anna Chen, Mei Zhou, Bethany Winans, Wei Guo, Alan K. Kutach, Marie Fanget, Michael Fox, Jie Tang, Jiping Zha, Husam S. Younis, D. T. Shen, Alex M. DePaoli, Hui Tian, Zhonghao Liu
Abstract
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.