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

ABSTRACT

Type 1 diabetes mellitus (T1D) is a chronic disease with potentially severe complications, and ß-cell deficiency underlies this disease. Despite active research, no therapy to date has been able to induce ß-cell regeneration in humans. Here, we discover the ß-cell regenerative effects of glucagon receptor antibody (anti-GcgR). Treatment with anti-GcgR in mouse models of ß-cell deficiency leads to reversal of hyperglycemia, increase in plasma insulin levels, and restoration of ß-cell mass. We demonstrate that both ß-cell proliferation and α- to ß-cell transdifferentiation contribute to anti-GcgR-induced ß-cell regeneration. Interestingly, anti-GcgR-induced α-cell hyperplasia can be uncoupled from ß-cell regeneration after antibody clearance from the body. Importantly, we are able to show that anti-GcgR-induced ß-cell regeneration is also observed in non-human primates. Furthermore, anti-GcgR and anti-CD3 combination therapy reverses diabetes and increases ß-cell mass in a mouse model of autoimmune diabetes.