Glucagon Receptor Antagonism-Mediated β-Cell Regeneration as an Effective Anti-Diabetic Therapy

Abstract

Type 1 Diabetes (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 discovered the β-cell regenerative effects of glucagon receptor antibodies (anti-GcgR). Treatment with anti-GcgR in mouse models of β-cell deficiency leads to reversal of hyperglycemia, increased plasma insulin and C-peptide levels, and restored 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 with treatment cessation and antibody elimination from the body. Importantly, we are able to show that anti-GcgR induced α- to β-cell transdifferentiation is also observed in non-human primates. Furthermore, anti-GcgR and anti-CD3 combination therapy reverses diabetes and increases β-cell mass in the non-obese diabetic (NOD) mouse model of T1D. Taken together, our novel findings suggest that the combination of anti-GcgR with an immune modulator may be an effective therapy for T1D.