Antagonistic Glucagon Receptor Antibody Promotes α-Cell Proliferation and Increases β-Cell Mass in Diabetic Mice

Abstract

Summary Under extreme conditions or by genetic modification, pancreatic α-cells can regenerate and be converted into β-cells. This regeneration holds substantial promise for cell replacement therapy in diabetic patients. The discovery of clinical therapeutic strategies to promote β-cell regeneration is crucial for translating these findings into clinical applications. In this study, we reported that treatment with REMD 2.59, a human glucagon receptor (GCGR) monoclonal antibody (mAb), lowered blood glucose without inducing hypoglycemia in normoglycemic, streptozotocin-induced type 1 diabetic (T1D) and non-obesity diabetic mice. Moreover, GCGR mAb treatment increased the plasma glucagon and active glucagon-like peptide-1 levels, induced pancreatic ductal ontogenic α-cell neogenesis, and promoted α-cell proliferation. Strikingly, the treatment also increased the β-cell mass in these two T1D models. Using α-cell lineage-tracing mice, we found that the neogenic β-cells were likely derived from α-cell conversion. Therefore, GCGR mAb-induced α- to β-cell conversion might represent a pre-clinical approach for improving diabetes therapy.

Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes

“…Therefore, developing a safe and efficacious GCGR antagonist remains highly needed. Being a fully human GCGR mAb, REMD 2.59 has several desirable attributes as potential therapeutic agents, including a high affinity to GCGR, a relatively long circulating half-life, the highly specific antagonistic activity against GCGR and minimal adverse effects 6 9. Consistent with the previous reports of our and other groups,6 8 9 this study demonstrated that the GCGR mAb lowered fasting blood glucose, improved glucose tolerance and increased active GLP-1 levels in T2D mice.…”

“…Importantly, a phase I/II randomized clinical trial showed that REMD 477, another human GCGR mAb that differs by only one amino acid (which is not involved in glucagon binding) and has an affinity for the GCGR equivalent to that of REMD 2.59, improved glycemic control in patients with T1D, and no serious adverse effects were detected 11. Interestingly, our previous study discovered that REMD 2.59 induced pancreatic β-cell regeneration, which derived at least partially from transdifferentiation of pancreatic α-cells or δ-cells 6 7. These results indicate that GCGR mAb represents a novel therapeutic approach for diabetes therapy.…”

“…Although gut-derived GLP-1 is essential for glucose homeostasis,30 it is worth noting that we could not exclude other sources of GLP-1. For example, our previous study showed that pancreatic α-cells could express PC1/3 and process Gcg into GLP-1 after GCGR mAb treatment,6 suggesting that the increased plasma GLP-1 level might also derive from pancreatic α-cells. The tissue-specific Gcg or Pcsk1 (the coding gene of PC1/3) knockout mice would be helpful.…”

“…However, in this study, GCGR mAb increased rather than decreased insulin level in T2D mice. We tried to answer this question from several aspects, including β-cell regeneration (eg, transdifferentiation of pancreatic α-cells or δ-cells)6 7 and elevated circulating GLP-1 level, due to gut-derived GLP-1 (in this study) and islet-derived GLP-1 (our ongoing study) production. How the promoting factors overwhelm the direct effect of glucagon remains to be clarified.…”

“…Accumulating evidence proves that disruption of GCGR signaling, using gene knockout, antisense oligonucleotide, antagonists or antibodies, can alleviate hyperglycemia in animals and humans 3–5. Recent data from our group and others have shown that REMD 2.59, a fully competitive antagonistic human GCGR monoclonal antibody (mAb), has a strong hypoglycemic effect in type 1 diabetic (T1D) and T2D rodents and non-human primates 6–10. Importantly, a phase I/II randomized clinical trial showed that REMD 477, another human GCGR mAb that differs by only one amino acid (which is not involved in glucagon binding) and has an affinity for the GCGR equivalent to that of REMD 2.59, improved glycemic control in patients with T1D, and no serious adverse effects were detected 11.…”