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

Area of Science:

• Endocrinology
• Diabetes Research
• Cell Biology

Background:

• Pancreatic alpha-cells can regenerate and convert to beta-cells under specific conditions.
• Beta-cell regeneration is a promising avenue for diabetes cell replacement therapy.
• Developing clinical strategies to promote beta-cell regeneration is critical for therapeutic application.

Purpose of the Study:

• To investigate the therapeutic potential of a glucagon receptor (GCGR) monoclonal antibody (mAb) in diabetes models.
• To determine if GCGR mAb treatment can promote beta-cell regeneration and improve glycemic control.

Main Methods:

• Treatment of normoglycemic, streptozotocin-induced type 1 diabetic (T1D), and non-obesity diabetic mice with REMD 2.59 (a human GCGR mAb).
• Measurement of blood glucose, plasma glucagon, and active glucagon-like peptide-1 levels.
• Assessment of pancreatic alpha-cell neogenesis, proliferation, and beta-cell mass using lineage-tracing mice.

Main Results:

• GCGR mAb treatment lowered blood glucose without inducing hypoglycemia in T1D mouse models.
• Treatment increased plasma glucagon and active glucagon-like peptide-1 levels.
• GCGR mAb induced alpha-cell neogenesis and proliferation, leading to increased beta-cell mass, likely via alpha- to beta-cell conversion.

Conclusions:

• GCGR mAb treatment effectively promotes alpha- to beta-cell conversion in preclinical diabetes models.
• This alpha- to beta-cell conversion represents a potential pre-clinical strategy for advancing diabetes therapy.
• GCGR mAb offers a promising approach for beta-cell regeneration in the context of diabetes.