Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-03, Vol.118 (9), p.1-8
• Main Authors: Wang, May-Yun, Dean, E. Danielle, Quittner-Strom, Ezekiel, Zhu, Yi, Chowdhury, Kamrul H., Zhang, Zhuzhen, Zhao, Shangang, Li, Na, Ye, Reshing, Lee, Young, Zhang, Yiyi, Chen, Shiuhwei, Yu, Xinxin, Leonard, Derek C., Poffenberger, Greg, Von Deylen, Alison, McCorkle, S. Kay, Schlegel, Amnon, Sloop, Kyle W., Efanov, Alexander M., Gimeno, Ruth E., Scherer, Philipp E., Powers, Alvin C., Unger, Roger H., Holland, William L.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Biological Sciences; Blood Glucose - metabolism; C-Peptide - metabolism; Cell Lineage - drug effects; Cell Transdifferentiation - drug effects; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - immunology; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - therapy; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - therapy; Gene Expression; Glucagon - antagonists & inhibitors; Glucagon - metabolism; Glucagon-Secreting Cells - drug effects; Glucagon-Secreting Cells - metabolism; Glucagon-Secreting Cells - pathology; Humans; Hypoglycemic Agents - pharmacology; Insulin - metabolism; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Islets of Langerhans - metabolism; Islets of Langerhans - physiology; Islets of Langerhans Transplantation; Mice; Mice, Inbred NOD; Organ Size - drug effects; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; Treatment Outcome
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2022142118

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin⁺ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust assessment of β-cell regeneration following caspase-8–induced diabetes, Ab-4 drove a 6.7-fold increase in β-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-β-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin⁺ islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.