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

Authors: WANG, MAY-YUN - University Of Texas Southwestern Medical Center; DEAN, DANIELLE - Vanderbilt University; QUITTNER-STROM, EZEKIEL - University Of Texas Southwestern Medical Center; ZHU, YI - Children'S Nutrition Research Center (CNRC); CHOWDHURY, KAMRUL - University Of Utah; ZHANG, ZHUZHEN - University Of Texas Southwestern Medical Center; ZHAO, SHANGANG - University Of Texas Southwestern Medical Center; LI, NA - University Of Texas Southwestern Medical Center; YE, RISHENG - University Of Texas Southwestern Medical Center; LEE, YOUNG - University Of Texas Southwestern Medical Center; ZHANG, YIYI - University Of Texas Southwestern Medical Center; CHEN, SHIUHWEI - University Of Texas Southwestern Medical Center; YU, XINXIN - University Of Texas Southwestern Medical Center; LEONARD, DEREK - University Of Texas Southwestern Medical Center; POFFENBERGER, GREG - Vanderbilt University; DEYLEN, ALISON - Vanderbilt University; MCCORKLE, S - University Of North Texas; SCHLEGEL, AMNON - University Of Utah; SLOOP, KYLE - Eli Lilly & Company; EFANOV, ALEXANDER - Eli Lilly & Company; GIMENO, RUTH - Eli Lilly & Company; SCHERER, PHILIPP - University Of Texas Southwestern Medical Center; POWERS, ALVIN - Vanderbilt University; UNGER, ROGER - University Of Texas Southwestern Medical Center; HOLLAND, WILLIAM - University Of Utah

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/7/2020
Publication Date: 2/22/2021
Citation: Wang, M., Dean, D.E., Quittner-Strom, E., Zhu, Y., Chowdhury, K.H., Zhang, Z., Zhao, S., Li, N., Ye, R., Lee, Y., Zhang, Y., Chen, S., Yu, X., Leonard, D.C., Poffenberger, G., Deylen, A.V., McCorkle, S.K., Schlegel, A., Sloop, K.W., Efanov, A.M., Gimeno, R.E., Scherer, P.E., Powers, A.C., Unger, R.H., Holland, W.L. 2021. Glucagon blockade restores functional B-cell mass in type 1 diabetic mice and enhances function of human islets. Proceedings of the National Academy of Sciences(PNAS). 118(9):e2022142118. https://doi.org/10.1073/pnas.2022142118.
DOI: https://doi.org/10.1073/pnas.2022142118

Interpretive Summary: The a-cells of the pancreas secrete glucagon to counteract insulin's action and increase blood glucose. Neutralizing glycogen in type 1 diabetes has been shown to improve glucose control. However, what neutralizing glucagon would do on islet insulin-producing B-cells was unknown. This report used an antibody to block glucagon action and showed it partially restored pancreatic islet B-cell function in type 1 diabetic mice and humans. These results support the development of this glucagon antibody as a therapy for type 1 diabetes.

Technical Abstract: 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 B-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 B-cell apoptosis which allows for robust assessment of B-cell regeneration following caspase-8–induced diabetes, Ab-4 drove a 6.7-fold increase in B-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by a-cell-to-B-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.