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

May Yun Wang, E. Danielle Dean, Ezekiel Quittner-Strom, Yi Zhu, Kamrul H. Chowdhury, Zhuzhen Zhang, Shangang Zhao, Na Li, Reshing Ye, Young Lee, Yiyi Zhang, Shiuhwei Chen, Xinxin Yu, Derek C. Leonard, Greg Poffenberger, Alison Von Deylen, S. Kay McCorkle, Amnon Schlegel, Kyle W. Sloop, Alexander M. EfanovRuth E. Gimeno, Philipp E. Scherer, Alvin C. Powers, Roger H Unger, William L. Holland

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 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.

Original languageEnglish (US)
Article numbere2022142118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number9
DOIs
StatePublished - Mar 2 2021

Keywords

  • Diabetes
  • Glucagon
  • Insulin
  • Islet
  • Regeneration

ASJC Scopus subject areas

  • General

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