Glucagon Blockade Restores Functional β-Cell Mass in Type 1 Diabetic Mice and Enhances Function of Human Islets

Authors

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 Efanov
Ruth E Gimeno
Philipp E Scherer
Alvin C Powers
Roger H Unger
William L Holland

Publication Date

3-2-2021

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2022142118

PMID

33619103

PMCID

PMC7936318

PubMedCentral® Posted Date

2-22-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Antibodies, Monoclonal, Blood Glucose, C-Peptide, Cell Lineage, Cell Transdifferentiation, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Gene Expression, Glucagon, Glucagon-Secreting Cells, Humans, Hypoglycemic Agents, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Islets of Langerhans Transplantation, Mice, Mice, Inbred NOD, Organ Size, Receptors, Glucagon, Treatment Outcome, insulin, glucagon, islet, regeneration, diabetes

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.