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.
Included in
Animals Commons, Cardiology Commons, Cardiovascular Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Medical Cell Biology Commons, Medical Genetics Commons
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