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


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

SUBMITTER: Wang MY 

PROVIDER: S-EPMC7936318 | biostudies-literature |

REPOSITORIES: biostudies-literature

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