In vivo studies of glucagon secretion by human islets transplanted in mice

Abstract Relatively little is known about regulated glucagon secretion by human islet α cells compared to insulin secretion from β cells, despite conclusive evidence of dysfunction in both cell types in diabetes mellitus. Distinct insulin sequences in humans and mice permit in vivo studies of β cell regulation after human islet transplantation in immunocompromised mice, whereas identical glucagon sequences prevent analogous in vivo measures of glucagon output from human α cells. We used CRISPR/Cas9 genome editing to remove glucagon-encoding codons 2-29 in immunocompromised (NSG) mice, preserving production of other proglucagon-derived hormones, like Glucagon-like-peptide 1. These NSG-Glucagon knockout (NSG-GKO) mice had phenotypes associated with glucagon signaling deficits, including hypoglycemia, hyperaminoacidemia, hypoinsulinemia, and islet α cell hyperplasia. NSG-GKO host metabolic and islet phenotypes reverted after human islet transplantation, and human islets retained regulated glucagon and insulin secretion. NSG-GKO mice provide an unprecedented resource to investigate unique, species-specific human α cell regulation in vivo.