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

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 insulins in humans and mice permit in vivo studies of human 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. Here we use CRISPR/Cas9 editing to remove glucagon codons 2–29 in immunocompromised NSG mice, preserving production of other proglucagon-derived hormones. Glucagon knockout-NSG (GKO-NSG) mice have metabolic, liver and pancreatic phenotypes associated with glucagon signaling deficits that revert after transplantation of human islets from non-diabetic donors. Glucagon hypersecretion by transplanted islets from donors with type 2 diabetes revealed islet-intrinsic defects. We suggest that GKO-NSG mice provide an unprecedented resource to investigate human α cell regulation in vivo.