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

Nat Metab. 2020 Jun;2(6):547-557. doi: 10.1038/s42255-020-0213-x. Epub 2020 Jun 8.


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 the production of other proglucagon-derived hormones. Glucagon knockout NSG (GKO-NSG) mice have metabolic, liver and pancreatic phenotypes associated with glucagon-signalling 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Animals
  • CRISPR-Cas Systems
  • Diabetes Mellitus, Type 2 / metabolism
  • Female
  • Glucagon / genetics
  • Glucagon / metabolism*
  • Glucagon-Secreting Cells / metabolism
  • Glucose Tolerance Test
  • Humans
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans Transplantation*
  • Liver / metabolism
  • Liver Glycogen / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged


  • Liver Glycogen
  • Glucagon