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Publication
In vivo studies of glucagon secretion by human islets transplanted in mice.
Authors Tellez K, Hang Y, Gu X, Chang CA, Stein RW, Kim SK
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal Nature metabolism
Year 2020
Date Published 6/1/2020
Volume : Pages 2 : 547 - 557
PubMed Reference 32694729
Abstract Little is known about regulated glucagon secretion by human islet a-cells
compared to insulin secretion from ß-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 ß-cell regulation after human islet
transplantation in immunocompromised mice, whereas identical glucagon sequences
prevent analogous in vivo measures of glucagon output from human a-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 a-cell regulation in vivo.





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