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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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