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Publication
Ankyrin-B metabolic syndrome combines age-dependent adiposity with pancreatic ß
cell insufficiency.
Authors Lorenzo DN, Healy JA, Hostettler J, Davis J, Yang J, Wang C, Hohmeier HE, Zhang
M, Bennett V
Submitted By Submitted Externally on 11/10/2015
Status Published
Journal The Journal of clinical investigation
Year 2015
Date Published
Volume : Pages 125 : 3087 - 102
PubMed Reference 26168218
Abstract Rare functional variants of ankyrin-B have been implicated in human disease,
including hereditary cardiac arrhythmia and type 2 diabetes (T2D). Here, we
developed murine models to evaluate the metabolic consequences of these
alterations in vivo. Specifically, we generated knockin mice that express either
the human ankyrin-B variant R1788W, which is present in 0.3% of North Americans
of mixed European descent and is associated with T2D, or L1622I, which is
present in 7.5% of African Americans. Young AnkbR1788W/R1788W mice displayed
primary pancreatic ß cell insufficiency that was characterized by reduced
insulin secretion in response to muscarinic agonists, combined with increased
peripheral glucose uptake and concomitantly increased plasma membrane
localization of glucose transporter 4 (GLUT4) in skeletal muscle and adipocytes.
In contrast, older AnkbR1788W/R1788W and AnkbL1622I/L1622I mice developed
increased adiposity, a phenotype that was reproduced in cultured adipocytes, and
insulin resistance. GLUT4 trafficking was altered in animals expressing mutant
forms of ankyrin-B, and we propose that increased cell surface expression of
GLUT4 in skeletal muscle and fatty tissue of AnkbR1788W/R1788W mice leads to the
observed age-dependent adiposity. Together, our data suggest that ankyrin-B
deficiency results in a metabolic syndrome that combines primary pancreatic ß
cell insufficiency with peripheral insulin resistance and is directly relevant
to the nearly one million North Americans bearing the R1788W ankyrin-B variant.




Strains
StrainDevelopment StatusCreation MethodOptions
B6.129-Ank2tm2BntPhenotyping ongoingknockin
View
B6.129(C)-Ank2tm3.1Bnt/JPhenotyping ongoingknockin
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