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dc.contributor.advisor Bennett, Vann en_US
dc.contributor.author Healy, Jane Anne en_US
dc.date.accessioned 2009-08-27T18:38:59Z
dc.date.available 2011-08-27T04:30:07Z
dc.date.issued 2009 en_US
dc.identifier.uri http://hdl.handle.net/10161/1329
dc.description Dissertation en_US
dc.description.abstract <p>Studies in the ankyrin-B+/- mouse reveal that ankyrin-B deficiency is associated with both the benefits of enhanced cardiac contractility and the costs of arrhythmia, early senescence, reduced lifespan, and impaired glucose tolerance. This constellation of traits is known as ankyrin-B syndrome, which may have important implications for humans possessing functional ankyrin-B mutations. We found that ankyrin-B variants are surprisingly common, ranging from 2 percent of European individuals to 8 percent in individuals from West Africa. Furthermore, by studying of the metabolic phenotype associated with ankyrin-B mouse, we have uncovered a major new dimension to ankyrin-B syndrome, a link between ankyrin-B and parasympathetic control of insulin secretion. Stimulation of pancreatic beta cells by acetylcholine augments glucose-stimulated insulin secretion by inducing inositol-trisphosphate receptor (InsP3R)-mediated Ca2+ release. We report that ankyrin-B is also enriched in pancreatic beta cells. Ankyrin-B-deficient islets display impaired potentiation of insulin secretion by the muscarinic agonist carbachol, blunted carbachol-mediated intracellular Ca2+- release, and reduced InsP3R stability. Ankyrin-B(+/-) mice also display postprandial hyperglycemia, consistent with impaired parasympathetic potentiation of glucose-stimulated insulin secretion. R1788W mutation of ankyrin-B impairs its function in pancreatic islets and associates with type 2 diabetes in Caucasians and Hispanics. Finally, we have generated knockin mice corresponding to the R1788W and L1622I mutations. Functional characterization of these animals will allow us to better understand the relationship between human ankyrin-B variants and ankyrin-B syndrome.</p> en_US
dc.format.extent 54305137 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Biology, Physiology en_US
dc.subject Biology, Molecular en_US
dc.subject acetylcholine en_US
dc.subject ankyrin-B en_US
dc.subject diabetes en_US
dc.subject knockin en_US
dc.subject parasympathetic en_US
dc.subject SNP en_US
dc.title Defining Ankyrin-b Syndrome: Characterization of Ankyrin-b Variants in Mice and Men and the Discovery of a Role for Ankyrin-b in Parasympathetic Control of Insulin Release en_US
dc.type Dissertation en_US
dc.department Biochemistry en_US
duke.embargo.months 24 en_US

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