TCF7L2 overexpression and type 2 diabetes: Dissecting the function of TCF7L2 as a regulator of glucose metabolism /

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Bibliographic Details
Author / Creator:Bailey, Kathleen Ann, author.
Ann Arbor : ProQuest Dissertations & Theses, 2015
Description:1 electronic resource (142 pages)
Format: E-Resource Dissertations
Local Note:School code: 0330
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Other authors / contributors:University of Chicago. degree granting institution.
Notes:Advisors: Marcelo Nobrega; Carole Ober Committee members: Graeme Bell; Matthew Brady.
Dissertation Abstracts International, Volume: 77-02(E), Section: B.
Summary:Despite the mounting evidence for a peripheral contribution of TCF7L2 overexpression in increasing type 2 diabetes (T2D) risk, there has been little inquiry into the function of Tcf7l2 beyond the pancreatic beta cell. Therefore, we aimed to establish the contribution of Tcf7l2 overexpression in each peripheral tissue individually, assaying the subsequent effect on glucose tolerance. In the first aim, we interrogated the effect of Tcf7l2 overexpression in beta cells and found that a reduction in Tcf7l2 expression in beta cells does indeed perpetuate a diabetic phenotype, however Tcf7l2 overexpression in another peripheral tissue overrides this pancreatic contribution. In the second aim, we utilized a similar approach to ascertain the effect of Tcf7l2 overexpression on glucose metabolism in the hypothalamus in an attempt to elucidate the function of Tcf7l2 in the periphery. These experiments highlighted a limited role for hypothalamus expression of Tcf7l2 in affecting glucose homeostasis. In the third aim, we studied the role of Tcf7l2 expression in adipocytes and identified the metabolic effects of Tcf7l2 overexpression in this tissue. Rescue of normal expression in adipocytes alone is sufficient to rescue whole-body glucose tolerance indicating overexpression in this tissue contributes significantly to the diabetic phenotype. Upon metabolic interrogation of this mechanism in adipocytes, we propose a model in which Tcf7l2 overexpression in adipocytes restricts proper adipogenesis which when challenged by high fat diet leads to adipocyte hypertrophy. The results of these studies lend particular insight into the metabolic mechanism by which TCF7L2 overexpression leads to increased T2D risk, providing new understanding in the etiology of such a widespread and prevalent disease. Furthermore, our data highlight new T2D therapeutic targets in adipose with the potential to establish better outcomes for T2D patients.