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Transcription Factors E2F Have a Role in Proliferation of Beta-Cells and Development of Type-2 Diabetes

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posted on 29.06.2015, 00:00 by Brian Rady
This work pertains to the search for genetic targets to induce beta-cell proliferation. This proliferation was intended to support the advancement of islet cell transplant as a therapy for type-1 diabetes. Since beta-cells are post-mitotic cells that rarely divide, we initially sought to find anything that would produce more insulin-secreting cells. By comparing proliferative insulinomas and wildtype islets, we identified a transcription factor, E2F3 that was differentially overexpressed in insulinomas. Mimicking this overexpression in wild type islets resulted in the induction of proliferation. These newly formed cells retained the beta-cell phenotype and didn’t undergo apoptosis as they were cultured. When transplanted into diabetic mice, these cells were able to reverse diabetes and restore normal blood glucose levels. We also investigated the role of E2F1 on the loss of beta-cell function that often accompanies type-2 diabetes. We found a link between the BMI of islet donors and E2F1 expression. Additionally, we observed that E2F1 controlled the expression of the potassium channel subunit Kir6.2, whose mutational overactivity results in diabetes. E2F1 knockout mice fed a high fat diet did not develop glucose intolerance, while wildtype mice did. Further investigation of the ion channel function in these cells revealed several differences between the E2F1 knockout and wildtype islets. While these differences impacted the over all function of the islets, they don’t appear to be responsible for imparting the resistance to glucose intolerance. Rather we suspect a metabolic change in adipocytes from of the global E1F1 knockout provided the protection.

History

Advisor

Oberholzer, Jose

Department

Bioengineering

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

Eddington, David Wang, Yong Salmon, Patrick Unterman, Terry

Submitted date

2013-05

Language

en

Issue date

28/06/2013

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