All ETDs from UAB

Advisory Committee Chair

Anath Shalev

Advisory Committee Members

Shannon Bailey

Robin Lorenz

Eric Sorscher

Martin Young

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Pancreatic beta cells secrete insulin to maintain normal blood glucose levels and allow cells of the body to use glucose. However, in diabetes, there is beta cell dysfunction and pancreatic beta cells undergo programmed cell death leading to inadequate insulin production and secretion. Thioredoxin-Interacting Protein (TXNIP) is a ubiquitously expressed protein, 46 kDa in size, which is an arrestin protein family member. Unique to this member of the arrestin family, however, is its ability to bind to, and reduce, thioredoxin. The TXNIP gene is increased in pancreatic islets more than any other gene in response to high levels of glucose. Previous studies have shown that TXNIP is increased in diabetes, and that increased TXNIP causes beta cell apoptosis. Interestingly, a deficiency in TXNIP can prevent diabetes, as TXNIP deficiency results in increased beta cell mass and decreased apoptosis. This is true in models of both type 1 diabetes and type 2 diabetes. It has also been recently shown that TXNIP can affect beta cell function by increasing microRNA-204 and decreasing insulin production. TXNIP was further found to affect other microRNAs, with many members of the microRNA-200 family among them. This dissertation investigates the role of the microRNA-200 family in beta cell biology. We found that one of the microRNA-200 family members which is increased by TXNIP also causes death of pancreatic beta cells. This microRNA targets and consequently decreases levels of the Zinc Finger E-Box Binding Homeobox 1 (Zeb1) mRNA. A knock-down of Zeb1 with siRNA also led to a similar increase in beta cell apoptosis. In addition to affecting beta cell apoptosis, we discovered miR-200 to affect factors related to Epithelial-Mesenchymal-Transition (EMT). EMT is a process in which cells go from an epithelial state, to a motile mesenchymal state, and it is characterized by a loss of cell-cell cadherins junctions and polarity, as well as a change in levels of E-Cadherin affecting transcription factors, such as Zeb1. This process, while controversial in beta cells, may be important in their development or in-vitro expansion. Thus, the results of this work demonstrate a novel mechanism by which TXNIP causes beta cell apoptosis, identify TXNIP as a novel regulator of E-Cadherin and possibly EMT in beta cells, and provide new insight into possible avenues for treating diabetes.

Share

COinS