The Role of Sox17 in Normal and Pathological Beta Cell

<p>Glucose homeostasis is a complex process involving many regulatory molecules and disruption of this process can result in diabetes. Sox17 is a transcription factor and a key regulator in various developmental and disease contexts. During endoderm development, Sox17 acts, in part, by transcriptionally regulating other important endodermal transcription factors including HNF1β and Foxa2, which are also known regulators of postnatal β cell function. Our data shows that Sox17 is expressed in all islet cells. Thus, we hypothesize that Sox17 is a key modulator of β cell homeostasis.</p><p>In the course of this study, we discovered a novel role for Sox17 in regulating insulin trafficking and secretion in normal and pathological β cells. Loss of Sox17 throughout pancreas development in a wildtype background resulted in mice with prediabetes. These mice had higher proinsulin protein content in the ER of the islet cells and dilated secretory organelles in β cells. In line with the prediabetes phenotype, these mice went on to develop additional symptoms of diabetes when placed on a high fat diet, including elevated fasting glucose levels and an inability to respond to a glucose challenge. This suggested that Sox17 affects either insulin processing and/or transit through the secretory system. To more directly investigate these possibilities, we used a tetracycline regulated transgenic system to overexpress Sox17 in mature β cells in wildtype background. Transgenic Sox17 expression resulted in rapid trafficking and secretion of improperly processed proinsulin. At the transcriptional level, Sox17 altered expression of genes involved in biological processes that regulate hormone transport, secretion, and cellular localization, which led to diabetes after prolonged exposure. This demonstrates that Sox17 affects insulin trafficking throughout the secretory pathway. We therefore wanted to explore the possibility that physiologic levels of Sox17 might be used to positively impact diabetic phenotypes using a genetic model of diabetes (MODY4). We did so by overexpressing Sox17 two-fold in a MODY4 mouse model (Pdx1-tTA hemizygote mice). Increased expression of Sox17 in the β-cells of MODY4 animals was sufficient to transiently normalize basal blood glucose and insulin levels as well as restore islet cell organization architecture; however, Sox17 overexpression was not able to rescue the inability of MODY4 animals to properly respond to glucose challenge.</p><p>Together, these data demonstrate new and critical role for Sox17 in regulating insulin trafficking and secretion processes in the adult pancreas that are important to ensure proper glucose homeostasis. This study also suggests that modulation of Sox17-regulated pathways can be used therapeutically to improve β cell function in the context of diabetes.</p>

Name thesis:degree_name

PhD

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Medicine: Molecular and Developmental Biology

Grantor dc:publisher

University of Cincinnati

Year dc:date

2012

Author dc:creator

• Jonatan, Diva

Contributors dc:contributor

• Wells, James

• Molecular Biology
• Sox17
• Prediabetes
• Insulin trafficking
• Adult islet

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353950080

OAI identifier oai:identifier

oai:etd.ohiolink.edu:ucin1353950080