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Examining the role of Myt3 in beta-cell function and survival

University of British Columbia

Diabetes is a chronic disease that results from the body’s inability to properly control circulating blood glucose levels. The loss of glucose homeostasis can arise either from a loss of β-cell mass because of immune-cell mediated attack, as in T1D, and/or from dysfunction of individual β-cells (in conjunction with target organ insulin resistance), as in T2D. Despite advances in current therapies to treat diabetes we are still far from a cure, and a greater understanding of the transcriptional pathways regulating islet development, function and survival will be critical if we are to achieve this goal. The aims of this dissertation were to delineate the role of the transcription factor Myt3 in β-cell function and survival. To this end we first examined the regulatory mechanisms involved in the control of Myt3 expression. We demonstrate that Myt3 expression is dependent on important islet transcription factors, including Foxa2, Pdx1 and Neurod1. We further established that Myt3 expression is regulated both developmentally, likely by the aforementioned factors, and by external stimuli including glucose and cytokines. From these early results we explored the effect of Myt3 suppression on the function and survival of β-cells. Our data show that reduced levels of Myt3 impair the ability of β-cells to migrate, which has potential implications for islet formation during development and compensatory islet neogenesis during diabetes progression, and leads to increased apoptosis. Lastly, to confirm these effects in vivo we studied the effects of Myt3 suppression in syngeneic islet transplants. Our data show that reduced Myt3 results in increased cell death in the grafts. Collectively, the data presented in this dissertation are an important step in clarifying the regulatory networks responsible for β-cell development, function and survival, and point to Myt3 as a potential therapeutic target for improving functional β-cell mass.

Text

2015-12-18

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/55926

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/