Abstract

A central aspect of type 1 and type 2 diabetes is decreased functional β-cell mass which leads to systemic glucose dysregulation. Functional β-cell mass takes into account β-cell insulin secretion, β-cell proliferation, and β-cell survival. Several treatments are currently used to help maintain glucose levels in individuals with diabetes. However, cures for these diseases are not available due to inability to expand functional β-cell mass. Transcription factors control expression of target genes critical for various functions, and transcription factors that control β-cell function, proliferation and survival play a significant role in β-cell development and function. A more thorough examination of the pathways controlled by key β-cell transcription factors is essential to develop pathways to enhance functional β-cell mass and ultimately cure diabetes. Our research group has previously shown that the β-cell transcription factor Nkx6.1 can increase functional β-cell mass and does this through upregulating expression of the orphan nuclear receptors Nr4a1 and Nr4a3. In this dissertation I explore the regulation downstream of Nkx6.1, physiological activators of Nr4a1, and the effects of β-cell loss of Nr4a1. I examined the role of CEBPA downstream of Nkx6.1 in the β-cell and showed that CEBPA increases β-cell proliferation inducing Nr4a3 expression and increases β-cell survival in response to ER stress through decreasing expression of the unfolded protein response effector Ire1Î±. In exploring physiological activators of the Nr4a family, I found that transitioning β-cells from a fasted glucose state to a fed glucose state increased Nr4a1 mRNA and protein expression. I showed that glucose derived Nr4a1 induction is dependent on the cAMP-PKA-CREB pathway, and that this Nr4a1 induction is necessary for glucose tolerance and insulin secretion due to Nr4a1 mediated induction of key glycolytic and glucose transport genes. I also sought to determine β-cell specific effects of Nr4a1. Using an Nr4a1 β-cell specific knock out I determined that high fat diet impaired glucose tolerance in female mice. In exploring the β-cell specific Nr4a1 function I developed a β-cell specific Nr4a1 knock out mouse. I found that β-cell specific Nr4a1 knock out impaired glucose tolerance in female mice fed a high fat diet, and that this was due to decreased β-cell mass and insulin secretion. I found that this was due to decreased expression of key glycolytic genes. Finally, I found that high fat diet increased estrogen levels in female mice, and that estrogen treatment increases Nr4a1 mRNA and protein expression. Results from these studies demonstrate the critical role of the Nr4aâ€™s in the Nkx6.1 mediated pathway to increase functional β-cell mass, that glucose mediated Nr4a1 expression is necessary for proper β-cell function, and that Nr4a1 is critical for β-cell adaptation to a high fat diet in female mice. These studies place Nr4a1 as a key regulator of β-cell function, proliferation and survival.

Degree

PhD

College and Department

Life Sciences; Microbiology and Molecular Biology

Rights

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