UBC Theses and Dissertations
The role of NPAS4 in glucose homeostasis Sabatini, Paul Vincent
Type 2 diabetes is characterized by hyperglycemia associated with reduced insulin secretion from pancreatic beta cells and impaired insulin sensitivity at peripheral target tissues. There is a growing body of evidence that supports the importance of bHLH-PAS domain transcription factors in promoting beta cell function. With the recent identification of neuronal PAS domain protein 4 (NPAS4) within the central nervous system, studies were undertaken to determine whether NPAS4 is expressed in beta cells, how its expression is regulated in response to changing environmental signals and uncover the functional significance of NPAS4 in the maintenance of glucose homeostasis. Together, experiments within this thesis demonstrate that NPAS4 is expressed within the pancreatic beta cell and is rapidly upregulated in response to membrane depolarization and calcium influx. Further, this induction was impaired in a mouse model of beta cell dysfunction and within islets from individuals with T2D. Overexpression studies performed in vitro identified NPAS4 as a novel negative regulator of insulin expression and GLP-1 potentiated insulin secretion. Furthermore, NPAS4 protected beta cells from maladaptive cellular pathways that promote cell dysfunction and death; including endoplasmic reticulum stress and activation of HIF1α. Finally, the characterization of three different Npas4 mouse knockout models suggests that continued NPAS4 expression in the beta cell is required to maintain differentiation status and cellular function. An independent role for NPAS4 in the maintenance of glucose homeostasis was also discovered in other Pdx1-Cre expressing cells, likely within the hypothalamus. Together, the data suggest beta cells induce NPAS4 expression during periods of cellular activity and acts as a protective factor to protect cells in order to promote the maintenance of euglycemia.
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