Show simple item record

dc.contributor.authorDurning, Sean Patrick
dc.date.accessioned2014-06-17T04:30:11Z
dc.date.available2014-06-17T04:30:11Z
dc.date.issued2013-12
dc.identifier.otherdurning_sean_p_201312_phd
dc.identifier.urihttp://purl.galileo.usg.edu/uga_etd/durning_sean_p_201312_phd
dc.identifier.urihttp://hdl.handle.net/10724/29839
dc.description.abstractO-linked β-N-acetylglucosamine (O-GlcNAc) is a ubiquitous post-translational protein modification found on serine and threonine amino acid residues of intracellular proteins. This inducible and dynamic PTM is mediated by two cycling enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in response to environmental stimuli. The nucleotide-sugar donor UDP-GlcNAc is the end product of the hexosamine biosynthetic pathway (HBP) and is responsive to glucose levels entering the cell. Provided its proposed role as a cellular nutrient sensor, O-GlcNAc has been implicated in contributing to the progression of type II diabetes. However, the molecular role for this PTM in the glucose-responsive, insulin secreting pancreatic β cell remains unclear. In this dissertation, I set out to study the role of O-GlcNAc in regulating molecular events in the β cell, specifically at the levels of insulin secretion and transcription. Using directed pharmacological approaches in the mouse insulinoma-6 (Min6) cell line, I demonstrate that elevating nuclear O-GlcNAc preserves glucose stimulated insulin secretion during chronic hyperglycemia. This observed secretory effect directly correlates with O-GlcNAc-induced elevation in perinuclear insulin under basal and prolonged hyperglycemic conditions. The molecular mechanism for these observed changes appears to be, at least in part, due to elevated O-GlcNAc-dependent increases in Ins1 and Ins2 mRNA levels via elevations in histone H3 transcriptional activation marks. Further, whole transcriptome shotgun sequencing reveals that hyperglycemia altered gene transcription is restricted to a subset of genes and that the majority of genes regulated by inhibiting OGA levels are similarly regulated by a shift from euglycemic to hyperglycemic conditions. Thus, my work demonstrates a role for O-GlcNAc as a glucose sensor and modulator of gene transcription in pancreatic β cells.
dc.languageeng
dc.publisheruga
dc.rightspublic
dc.subjectO-GlcNAc
dc.subjectOGT
dc.subjectOGA
dc.subjectHBP
dc.subjectMin6 pancreatic β cells
dc.subjectinsulin secretion
dc.subjectinsulin gene transcription
dc.subjectepigenetics
dc.subjectRNA-sequencing
dc.titleO-GlcNAc is a sensor in the pancreatic beta cell
dc.typeDissertation
dc.description.degreePhD
dc.description.departmentBiochemistry and Molecular Biology
dc.description.majorBiochemistry and Molecular Biology
dc.description.advisorLance Wells
dc.description.committeeLance Wells
dc.description.committeeMichael Tiemeyer
dc.description.committeeRobert Sabatini
dc.description.committeeHeather Flanagan-Steet


Files in this item

FilesSizeFormatView

There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record