MOLECULAR PHYSIOLOGY & BIOPHYSICS
Exploring the Function of G6PC2 in Pancreatic Islet Beta Cells
Kayla Boortz
Dissertation under the direction of Professor Richard OâBrien, Ph.D.
G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. Together with glucokinase, G6PC2 forms a substrate cycle that determines the glucose sensitivity of insulin secretion. Genetic and molecular studies show that elevated G6PC2 expression raises fasting blood glucose (FBG) but because chronically elevated FBG is detrimental, increasing type 2 diabetes risk, it is unclear why G6PC2 evolved. Studies have shown that single nucleotide polymorphisms (SNPs) in G6PC2 associate with variation in FBG and body mass index (BMI) in humans. Previously we confirmed these findings in mice and showed that FBG is repressed in G6pc2 knockout (KO) mice relative to wild type (WT) on a mixed or pure C57BL/6J genetic background. I further confirmed that 129SvEv KO mice also have reduced FBG. Moreover, I identified a glucocorticoid response element in the human and 129SvEv G6pc2 promoter that confers glucocorticoid responsiveness and induction of G6PC2 gene expression following treatment with Dexamethasone (Dex), 11-dehydrocorticosterone (11-DHC) or physical restraint in 129SvEv and C57BL/6J mice. Following stress generated by Dex or physical restraint, FBG is repressed in 6 hour fasted 129SvEv and C57BL/6J KO mice, respectively, enhancing the difference in FBG relative to controls. These data suggest that G6PC2 evolved to modulate FBG under conditions of glucocorticoid-related stress thereby conferring a transient, beneficial modulation of the set point for FBG. This thesis also addresses the observation that the common rs560887 G6PC2 SNP is associated with variation in BMI and adiposity. The results described here indicate that the effect of G6pc2 deletion on the response to diet induced obesity is dependent on genetic modifiers. Finally, an indirect analysis of the effects of human G6PC2 SNPs on protein expression and enzyme activity indicates that mutations at catalytically conserved residues may be critical for proper enzyme function and protein expression.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08052016-144905 |
| Date | 03 October 2016 |
| Creators | Boortz, Kayla |
| Contributors | Owen McGuinness, David Jacobson, Fiona Yull, Roger Cone, Richard O'Brien |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-08052016-144905/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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