The metabolic consequences of glucose-6-phosphate transporter (G6PT) depletion in mice and Investigating the role of transcriptional intermediary factor 1-γ (TIF1γ) in mitosis

Fletcher, Rachel (2013). The metabolic consequences of glucose-6-phosphate transporter (G6PT) depletion in mice and Investigating the role of transcriptional intermediary factor 1-γ (TIF1γ) in mitosis. University of Birmingham. Ph.D.

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Abstract

The glucose-6-phospate transporter (G6PT) translocates cytosolic glucose-6-phosphate (G6P) into the endoplamic/sacrcoplamic reticulum (ER/SR). In the liver, glucose-6- phosphatase metabolises G6P as the terminal step in gluconeogenesis, essential for maintaining fasting blood glucose levels. Conversely, in both muscle and liver G6P can be converted by hexose-6-phoshate dehydrogenase (H6PDH) to 6-phosphogluconate (6-PG). This process generates the cofactor NADPH which allows 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) to reduce cortisone to its active counterpart cortisol. This demonstrates the importance of the G6PT in glucose metabolism and glucocorticoid (GC) activation. H6PDHKO mice have shown GC independent myopathy thought to be attributed to disrupted glucose homeostasis and calcium (Ca2+) metabolism. In this study we used G6PT+/- mice to characterise the effects of G6PT depletion in respect to systematic glucose metabolism when challenged with diabetes inducing high fat diet, and separately the effect on muscle metabolic homeostasis. We found that G6PT depletion may promote weight gain and systemic insulin resistance despite normal fasted glucose levels on high fat diet. Furthermore, we found elevated intracellular Ca2+ in G6PT+/- primary muscle cells. As we show 11β-HSD1 enzyme activity was unaffected in G6PT+/- mice we propose novel GC-independent roles for G6PT in controlling glucose and calcium homeostasis.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Supervisor(s):
Supervisor(s)EmailORCID
Lavery, GarethUNSPECIFIEDUNSPECIFIED
Doig, CraigUNSPECIFIEDUNSPECIFIED
Licence:
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Clinical and Experimental Medicine
Funders: None/not applicable
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
URI: http://etheses.bham.ac.uk/id/eprint/4516

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