PI3K signaling in pancreatic β cells has been shown to be important in modulating β cell mass and function under basal condition. Evidence suggests that a specific group of insulin promoter-expressing neurons also modulates glucose metabolism and energy homeostasis through their PI3K signaling. Thus we hypothesize that PI3K activation via PTEN deletion under the control of rat insulin promoter (RIP) in pancreatic β cells and RIP-expressing neurons will protect against hyperglycemia and diabetes in experimentally induced mouse models of type 2 diabetes. In Chapter IV, we showed that RIP-mediated PTEN deletion in pancreatic β cells led to PI3K activation and subsequent increased β cell mass and function, thus protected the mice from high fat diet (HFD)-induced diabetes. Furthermore in the absence of global leptin signaling, β cell-specific PTEN deletion maintained β cell function in the setting of severe insulin resistance, therefore prevented diabetes development. Interestingly, RIP-mediated PTEN deletion also resulted in increased peripheral insulin sensitivity due to PI3K activation in central nervous system. In Chapter V, we showed this increased insulin sensitivity was maintained after HFD feeding, which also contributed to the protection against diabetes. These mice also showed increased visceral adipogenesis and subcutaneous adiposity on HFD, which were dramatically attenuated in the absence of leptin signaling, indicated the essential role of peripheral leptin action in mediating the insulin sensitive phenotype from neuronal RIP PTEN deletion. Finally, we demonstrated that the insulin sensitizing phenotype in these mice was not mediated through ventromedial hypothalamic nuclei (VMH), such that VMH-specific PTEN deletion did not alter energy homeostasis or glucose metabolism. Together, the data from this thesis points to an inhibitory role of PTEN in both central nervous system and pancreatic β cells in glycemic control. Therefore, PTEN may represent a potential target for diabetes prevention and treatment.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/33890 |
| Date | 06 December 2012 |
| Creators | Wang, Linyuan |
| Contributors | Woo, Minna |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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