Current treatment strategies for Type 2 Diabetes Mellitus (T2DM) include a range of anti-diabetic drugs, supplemented by lifestyle modifications to reduce dietary fat intake and body fat. However, for their anti-diabetic action, most drugs recruit insulin signaling pathways, which are already impaired in T2DM. Also, compliance and success in achieving sustained improvements in diet or obesity over the long term is marginal. Therefore, an agent that improves diabetes independent of insulin signaling or lifestyle changes may be highly useful. Human adenovirus Ad36 offers such a model. Ad36 improves glycemic control in chow-fed mice or rats and attenuates diabetes and hepatic steatosis in high fat(HF)-fed mice, despite the HF intake and without reducing adiposity. In human adults, natural Ad36 infection predicts better glycemic control and lower hepatic lipid stores. Ex-vivo cell signaling studies suggest that in mice, Ad36 activates Ras-mediated phosphatidyl- inositol 3-kinase (PI3K) pathway (Ras/PI3K) to up-regulate glucose uptake in skeletal muscle and adipose, and suppresses glucose output from the liver. This study determined if the anti-diabetic properties of Ad36 could be creatively harnessed. Objective 1 determined that Ad36 seropositivity was associated with improved glycemic control and lower hepatic lipids in Caucasian, Hispanic, and African American children and adolescents. Objective 2 determined which of the conventional contributors of insulin sensitivity are modulated by Ad36. In vitro, Ad36 increased preadipocyte differentiation, de-novo lipogenesis, and fat oxidation. Ad36 increased the proportion of small adipocytes in mice on a chow diet, whereas in HF-fed mice, Ad36 increased the proportion of large adipocytes. Adipose tissue macrophage infiltration and angiogenesis were not affected by Ad36. Objective 3 determined the E4orf1 protein of Ad36 mediates its anti-hyperglycemic property. E4orf1 is sufficient and necessary to improve glucose uptake. Mirroring the actions of Ad36, in vitro, E4orf1 also up-regulates the Ras/PI3K pathway, and adiponectin an insulin sensitizing adipokine, and down-regulates inflammatory cytokine expression. E4orf1 increases glucose uptake in, preadipocytes and adipocytes. In hepatocytes, E4orf1 reduces glucose output and the metabolic studies indicate it favors less hepatic lipid storage. Overall, this study offers a broad foundation to further determine the potential of E4orf1 as an anti-diabetic agent.
| Identifer | oai:union.ndltd.org:LSU/oai:etd.lsu.edu:etd-06082011-093407 |
| Date | 08 June 2011 |
| Creators | Dhurandhar, Emily Jane |
| Contributors | Martin, Roy, Keenan, Michael, Ye, Jianping, Greenway, Frank, Sabliov, Christina, Yoshimura, Masami, Mynatt, Randall |
| Publisher | LSU |
| Source Sets | Louisiana State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lsu.edu/docs/available/etd-06082011-093407/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached herein 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 LSU or its agents the non-exclusive license to archive and make accessible, under the conditions specified below and in appropriate University policies, 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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