This dissertation focused on effects of the biological mediators, nitric oxide (NO) and serotonin in the regulation of net hepatic glucose uptake (NHGU). This work demonstrated that NHGU was suppressed by an increase in hepatic NO or cGMP, resulting from intraportal infusion of an NO donor SIN-1 or a cGMP analog 8-Br-cGMP, respectively. Conversely, NHGU was enhanced by the decrease in hepatic cGMP resulting from the intraportal infusion of a soluble guanylate cyclase inhibitor ODQ. These data raise the possibility that under basal conditions, there is an inhibitory tone due to hepatic NO/cGMP that restrains NHGU, and that this inhibitory signal is removed in response to portal glucose delivery thereby enhancing NHGU. In addition, this work showed that NHGU was enhanced by the increase in hepatic serotonin which resulted from intraportal infusion of the selective serotonin reuptake inhibitor escitalopram. This raises the possibility that the serotonergic input to the liver could increase with portal glucose delivery thus explaining part of its ability to increase NHGU. Taken together, these data give rise to the possibility that portal glucose delivery results in removal of an inhibitory signal (NO) and the simultaneous augmentation of a stimulatory signal (serotonin), thereby augmenting glucose uptake by the liver.
The studies described in this dissertation have a number of important implications. First, the data provide insight into mechanisms which can regulate NHGU in vivo. Second, they suggest a possible mechanism by which the portal glucose signal may work. Third, they suggest targets for pharmaceutical consideration as a means of correcting postprandial hyperglycemia in individuals with diabetes.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07282009-114851 |
| Date | 28 July 2009 |
| Creators | An, Zhibo |
| Contributors | Masakazu Shiota, Alvin C. Powers, Jackie D. Corbin, David H. Wasserman |
| 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-07282009-114851/ |
| 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. |
Page generated in 0.002 seconds