It is well known that the arterial plasma insulin/glucagon level, the hepatic glucose load, and the route of glucose delivery (the portal glucose signal) are the three major determinants of NHGU. Recent studies have reported that the ability of insulin and glucose to stimulate splanchnic glucose uptake is impaired in individuals with type 2 diabetes. Thus, in specific aim I of this thesis we explored the ability of first phase insulin release to control the glycemic excursion on the background of basal insulin and a duodenal glucose infusion. It was determined that the pulse of insulin acutely affected net hepatic glucose production and increased NHGU while it still had significant effects on plasma glucose levels 4.5 hours later due to its ability to affect non hepatic glucose clearance.
Although it has been demonstrated that the portal glucose signal is an important regulator of NHGU, the mechanism of action by which it exerts its effects is not completely understood. The relative importance of the sympathetic and parasympathetic nerves was not known. Other investigators had suggested that the portal signal may exert its effects through an intrahepatic reflex involving other mediators and neurotransmitters. Thus the remaining portion of this thesis was to further elucidate the potential regulators of the portal glucose signal and NHGU.
Our attention first turned towards the role of the sympathetic nerves in the regulation of NHGU. The data from specific aim II suggest that the sympathetic nerves exert a tonic inhibition on NHGU in the presence of hyperglycemia, and that removal of these nerves, results in an increase in NHGU.
Our conclusions from specific aim II led us to further investigate the vagus nerve and the role of the vagal afferents in mediating the portal glucose signal. The data from specific aim III suggested that the vagus nerve does not play a role in the regulation of NHGU suggesting that the afferent nerves found in the vagus are not the transmitters of the portal glucose signal.
The data from specific aims II and III suggested that the sympathetic nerves exerted a dominant effect on NHGU while the input from the vagus nerve is not essential for the regulation of the portal glucose signal. Thus, the possibility exists that a local effect of the portal signal might be occurring via an intrahepatic reflex. Thus we hypothesized that nitric oxide may be involved in the regulation of NHGU. It is clear that the intraportal administration of the nitric oxide donor SIN-1 significantly decreased NHGU in the presence of the portal signal. This effect may be due to either a direct or an indirect mechanism.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-10252005-150257 |
| Date | 02 November 2005 |
| Creators | DiCostanzo, Catherine Anne |
| Contributors | Masakazu Shiota, Stephen Davis, Deborah Clegg, Naji Abumrad, David 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-10252005-150257/ |
| 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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