Thesis (Ph.D.)--University of Melbourne, Dept. of Physiology, 2002. / Typescript (photocopy). Includes bibliographical references (leaves 268-306).

Thesis (Ph. D.)-- University of Sydney, 1999. / Title from title screen (viewed Apr. 21, 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Depts. of Psychological Medicine and Medicine. Includes tables. Includes bibliography. Also available in print form.

Thesis (Ph.D.) -- University of Adelaide, Dept. of Medicine, 2000. / Bibliography: leaves 206-251.

Thesis--University of Wisconsin--Madison. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 203-227).

The human colonic carcinoma cell lines HT-29 and Caco-2 both exhibit structural and functional differentiation under appropriate culture conditions. HT-29 can be induced to differentiate by treatment with short-chain fatty acids or acetoacetate. Caco-2 cells differentiate spontaneously upon contact inhibition. In this study HT-29 cells were treated with 5 mM acetate, propionate, butyrate and acetoacetate (physiological inducers) to assess their effects on the expression of carbonic anhydrase 1, sucrase-isomaltase and alkaline phosphatase which are reported to be markers of gastrointestinal differentiation. The maturation induction observed was compared to that of the spontaneous differentiation observed in Caco-2 cells. Assays were performed over an 18 day period. Results showed a close correlation (p < 0.05) between HT-29 and Caco-2 cell on days 4 and 12. These results indicate that differentiation reported in both cell lines is comparable and can be used as a basis for further comparative studies. In addition, parallel experiments to the above were conducted using a selection of nine rationally designed cyclic dipeptides (CDPs) potential drug entities which were chosen as non-physiological inducers. The results showed that the cyclic dipeptides were able to induce the gastrointestinal phenotype as observed in HT-29 cells treated with physiological inducers. Studies on the effects of energy-related metabolism in HT-29 and Caco-2 cells as induced by physiological and non-physiological inducers indicated that energy metabolism is a significant role player in gastrointestinal differentiation. The results reported show a decrease in ATP concentrations indicating that the cyclic dipeptides, like physiological inducers, affect the energy state of the HT-29 cells and thus may effect the differentiation of these cells. A positive correlation was found between histone phsophorylation and differentiation confirming that histone phsophorylation was partly responsible for the decrease in ATP concentrations. It is suggested that the induction of differentiation in HT- 29 cells could be either due to non-specific transcription of genes by activation of a chromatin switch or specific by the activation of signal transduction pathways based on the flux of ATP through the cells. Differential display RT-PCR is probably the most sensitive method that could be used to validate the suggestion of either a nonspecific transcription of genes or a specific differentiation reported for HT-29 cells.

published_or_final_version / abstract / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / Community Medicine / Master / Master of Public Health

Bibliography: leaves 206-251. The motor and sensory interactions between nutrients and proximal gut in humans are not well understood, despite the pivotal importance of these interactions on appetite, absorption and thus, nutrition. In part, this lack of knowledge results from technical difficulties in studying motor function in the human gut. In particular, the inability to continuously measure intraluminal flow with any degree of temporal resolution, has impeded progress in this field. The studies described in this thesis focus on nutrient-gut interactions, and also on the development of novel methodologies aimed at advancing the understanding and interpretation of the relationships between intraluminal pressures and flows.

Gastric emptying, and small intestinal glucose exposure and absorption, are potentially important determinants of postprandial blood glucose homeostasis and energy intake. The studies presented in this thesis were designed to provide novel insights into the interrelationships of upper gastrointestinal function with glycaemia and appetite in both health and type 2 diabetes. The issues which were addressed relate in particular to : ( i ) the physiology, regulation and measurement of gastric and small intestinal motility, ( ii ) the relationships between small intestinal glucose exposure, incretin hormone release, antropyloroduodenal motility and appetite, and ( iii ) the impact of gastric and small intestinal motility on glycaemia. The study reported in chapter 4 evaluated the effect of variations in small intestinal glucose delivery on blood glucose, plasma insulin, and incretin hormone ( GLP - 1 and GIP ) concentrations in healthy subjects. While initially rapid, and subsequently slower, duodenal glucose delivery potentiated incretin and insulin responses when compared to constant delivery of an identical glucose load, the overall glycaemic excursion was not improved. These observations add to the rationale for the use of dietary and pharmacological strategies designed to reduce postprandial glycaemic excursions in health and type 2 diabetes by slowing gastric emptying, rather than initially accelerating it. Fat is a potent inhibitor of gastric emptying. In chapter 5, the acute effect of slowing gastric emptying by fat, on postprandial glycaemia in type 2 diabetes, has been evaluated. Ingestion of a small amount of olive oil, as a 'preload' 30 min before a carbohydrate meal, was shown to markedly slow gastric emptying, affect intragastric meal distribution, delay the postprandial rises in blood glucose, plasma insulin, and GIP, and stimulate GLP - 1. In contrast, the effects of including the same amount of oil within the meal, on gastric emptying, as well as glycaemic and incretin responses, were relatively modest. As blood glucose levels had not returned to baseline by 210 min ( the end of each experiment ), effects on the overall glycaemic ( or insulinaemic ) response could not be determined ; this represents a priority for future studies. The energy content of a meal is a major determinant of its rate of gastric emptying. The study reported in chapter 6 demonstrated that the substitution of an artificial sweetener ( "diet" mixer ) for sucrose ( "regular" mixer ) in a mixed alcoholic beverage has a major impact on the rate of gastric emptying and alcohol absorption in healthy adults. A low calorie alcohol - containing drink ( made with "diet" mixer ) emptied from the stomach much more rapidly and resulted in higher blood alcohol concentrations when compared with a relatively high calorie alcoholic drink ( made with "regular" mixer ). These observations highlight the need for community awareness of factors, other than the alcohol content of a beverage, which should be taken into account in considering safe levels of consumption and the potential for inebriation. Upper gastrointestinal motor function and incretin hormone ( GLP - 1 and GIP ) secretion are known to be major determinants of postprandial glycaemia and insulinaemia, however, the impact of small intestinal flow events on glucose absorption and incretin release has not been evaluated. In the study reported in chapter 7, intraduodenal pressures and impedance signals were recorded simultaneously in healthy humans, while glucose was infused into the duodenum in the presence and absence of the anticholinergic drug, hyoscine butylbromide. The frequency of duodenal flow events ( evaluated by impedance ) was suppressed by hyoscine much more than that of duodenal pressure waves, or propagated pressure wave sequences ( evaluated by manometry ). Blood glucose and plasma 3 - OMG concentrations ( the latter provide an index of glucose absorption ) were lower during hyoscine than saline. Plasma insulin, GLP - 1, and GIP concentrations were initially lower during hyoscine. The disparity between impedance measurements and manometry in detecting alterations in flow during hyoscine infusion was marked and, accordingly, supports the potential utility of small intestinal impedance monitoring to evaluate alterations in gastrointestinal transit in various disease states. The observations also indicate that the frequency of small intestinal flow events is a determinant of both glucose absorption and incretin release. Intraduodenal administration of the local anaesthetic, benzocaine, has been shown to attenuate the release of cholecystokinin ( CCK ) by small intestinal lipid, and the perceptions of fullness, discomfort, and nausea induced by gastric distension during small intestinal lipid infusion, implying that local neural mechanisms may regulate CCK release in response to intraduodenal nutrients. In chapter 8, the effects of intraduodenal administration of benzocaine on : ( i ) blood glucose, incretin hormone and insulin concentrations ( ii ) antropyloroduodenal motility, and ( iii ) gut sensations and appetite, in response to an intraduodenal glucose infusion, were evaluated in healthy subjects. Benzocaine attenuated the perceptions of abdominal bloating and nausea, but had no effect on antro - pyloro duodenal motility, blood glucose concentrations, or incretin responses. These observations indicate that the induction of sensations by small intestinal glucose is mediated by local neural pathways. GLP - 1 is released from L - cells whose density is greatest in the distal jejunum and ileum, GIP predominantly from duodenal K cells, and cholecystokinin ( CCK ) from I cells, which appear confined to the duodenum and jejunum. The study reported in chapter 9 evaluated the effects of infusion of glucose into different gut regions ( mid - jejunal vs duodenal ) on incretin hormones, CCK, appetite and energy intake in healthy subjects. There was no difference in the incretin responses between infusion at the two sites ( 85 cm apart ), however the stimulation of CCK and suppression of hunger and energy intake, were greater with the duodenal compared to the jejunal infusion. These observations indicate that the site of small intestinal glucose exposure is a determinant of CCK release and appetite. Both glucose and fat are known to be potent stimuli for incretin secretion, but the effect of protein is uncertain. Protein may also stimulate insulin secretion directly via absorption of amino acids. In the study reported in chapter 10, gastric emptying, and the blood glucose, insulin and incretin responses, alter a 300 mL drink containing 50 g glucose, 25 g protein, or both 50 g glucose and 25 g protein, were evaluated in healthy subjects. This study established that the addition of protein to an oral glucose load improved the glycaemic response, predominantly by slowing gastric emptying. However, protein also stimulated incretin and insulin secretion. These observations have implications for the use of protein in the dietary management of type 2 diabetes. The relationship between glycaemia, incretin hormones, appetite suppression and modulation of antropyloroduodenal motility with duodenal glucose delivery is poorly defined. In chapter 11, the effects of intraduodenal glucose infusions at different caloric rates ( of 1 kcal / min, 2 kcal / min and 4 kcal / min, or control ( saline ) ) on antropyloroduodenal motility, plasma GLP - 1, GIP and CCK, appetite and energy intake have been evaluated in healthy subjects. While there was a rise in blood glucose in response to all the intraduodenal glucose loads, there was no significant difference in the response to infusions at 2 kcal / min and 4 kcal / min. An initial, transient, small rise in GLP - 1 was evident, in response to all glucose loads, but a sustained and progressive rise only occurred with the 4 kcal / min infusion. In contrast, a load - dependent stimulation of GIP occurred in response to all glucose infusions. The stimulation of CCK was much greater in response to the 4 kcal / min infusion. While antral pressures were suppressed by all rates of glucose infusion, the stimulation of basal pyloric pressure was load - dependent. Energy intake was suppressed only by the 4 kcal / min infusion. This may potentially reflect the substantially greater stimulation of CCK, consistent with the observations reported in chapter 9. This study establishes that there is a substantial discordance in the acute effects of small intestinal glucose on glycaemia, incretin hormones, CCK, motility and appetite. It is planned to perform measurements of plasma insulin on the stored samples - these results were, unfortunately, not available at the time of the submission of this thesis and are critical to the overall interpretation of the data. / Thesis (Ph.D.)--University of Adelaide, School of Medicine, Discipline of Medicine, 2007.

Thesis (M.S.)--The University of North Carolina at Greensboro, 2008. / Title from PDF t.p. (viewed Mar. 19, 2010). Directed by Dennis LaJeunesse; submitted to the Dept. of Biology. Includes bibliographical references (p. 70-73).