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.

Bibliography: leaves 322-368. / xii, 368 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Presents studies relating to normal and disordered gastric motility and the role of the gastrointestinal tract in appetite regulation in humans. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1997

Bibliography: leaves 206-251. / xii, 251 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / 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. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2000

Includes bibliographical references (leaves 349-440). / 440 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The broad areas addressed are: the effect of physiological changes in the blood glucose concentration in the regulation of gastroduodenal motor and sensory function; the effect of acute hyperglycaemia on gastric motor and sensory function in patients with diabetes mellitus and the motor response to prokinetic therapy; the relationships between small intestinal nutrient exposure, gastrointestinal peptide hormone release, antropyloric motility and appetite; and, the effect of aging on the proximal gastric response to distension and food intake. / Thesis (Ph.D.)--Adelaide University, Dept. of Medicine, 2001

Bibliography: leaves 258-294. / xv, 294 leaves : ill. (1 col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines the organisation and control of the antropyloroduodenal motor unit in both healthy human volunteers and patients with gastroparesis. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1992

There is a need for a simple, safe, reproducible and non-invasive method for studying upper gastrointestinal motility in humans. Existing methods, measuring electrical contractions and intraluminal pressure changes have limitations in their correlation with the physiology of what is actually happening to ingested food. Transit time has been suggested as a more physiologic means of studying gut motility; therefore a method was developed to measure transit time and secretory changes in response to ingested liquids, using ileostomy patients. 2.5 gm of polyethylene glycol (PEG) was added to 500 ml of normal saline, and given orally to volunteers with ileostomies. The ileostomy effluent was collected for 2 hours in 10 minute aliquots. PEG assay was performed by the turbidimetric method of Hyden, using Malawer's modification with an emulsifier. The following were measured: most rapid, mode, median, mean and total transit t imes. A study was then performed to determine if different foodstuffs -carbohydrate, fat, and protein - produce measurable changes in transit time. 2.5 gm of PEG was added to 500 ml of (a) 90 ml Lipomul in 410 ml normal saline (b) 5% dextrose (c) 100 ml of Travasol 10% in 400 ml distilled water. The volumes were chosen to produce isoosmolar test feeds. Validating studies showed satisfactory reproducibility and individual variation (r = 0.68 for volume recovery, r = 0.69 for PEG recovery, p = < 0.5) The recovery pattern of a test feed of 500 ml normal saline was found to follow a skew distribution, with mode, median and mean transit times all different. The most reproducible and easily measured was mode, or peak, transit time (average 40 minutes for volume and PEG recovery). Significant delays in all transit times were found (p = < 0.01) using each of the test feeds: (a) for Lipomul a peak volume recovery of 60 minutes and PEG recovery of 70 minutes; (b) for 5% dextrose a peak volume recovery of 90 minutes and PEG recovery of 90 minutes; (c) with Travasol, negligible amounts of ileostomy output were obtained over 2 hours. The most rapid transit time was consistently less than 10 minutes, as measured by PEG appearance from the ileostomy. This is far less than previously described by standard methods, but is in accordance with transit times measured to the ileocaecal valve in intact gastrointestinal tracts using the recently-introduced breath hydrogen method following lactulose ingestion. Comparison of total volume recovery with total PEG recovery over 2 hours indicates whether net absorption or secretion has occurred: (a) with normal saline a volume recovery of 62% and PEG recovery of 48% indicates net secretion; (b) with Lipomul a volume recovery of 66% and PEG recovery of 58% also indicates net secretion, with no significant difference from normal saline (p = < 0.05); (c) with 5% dextrose a volume recovery of 4% and PEG recovery of 13% indicates net absorption, significantly different from normal saline (p = < 0.01); (d) for Travasol a volume recovery of 1% and PEG recovery of 1% indicates no net absorption or secretion, but confirms the above finding of a very large delay in transit time. These studies have shown that isotonic solutions of normal saline, glucose, fat and protein result in widely different peak transit times in ileostomy patients. They also result in widely different fluid outputs from the ileostomy due to net absorption or secretion. These differences have not been described before. / Surgery, Department of / Medicine, Faculty of / Graduate

No description available.

The complex interaction between the central nervous system, the enteric nervous system and local and endocrine hormones enables drugs affecting gastrointestinal motility to produce their effects through multiple sites and mechanisms of action. Opiates are one class of drugs which can have dramatic effects on gastrointestinal function and the mechanisms for these actions have been the subject of intense study in recent years. These changes in motility have assumed increased importance following the discovery of several endogenous opioid peptides. In the present studies, centrally-administered morphine was more potent than peripherally-administered morphine at inhibiting intestinal propulsion and gastric emptying in rats. Direct measurement of intestinal motility revealed that the antipropulsive effects of morphine were due to an inhibition of intestinal contractions. The opioid peptide, β-endorphin, and a stabilized enkephalin analog, [D-Ala², Met⁵] enkephalinamide, also inhibited intestinal propulsion only after central administration. These effects were not blocked by a peripherally selective opioid receptor antagonist, diallylnormorphinium. These data indicated that there is an opioid sensitive mechanism in the brain of rats that, when activated, can inhibit intestinal motility. Physiological activation, by electroconvulsive shock or inescapable footshock, or pharamcological activation by kyotorphin (Tyr-Arg) treatment, did not affect gastrointestinal motility but did produce naloxone-reversible analgesia. These data indicate that the opioid mechanisms mediating analgesia and inhibition of intestinal motility are independent and may be a function of different receptor systems. Several opioid receptor selective agonists were used to determine the specific receptors mediating the analgesic and motility effects of centrally-administered opioids. Mu selective agonists produced analgesia and inhibition of intestinal transit, while delta receptor agonists produced analgesia only. Kappa agonists did not produce analgesia or an inhibition of intestinal motility. Mu receptors mediate the analgesic and intestinal motility effects of exogenously administered opioids, while delta receptors can mediate analgesia without altering gut motility. It appears then, that electroconvulsive shock, inescapable footshock and kyotorphin may produce their analgesic effects by releasing enkephalins, which are delta selective agonists. This accounts for the failure of these treatments to alter gastrointestinal motility while still producing the analgesic effects reported here.

Motility of the small intestine is a result of complex neurochemical and hormonal interactions within the intestine. The net motility (contraction) of the intestine is a balance of the influences from the central nervous system, enteric nervous system and hormonal changes in the body. Recently, the discovery of several peptide neurotransmitters common to the brain and the intestine has stimulated new research into the influence of these novel neurotransmitter candidates on intestinal motility at the level of the enteric (intestinal) nervous system. The present studies examined the contractile actions of three families of peptides, the opioids, tachykinins and motilin. Each of these peptide groups has been localized in the intestine, and suggested to function in the control of intestinal motility. The peptides were administered by intraarterial injection to isolated segments of canine small intestine and the resulting contractile activity measured. The results of these experiments demonstrate that all of these peptides may elicit contractile activity of the intestine in very low doses. These actions were further examined, using pharmacological antagonists, to determine the mechanism of action and the receptor types involved in the contractile actions. The opioid peptide induced responses were found to be mediated by two receptor types, mu and delta, located on the enteric nerve and smooth muscle, respectively. Similarly, the tachykinin induced contractions were also found to be due to actions on two receptor types, SP-P and SP-K, located on the nerve and muscle layers, respectively. These data suggest that the opioids and tachykinins may have multiple functions in the intestine dependent on the site of action and the receptor type involved in the response. Administration of motilin induced long-lasting contractile patterns in the intestine. The results also suggest that the actions of motilin are mediated by intermediate neurons of the enteric plexes which synapse on terminal cholinergic motor neurons.