Pilot Double-Blind Randomised Controlled Trial: Effects of Jejunal Nutrition on Postprandial Distress in Diabetic Gastropathy (J4G Trial)

Nausea, vomiting and abdominal pain in diabetic patients are often attributed to diabetic gastropathy (DG). Post-pyloric (“jejunal”) enteral nutrition (JN) may improve nutrition and glycaemia in difficult cases. The acute effects of JN on postprandial symptoms and gastric function in DG patients has not been studied. DG patients with moderate to severe symptoms (gastroparesis cardinal symptom index (GCSI) > 27), diabetic controls without symptoms (DC; GCSI < 14) and healthy controls (HV) were entered into a randomized, double blind controlled trial. JN with liquid nutrient (2 kcal/min) or water was infused for 60 min prior to ingestion of a standardized mixed solid/liquid test meal. Outcomes included postprandial symptoms and effects on gastrointestinal (GI)–peptide hormones and gastric emptying (GE) assessed by magnetic resonance imaging (MRI). Nine DG, nine DC and twelve HV were recruited. DG patients reported more symptoms after meals than other groups (p < 0.05). Post-prandial symptoms were reduced after JN in DG patients (p < 0.01). GE was more rapid after JN in DG and DC patients (p < 0.05). JN induced a GI–peptide response in all subjects; however, this was less pronounced in diabetic groups. JN has beneficial effects on DG patients’ symptoms after a meal. The mechanism is not primarily mediated by effects on GE, but appears to involve other aspects of GI function, including visceral sensitivity

Oral and small intestinal sensitivity to fats in lean and obese humans : implications for energy intake regulation in obesity.

The research presented in this thesis focuses on the complex and interrelated oral and gastrointestinal mechanisms involved in the regulation of appetite and energy intake in lean and obese individuals. The three broad areas of research that have been investigated in the thesis include: i) the gastrointestinal motor and hormonal functions involved in the regulation of energy intake in healthy individuals; ii) the effects of oral and intraduodenal nutrients on gastrointestinal motility and hormone release, appetite and energy intake in obese compared with lean individuals; and iii) the effects of acute and prolonged energy restriction on gastrointestinal function, appetite and energy intake. Following ingestion of a meal, the interaction of nutrients with receptors in the small intestinal lumen modulates gastro-pyloroduodenal motility, stimulates the release of gastrointestinal hormones, and suppresses appetite and energy intake. It appears that modulation of gastrointestinal functions, that is, gastrointestinal motility and hormone release/suppression, mediate the regulation of appetite and acute energy intake in humans, at least in part. Changes in motility and hormone secretion occur concurrently with changes in appetite; however, there is little information regarding which, if any, of these factors are independent determinants of energy intake. In the study presented in Chapter 5, we determined independent predictors of energy intake and identified specific changes in gastrointestinal motor and hormone functions (i.e. stimulation of pyloric pressures and plasma cholecystokinin) that are associated with the suppression of acute energy intake in healthy lean males. The incidence of obesity is rapidly increasing and, currently, the therapies used for the prevention and management of obesity have limited long-term benefits. In addition, the available therapies have largely ignored the pivotal role of the gastrointestinal tract in the regulation of appetite. There is evidence that gastrointestinal function in obesity is modified, which may be the result of the eating habits of obese individuals and, in turn, may also contribute to the maintenance of obesity by causing insufficient suppression of energy intake. However, much of the literature relating to gastrointestinal function in the obese is inconclusive and controversial. A better understanding of any adaptations that occur in obesity is important, particularly in regards to treatment approaches for weight loss. There is also evidence that previous patterns of energy intake, in excess or in restriction, even when sustained for short periods, have the capacity to modify gastrointestinal function and energy intake. For example, in humans following a high fat diet for two weeks, gastric emptying and mouth-to-caecum transit in response to a high fat test meal were faster. In contrast, fasting had the opposite effect and a four-day fast slowed gastric emptying of a glucose drink in both lean and obese subjects, suggesting that a reduction in nutrient exposure may increase the sensitivity of gastrointestinal responses to nutrients in the obese. Although many studies have addressed aspects of gastrointestinal function in the obese, there is a lack of studies that have evaluated gastric emptying and gastrointestinal hormone release specifically GLP-1 and GIP, given the risk of diabetes in obesity, as well as previous patterns of nutrient intake concurrently. In the study presented in Chapter 6, we evaluated the effects of oral ingestion of a nutrient liquid on gastric emptying, oro-caecal transit, plasma GLP-1 and GIP, appetite and energy intake, as well as, habitual energy and fat intake in lean, overweight and obese individuals. We reported no differences in gastric emptying, intragastric distribution or oro-caecal transit between the lean, overweight and obese groups. After the drink, blood glucose and plasma insulin were greater in the obese, when compared with both the lean and overweight groups, however, there were no differences in plasma GLP-1 or GIP concentrations, appetite and energy intake at the buffet meal or habitual energy intake between the groups. In the obese, the magnitude of the rise in blood glucose was inversely related to the gastric emptying, suggesting that obesity per se, in the absence of differences in habitual energy intake, has no effect on gastric emptying or incretin hormone release and that gastric emptying influences postprandial blood glucose in the obese. In Chapter 7, we investigated the hypothesis that gastrointestinal and oral sensitivity to fat is compromised in the obese and directly related to their high fat/energy consumption. For this purpose, we investigated the effects of an intraduodenal infusion (to bypass gastric emptying), of a fatty acid (oleic acid) on gastrointestinal function, appetite and energy intake, and relationships with habitual energy intake and oral fatty acid detection threshold in lean and obese individuals. We report that pyloric pressure, which plays a major role in the regulation of gastric emptying, was lower in response to intraduodenal oleic acid infusion, with trends for reduced cholecystokinin stimulation and energy intake responses in the obese compared with lean. Oral fatty acid detection thresholds were higher in obese compared with lean subjects, and obese subjects also had greater habitual energy and fat intakes than lean subjects. The results suggest that the ability to detect fats both orally and within the gastrointestinal tract is compromised in obese males, probably due to their increased fat consumption. In the study presented in Chapter 8, we evaluated the hypothesis that in obese individuals, the effects of duodenal fat on gastrointestinal motor and hormone function, and appetite would be enhanced by a short period on a very low calorie diet. We demonstrated that following a 70% four-day very low calorie diet there was a significant increase in pyloric pressure and the stimulation of PYY and suppression of ghrelin was greater during an intraduodenal lipid infusion. In addition, following the four-day very low calorie diet, appetite perceptions and energy intake in response to intraduodenal lipid were reduced, indicating that gastrointestinal function, appetite and energy intake in obese can be enhanced over a short period. Given that gastrointestinal function is sensitive to changes even over short periods of dietary restriction, it is important to determine whether these changes are maintained in the long term in order to determine the efficacy of energy restriction therapies for obesity. To maintain dietary restriction and weight loss in the longer term, we used a 30%, as opposed to 70%, energy-restricted diet. In the study presented in Chapter 9, we evaluated the effects of an acute (in lean and obese) and prolonged (in obese only) 30% energy restriction on gastrointestinal function and appetite in response to an intraduodenal lipid infusion. In contrast to the previous 70% very low calorie diet study, there were no differences in gastrointestinal motor or hormonal function in the obese following the acute or prolonged 30% dietary restriction period, although there was a trend for energy intake to be reduced. However, in the lean, there was a decrease in plasma CCK and an increase in ghrelin concentrations following the acute period of dietary restriction with no differences in gastrointestinal motility or energy intake, suggesting that a 30% energy-restricted diet diminishes gastrointestinal hormone responses in lean, but not obese, which may suggest that obese are less sensitive to this caloric restriction. These observations will contribute to the advances in basic appetite physiology and will have clinical implications for further development of dietary interventions for the treatment of obesity.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 201

Investigating PYY3-36 and PYY3-36 analogues in the development of an obesity therapy

Obesity, defined as a body mass index greater than 30kg/m2, has reached the scale of a pandemic. The increasing prevalence of obesity, and its associated morbidity and mortality, together with limited treatment options, underscores an urgent need for effective therapeutic interventions. Gut hormones have been identified as integral factors in the regulation of appetite. One such gut hormone is Peptide YY (PYY), a postprandial satiety hormone that communicates nutritional status to the central nervous system. PYY is processed to generate the principle circulating form PYY3-36, which acts on Y2 receptors in the brainstem and hypothalamus to reduce appetite. Chronic intravenous infusion of PYY3-36 induces weight loss in rodents and acute intravenous infusion to obese humans reduces food intake. Furthermore, obese humans have been reported to display a blunted postprandial rise in PYY3-36, suggesting PYY3-36 is a potential anti-obesity drug target. However, exogenous PYY3-36 is rapidly cleared and has a short circulating half-life. Additionally, at supraphysiological levels PYY3-36 can produce nausea in humans. The administration of long-acting PYY3-36 analogues to the obese may overcome these limitations. This thesis investigates the design and development of PYY3-36 analogues, and their potential in the treatment of obesity. I have investigated modifications to different domains within the primary structure of PYY3-36 in order to elucidate Y2R affinity, susceptibility to proteolytic degradation and biological activity. I demonstrated that a combination of substitutions in different domains can create a long acting analogue. I have examined sites at which PYY3-36 is susceptible to degradation by specific proteases and identified that inhibition of meprin metalloendopeptidases can prolong the plasma longevity and anorectic actions of PYY3-36. I also found that substitution of a section of the α-helix of PYY3-36 with a conserved α-helical epitope creates a long-acting analogue, that is more efficacious than PYY3-36 in chronically reducing food intake and body weight in a diet-induced obese rodent model. Finally, in investigating a slow-release delivery system for PYY3-36 analogues, I have shown that substituting His residues into the α-helix-substituted analogue promotes chelation with Zn in vitro, and facilitates a slow-release pharmacokinetic profile in vivo, that may circumvent the side effects associated with administering high levels of PYY3-36