Effects of protein on gastrointestinal function and appetite regulation

Abstract

The prevalence of obesity and associated diseases, including type-2 diabetes mellitus, continues to increase at an alarming rate. The available therapies have largely ignored the key role of the gastrointestinal tract in determining appetite and blood glucose regulation in responses to ingested nutrients. A detailed understanding of these gastrointestinal mechanisms is critical in aiding development of new and effective interventions for obesity. The research presented in this thesis focuses on the complex gastrointestinal mechanisms involved in the regulation of glycaemia, appetite and energy intake in response to protein in lean and obese individuals. In particular, this research explores the gastrointestinal motor and hormonal responses to nutrients involved in energy intake regulation and blood glucose control in both healthy lean and obese individuals. Using the novel, non-invasive technique of 3-dimensional ultrasound, the study described in chapter 5 reports that, in lean individuals, the rate of gastric emptying of drinks containing 30g and 70g of protein was comparable (kcal/min; 30g: 2.6±0.2, 70g: 2.9±0.3), and within the ranges previously observed for fat and carbohydrate (1-4 kcal/min). This was reflected by similar releases of cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), glucose-dependent inhibitory polypeptide (GIP), insulin and glucagon, for ~45 min following the drinks. Beyond 45 min, the 70g load resulted in more sustained hormone release, reflecting greater total calories and thus prolonged delivery of nutrient to the small intestine. Energy intake was comparable between the two loads, suggesting that a threshold amount of protein may exist, beyond which no additional appetite-suppressive benefit occurs. In the studies described in chapters 6-8, intraduodenal infusions, combined with high-resolution manometry, were used to evaluate the effects of nutrients in the small intestine on antropyloroduodenal motility and gastrointestinal hormone release. Nutrients were infused directly into the duodenum at standardised rates, reflecting the normal range of gastric emptying; intraduodenal infusion bypasses orosensory and gastric influences, isolating the effects of nutrient to the small intestine. The first of these studies reported that intraduodenal protein has load-dependent effects on antropyloroduodenal motility, ghrelin, CCK, GLP-1, peptide tyrosine tyrosine (PYY), insulin and glucagon, glycaemia, and energy intake at a subsequent meal in lean individuals. The second study reported that load-dependent effects of protein on antropyloroduodenal motility and CCK, GLP-1, GIP, insulin and glucagon release are also apparent in obese individuals, suggesting that small intestinal sensitivity to protein remains intact in obesity. The final study demonstrated, in lean individuals, that intraduodenal lipid modulates gastrointestinal motor responses and CCK and GLP-1 concentrations more potently than an equicaloric protein load. In contrast, protein had more pronounced effects on insulin and glucagon release. Despite these differences, protein and lipid suppressed energy intake comparably, suggesting that different mechanisms may underlie the suppression of energy intake by these nutrients. These data provide novel insights into the roles that gastrointestinal motor and hormone responses to dietary protein play in the regulation of blood glucose, appetite and energy intake in lean and obese individuals. These observations provide potential mechanistic explanations for the effects of high-protein diets on glycaemic control, and appetite. Importantly, they provide a basis for future development of nutrition-based interventions for the treatment of obesity.