Insight into appetite and blood glucose regulation in anorexia nervosa and health: Examining gastrointestinal changes in starvation and with short-term refeeding

Abstract

Anorexia nervosa (AN) is a mental health disorder characterised by a restriction of energy intake relative to requirements, typically leading to a significantly low body weight, an intense fear of gaining weight or becoming fat, and a disturbance in the way in which one’s body weight or shape is experienced (1). Patients frequently experience high levels of anxiety (2), as well as numerous other psychological and medical comorbidities (3), including hypoglycemia (4, 5). Despite severe malnutrition due to chronic dietary restriction, patients with AN also commonly report reduced perceptions of hunger and increased fullness (6, 7), and a high frequency of gastrointestinal (GI) symptoms, including nausea, abdominal pain, bloating and heartburn (8-10), all of which may contribute to the disordered eating behaviour. Current treatment of AN focuses on medical stabilisation followed by nutritional rehabilitation and either individual or family-based psychological therapies (11). However, disordered eating behaviour frequently continues post-treatment, with studies reporting between 30 and 67 % of patients relapsing within two years (12-14), and up to ~50% (13, 15) developing binge eating and/or purging. Hence, there is an urgent need to develop a better understanding of the mechanisms underlying the disturbances in glycemia, appetite and GI symptoms in patients with AN. The GI tract plays a critical role in the regulation of glycemia and appetite in health, however, its role in mediating changes in patients with AN remains poorly defined. This thesis examined the GI mechanisms involved in appetite and glycemic control in anorexia nervosa, during starvation and with nutritional rehabilitation. The work submitted for this thesis comprises a mechanistic study in health, as well as the outcomes of a large multi-variable study in patients with anorexia nervosa. In health, the presence of nutrients in the GI tract results in increased fullness, and decreased hunger and subsequent energy intake. This is mediated by several inter-related changes in GI function, including the slowing of gastric emptying (which prolongs gastric distension and the perception of fullness), and the release of GI hormones including cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY), as well as the suppression of ghrelin. The rate of gastric emptying and the secretion of the incretin hormones, GLP-1 and glucose-dependent insulinotropic peptide (GIP) are also important determinants of postprandial glycemia (16). The study presented in Chapter 2 generated new knowledge regarding the physiological effects of active GLP-1 and GIP concentrations on responses to fat in healthy lean males. The actions of endogenous GLP-1 and GIP to slow gastric emptying and reduce postprandial glycemia are limited by their rapid degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). We utilised the DPP-IV inhibitor, vildagliptin, to modulate the effects of intraduodenal (ID) fat, examining downstream effects on glycemia, postprandial triglycerides, energy intake and energy expenditure. Both gastric emptying and GI hormone secretion are sensitive to changes in nutrient exposure (17, 18). For example, a 4-day fast slows gastric emptying in health (17), and a 30% dietary restriction for 12 weeks modifies postprandial GI hormone release in obesity (18). The studies outlined in Chapters 3 and 4 of this thesis explored the hypotheses that in patients with AN (i) prolonged energy restriction induces pathophysiological changes in the GI nutrient sensing mechanisms involved in appetite regulation and glycemia when compared with healthy controls (HCs), and (ii) refeeding would rapidly alter GI function leading to improvements in appetite perceptions and postprandial glycemia.