The role of gastrointestinal function in the regulation of postprandial glycaemia and energy balance in health and type 2 diabetes

Abstract

This thesis includes a series of clinical studies, focussing on the pivotal role of gastrointestinal (GI) function, particularly gastric emptying and GI hormones (e.g. glucagon-like peptide-1 (GLP-1)), in the regulation of postprandial glycaemia, energy expenditure and energy intake in both health and type 2 diabetes (T2D). The key themes relate to evaluation of: 1) gastric emptying of solid and liquid meals in healthy individuals and subjects with T2D, 2) the bidirectional relationship between gastric emptying and postprandial secretion of GLP-1, 3) the role of endogenous GLP-1 signalling in the regulation of postprandial glycaemia and energy expenditure in T2D, and 4) effects of intestinal bitter taste signalling on GI hormone secretion, gastric emptying, postprandial blood glucose and energy intake in health and T2D. Gastric emptying is a major determinant of the blood glucose response to dietary carbohydrate in both health and diabetes. The interaction of luminal nutrients and bioactive compounds with the intestines gives rise to the secretion of numerous GI hormones. Of particular importance to glycaemic control in T2D is the so-called incretin hormone, GLP-1, which has the capacity to stimulate insulin, suppress glucagon secretion and energy intake and slow gastric emptying. In T2D, gastric emptying is frequently abnormal, but may be either delayed, unchanged or accelerated. This discrepancy has reflected the substantial heterogeneity in subject characteristics (e.g. age, duration of diabetes, glycaemic status, pharmacotherapy and presence or absence of diabetic complications) of cohorts studied and the test meals employed (e.g. emptying of solid and liquid test meals is frequently disconcordant). The study reported in Chapter 4 evaluated gastric emptying of a semisolid high carbohydrate meal in a group of community-based individuals with relatively well-controlled T2D (HbA1c ≤ 7.9%), managed by diet or metformin monotherapy, in comparison with a cohort of age- and body mass index (BMI)-matched healthy subjects, and a group of healthy young subjects. The study described in Chapter 5, evaluated the gastric emptying of an oral glucose drink in two groups of community-based individuals with relatively well- (HbA1c ≤ 7.9%) and poorly- (HbA1c ≥ 9%) controlled T2D managed by diet or metformin alone, together with young and older subjects without diabetes. There is a complex bidirectional relationship between gastric emptying and the secretion of GLP-1 after a meal. In a given individual, the magnitude of GLP-1 secretion is related to the rate of nutrient delivery into the small intestine (i.e. gastric emptying); conversely, GLP-1 signalling slows gastric emptying. Gastric emptying exhibits a relatively modest intra-individual, but substantial inter-individual, variation. It remains unknown whether the latter reflects the differences in the ‘intestinal sensitivity’ to nutrients and hence secretion of GLP-1. In Chapter 6, the relationship between gastric emptying and the postprandial GLP-1 response was evaluated in subjects with T2D, the inter- and intra-individual variations in plasma GLP-1 response to enteral nutrient infusions were evaluated in health and T2D, and the relationship between gastric emptying of a glucose drink and the responsiveness of GLP-1 to intestinal glucose was further evaluated in subjects with and without T2D. Subsequent to its secretion, GLP-1 is rapidly degraded by the enzyme, dipeptidyl peptidase 4 (DPP-4). DPP-4 inhibitors are therefore a logical treatment option to augment intact GLP-1 levels for glycaemic control in T2D. In healthy humans, a single dose of DPP-4 inhibitor was shown to lower the blood glucose response to fat and increase energy expenditure and the thermic effect of feeding; the latter would favour a reduction in body weight with sustained use of DPP-4 inhibitors. The fact that DPP-4 inhibitors are weight neutral in subjects with T2D suggests that the effect of DPP-4 inhibition on energy expenditure may be compromised in this disorder. The study reported in Chapter 7, therefore, evaluated the effect of DPP-4 inhibition on the glycaemic and energy expenditure responses to an intraduodenal fat in subjects with T2D, including the role of endogenous GLP-1, assessed using the GLP-1 receptor antagonist, exendin (9-39). There is emerging evidence from preclinical studies suggesting that stimulation of GI bitter taste receptors (BTRs) has the potential to reduce postprandial glycaemia and suppress energy intake by modulating the secretion of GI hormones and slowing gastric emptying. The study reported in Chapter 8 evaluates the effects of a non-nutritive bitter taste compound, denatonium benzoate (DB), encapsulated for oral administration, on gastric emptying, postprandial glycaemia and energy intake in subjects with T2D. In Chapter 9, the effects of DB and a bitter tasting bile acid, taurocholic acid, administered via rectal perfusion, on GLP-1 and peptide YY secretion were evaluated in the presence or absence of a BTR antagonist, probenecid, in healthy humans.