Gastrointestinal motor and sensory function, and hormone secretion: implications for postprandial blood glucose regulation in type 2 diabetes mellitus.

Abstract

This thesis focuses on the role of gastrointestinal motor and sensory function, and gut hormone secretion, in postprandial blood glucose regulation in health and type 2 diabetes. The key themes relate to: 1) evaluation of the effects of potential dietary and/or pharmacological strategies on gastric emptying, secretion of ‘incretin’ hormones (i.e. glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)), and postprandial glycaemia, 2) effects of intraluminal bile acids on GLP-1 secretion and blood glucose homeostasis, and 3) the role of the sweet taste sensing pathway in gastrointestinal motor, secretory, and absorptive function in health and type 2 diabetes. Macronutrient ‘preloads’ taken before a meal can stimulate endogenous GIP from the proximal gut, and GLP-1 from the distal gut, slow gastric emptying, and reduce postprandial glycaemic excursions, but entail additional energy intake. The study reported in Chapter 4 evaluates the effects of 1) 3-Omethylglucose (a non-metabolised substrate of sodium glucose co-transporter-1) and 2) a mixture of poorly absorbed tagatose and isomalt, when given as preloads in healthy humans. Since the incretin hormones are rapidly degraded by the enzyme, dipeptidyl peptidase 4 (DPP-4), the study in Chapter 5 evaluates whether the effects of a D-xylose preload (a poorly absorbed, low-energy pentose) could be further optimised by concurrent DPP-4 inhibition with sitagliptin, in patients with type 2 diabetes. It was recently established that a small dose of lauric acid, delivered to a long segment of distal gut via enteric-coated pellets, can stimulate GLP-1 and attenuate postprandial glycaemia in well controlled type 2 patients. The study reported in Chapter 6 evaluates the glucose-lowering effect of these pellets in less well-controlled type 2 patients, when given concurrently with sitagliptin. The effects of DPP-4 inhibition on the incretin hormone, glycaemic, and gastrointestinal motor responses to intraluminal glucose have not been well characterised in obesity and type 2 diabetes. It has been suggested that metformin has the capacity to augment plasma GLP-1 concentrations, and may synergise with DPP-4 inhibitors to improve glycaemia in type 2 diabetes. The study described in Chapter 7 examines the effects of sitagliptin on glycaemia and antropyloroduodenal motility in response to intraduodenal glucose infusion in health, obesity, and type 2 diabetes treated with or without metformin. It is emerging that bile acids function as important signalling molecules, and are essential in blood glucose regulation. In animal models, intraluminal bile acids have been shown to stimulate GLP-1 and peptide YY (PYY) via activation of theTGR5 receptor. The study reported in Chapter 8 evaluates the effects of rectally administered taurocholic acid (TCA) on the release of GLP-1 and PYY in healthy humans. In Chapter 9, the effects of intrajejunal TCA on blood glucose, GLP-1 and insulin responses to intrajejunal glucose infusion are evaluated. The mechanisms underlying nutrient detection in the small intestine and consequent stimulation of incretin hormone release are poorly understood. Emerging data support the involvement of intestinal sweet taste receptors (STR) in carbohydrate sensing. In rodents, intestinal STR transcript and protein levels are rapidly down-regulated upon acute luminal exposure to glucose or artificial sweeteners. In Chapter 10, the capacity for the non-caloric artificial sweeteners, sucralose and acesulfame potassium, to stimulate GLP-1 release, slow gastric emptying, and modify postprandial glycaemia when given with oral glucose is evaluated. In Chapter 11, the modulation of duodenal STR expression in response to acute changes in luminal and systemic glucose exposure in healthy humans is assessed, and comparison is made to patients with type 2 diabetes. Furthermore, relationships between STR expression, glucose absorption and gut hormone secretion are examined in both groups.