Understanding intestinal and pancreatic hormone secretion in health and type 2 diabetes: (pre-)clinical studies and technical innovations
Files
(Library staff access only)
Date
2023
Authors
Huang, Weikun
Editors
Advisors
Wu, Tongzhi
Rayner, Christopher K.
Ebendorff-Heidepriem, Heike
Zhao, Jiangbo (The University of Hull)
Rayner, Christopher K.
Ebendorff-Heidepriem, Heike
Zhao, Jiangbo (The University of Hull)
Journal Title
Journal ISSN
Volume Title
Type:
Thesis
Citation
Statement of Responsibility
Conference Name
Abstract
The gastrointestinal (GI) tract and pancreatic islets are key components of the endocrine system, responsible for the release of an array of peptide hormones, which orchestrate metabolic homeostasis through regulation of energy intake, nutrient digestion, absorption and metabolism. Of numerous hormones released from the gut, the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), govern the secretion of both insulin and glucagon from pancreatic islets. Together, these hormones play a critical role in maintaining glucose homeostasis. Disrupted secretion and/or action of the incretins and pancreatic hormones underpins the development of type 2 diabetes (T2D) - a global epidemic characterised by elevated blood glucose concentrations and associated with devastating micro- and macro-vascular complications. Accordingly, an improved understanding of the physiology and pathophysiology of GI and pancreatic hormones in health and T2D is of major relevance to the development of effective strategies to both prevent and better manage T2D. This thesis comprises a series of clinical and preclinical evaluations that provide novel insights into the determinants of GI and islet hormone secretion (Chapters 3-6). In addition, it details the cross-disciplinary collaborative development of two ‘organ-on-a-chip’ platforms for dissecting the secretory function of both intestinal tissues and pancreatic islets (Chapters 7-8). Chapter 1 provides an overview of the secretion and action of GI hormones arising from the complex interaction between luminal nutrients/bioactive compounds and the gut mucosa, and details conventional and innovative research tools/platforms that are indispensable for the investigation of GI hormone secretion. Chapter 2 summarises the molecular mechanisms underlying insulin secretion from pancreatic islets, with a focus on the role of Ca2+ signalling, and systematically reviews the development of diverse research platforms that are fundamental to progressing islet research. Given the substantial sex-related differences in glucose metabolism and risk of T2D, the study described in Chapter 3 explores the sex disparity in incretin hormone secretion, and compares the incretin and glycaemic responses to standardised intraduodenal glucose infusions within the physiological range of gastric emptying between healthy young men and women. While insulin resistance and consequently a relative deficiency in insulin secretion are recognised as key metabolic derangements in T2D, there is accumulating evidence indicating that excessive glucagon secretion also underpins the development of dysglycaemia during both the fasting and postprandial phases. In the liver, insulin and glucagon signalling pose counter-regulatory effects on hepatic glucose production. Alterations in hepatic function have the potential to disrupt hepatic insulin and glucagon signalling, leading to pathological changes in insulin and glucagon secretion. The study reported in Chapter 4 evaluates the relationships of blood glucose, plasma insulin, C-peptide and glucagon, both during fasting and after 75g oral glucose, with serum liver enzymes in healthy and T2D subjects, and in T2D subjects before and after a mixed meal. Given the major role of the rate of gastric emptying (GE) in determining nutrient digestion and absorption, GE may influence the glucagon and glycaemic responses in T2D. Therefore, Chapter 5 further examines the relationships of plasma glucagon and blood glucose with the rate of gastric emptying (GE) of a standardised mashed potato meal in individuals with well-controlled T2D. Strategies that are effective for modulating GI and pancreatic hormone secretion have the potential to improve glycaemic control in T2D. The recent recognition that the GI tract can detect a range of physiological and pharmacological bitter substances via a family of type 2 monomeric G-protein-coupled receptors, namely bitter taste receptors (BTRs), to release GI hormones has led to growing interest in the administration of bitter tastants to stimulate GI hormone secretion for the management of metabolic disorders, including T2D. However, the effects of bitter substances beyond the GI tract have received little attention. Chapter 6 reports the effect of a bitter substance, denatonium benzoate (DB), on insulin secretion in a series of in vitro and ex vivo experiments using a rodent pancreatic β-cell line, INS-1 832/13 cells, and isolated mouse pancreatic islets. In the latter, the effects of DB on the secretion of other islet hormones, including glucagon, GLP-1 and somatostatin, were also characterised. While the currently available cell/tissue models and in vivo tools have substantially advanced the knowledge on the physiology and pathophysiology of incretins and islet hormones, there is rising demand for sophisticated biomimetic platforms to address the increasingly complicated biological challenges and improve the translational success from benchtop to bedside. To this end, the development of a gut-on-a-chip (GOC) system is described in Chapter 7 which facilitates continuous monitoring of dynamic GLP-1 secretion from primary mouse intestinal tissue. Similarly, the development and customisation of a microfluidic sensing platform is described in Chapter 8, allowing quantification of the dynamic changes of Ca2+ and insulin concurrently, enabling investigation of the secretory function of isolated islets.
School/Discipline
Adelaide Medical School
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2023
Provenance
This thesis is currently under Embargo and not available.