Investigating the role of indole in glucose homeostasis
File(s)
Author(s)
Phuah, Hi Qi Phyllis
Type
Thesis
Abstract
There is a global health epidemic of obesity and type 2 diabetes mellitus (T2DM). Current anti-obesity therapies show limited efficacy, and despite the availability of T2DM therapies that improve glycaemic control, people living with T2DM still have significant morbidity and lower life expectancy. One well-established therapeutic target for T2DM is the gut hormone system, and in particular, the gut hormone glucagon-like peptide 1 (GLP-1). GLP-1 is an incretin, that is, a hormone that stimulates insulin release. GLP-1 analogues and agents that increase the half-life of endogenous GLP-1 are used as pharmacotherapies for T2DM, but they have limitations. A novel treatment approach could be to modulate endogenous GLP-1 release via dietary supplementation.
Growing evidence implicates gut microbiota-derived metabolites in metabolic homeostasis, with gut microbial dysbiosis widely associated with T2DM pathophysiology. Understanding how the gut responds to microbial metabolites may identify mechanisms that improve glucoregulation, revealing new therapeutic targets.
Indole is generated following gut microbial catabolism of the essential amino acid L-tryptophan, and has been reported to enhance GLP-1 secretion in vitro. Additionally, recent epidemiological studies have revealed an inverse association between indole derivatives and the risk of T2DM. The work presented in this thesis explores the hypothesis that indole improves in vivo glucose tolerance by modulating the GLP-1 system.
The acute oral administration of indole significantly improved glucose tolerance but had no effect on food intake in mice. Indole stimulated the secretion of GLP-1 from STC-1 cells and primary murine colonic crypts in vitro, and in mice in vivo; this effect of indole on GLP-1 secretion was attenuated by Transient receptor potential A1 (Trpa1) ion channel inhibition...
Growing evidence implicates gut microbiota-derived metabolites in metabolic homeostasis, with gut microbial dysbiosis widely associated with T2DM pathophysiology. Understanding how the gut responds to microbial metabolites may identify mechanisms that improve glucoregulation, revealing new therapeutic targets.
Indole is generated following gut microbial catabolism of the essential amino acid L-tryptophan, and has been reported to enhance GLP-1 secretion in vitro. Additionally, recent epidemiological studies have revealed an inverse association between indole derivatives and the risk of T2DM. The work presented in this thesis explores the hypothesis that indole improves in vivo glucose tolerance by modulating the GLP-1 system.
The acute oral administration of indole significantly improved glucose tolerance but had no effect on food intake in mice. Indole stimulated the secretion of GLP-1 from STC-1 cells and primary murine colonic crypts in vitro, and in mice in vivo; this effect of indole on GLP-1 secretion was attenuated by Transient receptor potential A1 (Trpa1) ion channel inhibition...
Version
Open Access
Date Issued
2022-09-30
Date Awarded
2023-02-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Murphy, Kevin
Owen, Bryn
Sponsor
Singapore. Agency for Science, Technology and Research
Society for Endocrinology
Publisher Department
Department of Metabolism, Digestion and Reproduction
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)