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University of Cambridge

1. Yang, Ming. The effects of metformin on the gastrointestinal tract.

Degree: PhD, 2020, University of Cambridge

Metformin is the world’s most prescribed drug and is recommended first-line therapy for the treatment of Type 2 Diabetes Mellitus (T2DM). Numerous clinical studies have demonstrated that metformin is an effective oral agent in normalising blood glucose levels. Metformin is also one of the very few antidiabetic agents that causes modest weight loss in overweight and obese subjects. Despite its introduction into the clinic over 60 years ago, the mechanisms of metformin action are still elusive. Many of the previous studies into metformin action have focussed on its role in inhibiting endogenous glucose production in the liver, due the central role of the liver in insulin resistance and glycaemic control. However, metformin also accumulates at the highest concentrations in the small intestine, and clinical studies demonstrate that metformin formulations with low bioavailability achieve similarly effective glycaemic control compared to standard metformin formulations. These studies suggest that the gastrointestinal tract may also be an important site of metformin action. In this thesis, 2D monolayer cultures generated from intestinal organoids were used to investigate the mechanisms of metformin action in intestinal cells. Bulk RNA-sequencing and pathway analysis identified changes in glucose and amino acid metabolism pathways, as well as the upregulation of novel signalling pathways associated with the metformin response in intestinal cells. The results from RNA-seq experiments were used as the basis for functional studies into metformin action in intestinal cells. GDF-15 is a stress activated hormone that acts on its cognate receptor GFRAL expressed almost exclusively in the brainstem to elicit an inhibition of food intake. GDF-15 was one of the serum biomarkers identified in T2DM patients associated with metformin use. In a multidisciplinary collaboration, we demonstrated that Gdf15 upregulation in the distal small intestine and colon were associated with the weight loss effects of metformin. The results from transcriptomic analysis in this study identified Gdf15 as one of the most significantly upregulated genes in metformin treated intestinal cultures. Transcriptomic analysis of selected genes involved in mitochondrial function, and secretion studies reported that metformin stimulated GDF-15 secretion through mitochondrial stress and activating the integrated stress response. Previous observations from Position Emission Tomography-Computed Tomography (PET-CT) imaging in mice and T2DM patients demonstrated that oral metformin administration caused non-metabolisable fluoro-deoxyglucose (F-2DG) tracer to accumulate predominantly in the gut. This suggests that metformin increased intestinal glucose utilisation as one mechanism associated with its glucose lowering effects. In intestinal cells, metformin increased the expression of Slc2a1 (encoding GLUT1), whilst decreasing the expression of Slc2a2 (GLUT2) and Slc5a1 (SGLT1). This was replicated in the distal small intestine of HFD-fed mice treated with metformin.…

Subjects/Keywords: Organoids; Gastrointestinal tract; Pharmacology; Metformin; GDF-15; Metabolism; Mitochondria

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Yang, M. (2020). The effects of metformin on the gastrointestinal tract. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/303547

Chicago Manual of Style (16th Edition):

Yang, Ming. “The effects of metformin on the gastrointestinal tract.” 2020. Doctoral Dissertation, University of Cambridge. Accessed April 09, 2020. https://www.repository.cam.ac.uk/handle/1810/303547.

MLA Handbook (7th Edition):

Yang, Ming. “The effects of metformin on the gastrointestinal tract.” 2020. Web. 09 Apr 2020.

Vancouver:

Yang M. The effects of metformin on the gastrointestinal tract. [Internet] [Doctoral dissertation]. University of Cambridge; 2020. [cited 2020 Apr 09]. Available from: https://www.repository.cam.ac.uk/handle/1810/303547.

Council of Science Editors:

Yang M. The effects of metformin on the gastrointestinal tract. [Doctoral Dissertation]. University of Cambridge; 2020. Available from: https://www.repository.cam.ac.uk/handle/1810/303547

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