The effects of metformin on the gastrointestinal tract
Abstract
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…
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