Metformin is considered an effective agent with a favorable safety profile for the treatment of type 2 diabetes. Although metformin predominantly acts on the hepatic site, studies in the recent past indicate a complex link with the gut, especially in terms of drug response. In the gut, it exhibits direct effects on glucose uptake and metabolism, through directly or indirectly increasing glucagon-like peptide-1, enhancing bile acid exposure and by altering the microbiome. These findings are in accordance with a recent study that showed the glucose-lowering effects of metformin to be strongly influenced by its effects on the gut.¹

Metformin decreases hepatic glucose production and absorption of glucose in the intestine. Moreover, it reduces oxidation of fatty acids. In the gut, glucagon-like peptide-1 and glucose-dependent insulinotropic peptide are secreted by enteroendocrine cells. These peptides are considered key determinants for the disposal of glucose following a meal. The production of glucose is decreased either by reducing gluconeogenesis or by glycogenolysis. As metformin is found in higher concentrations in the small intestine, it may also reducethe absorption of glucose in the intestine, thereby, influencing postprandial hyperglycaemia. Metformin enhances insulin sensitivity, leading to reduced resistance of insulin, a common concern in patients with type 2 diabetes mellitus. It has been shown that metformin therapy could reduce fasting plasma glucose concentrations by 25-30% and decrease the production of glucose.²

Furthermore, evidence is available to suggest the modulatory effect of metformin on gut microbiota disturbances in type 2 diabetes patients, thus, improving the disease outcome. A marked change in the composition of the microbiota under metformin therapy regarding intestinal permeability could be represented by a rise in Akkermansia muciniphila population. Although the precise mechanism underlying this process remains unknown, it is likely that these bacteria metabolize unabsorbable carbohydrates and mucin in short-chain fatty acids, which, are subsequently used as fuel for goblet cells. Consequently, stimulated goblet cells produce mucin and cause thickening of the mucus layer. This will, in turn, be responsible for reducing epithelial permeability. Therefore, it can be stated that metformin exerts a significant impact on the bacterial populationpresent in the gut, contributing significantly to restoring its balance.³

References

1. McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426-435.
2. Fatima M, Sadeeqa S, Nazir UR. Metformin and its gastrointestinal problems: A review. Biomedical Research. 2018;29(11):2285-2289.
3. Metformin and Its Benefits in Improving Gut Microbiota Disturbances in Diabetes Patients. Available at: https://www.intechopen.com/books/metformin/metformin-and-its-benefits-in-improving-gut-microbiota-disturbances-in-diabetes-patients. Accessed on 19 Nov 2020