Metformin, a biguanide derivate, is the first line of treatment in patients with type 2 diabetes mellitus, in conjunction with lifestyle modification, as indicated in the guidelines issued by the American Diabetes Association and European Association for the Study of Diabetes. Metformin enters hepatocytes through the organic cation transporter-1 transporter, and there it is thought to alter mitochondrial function and AMP kinase activity, resulting in decreased hepatic glucose production and glucose lowering, while AMPK activation in skeletal muscle may increase glucose utilization. In addition, metformin improves the lipid profile, restores ovarian function in polycystic ovary syndrome, reduces fatty infiltration of the liver, and lowers microvascular and macrovascular complications associated with T2DM. Recently, metformin has been proposed as an adjuvant treatment for cancer, as a treatment for gestational diabetes and for the prevention of T2DM in pre-diabetic individuals. Mitochondrial function and AMPK activity in liver and skeletal muscle have received much attention as potential mechanisms by which metformin has its beneficial effects. In Ibrutinib contrast to oral dosing, intravenously-administered metformin does not improve glucose metabolism, suggesting that other organs, such as the gastrointestinal tract, may be the principal site of action of this drug, although those mechanisms are unclear at present. Glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, secreted by enteroendocrine cells in the gut, are important determinants of glucose disposal following a meal. In T2DM, fasting and post-prandial circulating levels of GIP are normal or increased, but the b-cell response to this peptide is diminished. In contrast, b-cells remain responsive to the insulinotropic action of GLP-1, but meal-stimulated GLP-1 increases are diminished. Enteroendocrine cells also secrete peptide tyrosine-tyrosine, a peptide implicated in the control of food intake. Dipeptidyl peptidase-IV is the protease responsible for the rapid degradation of active GLP-17–36 and GIP1–42, and for the conversion of PYY1–36 to PYY3–36. Some have reported that metformin increases circulating active GLP-17–36 or total GLP-1, while others describe a lack of effect on DPP-IV or variable inhibition. Metformin may also facilitate the secretion of active GLP-17–36, perhaps through a muscarinic receptor subtype 3/gastrin-releasing peptide pathway. There is also evidence that metformin may reduce bile acid reabsorption in the distal ileum, and this may result in greater availability of bile acids in the colon for interaction with the farnesoid-X receptor and TGR5 receptors. Increasing evidence links changes in the gut microbial community or the microbiome to disease severity of obesity and T2DM. Moreover, there is growing appreciation of the effects of drugs, besides antibiotics, on gut microbial communities. Although metformin is one of the most widely prescribe drugs for the treatment of T2DM, there is little information on its effects on the human gut microbiome. Intriguingly, a recent study found that metformin does alter the gut microbiota in the worm Caenorhabditis elegans.