The article "Understanding the Action Mechanisms of Metformin in the Gastrointestinal Tract" by Cheng et al. (2024) reviews the mechanisms by which metformin, a widely used medication for treating type 2 diabetes (T2DM), operates in the gastrointestinal tract. Metformin, derived from *Galega officinalis*, was first identified in the early 1900s and has since been recognized for its glucose-lowering properties. The primary liver-centric view of metformin's action has evolved to include significant gastrointestinal effects, particularly in glucose uptake and absorption, GLP-1 secretion, gut microbiota modulation, and immune response modulation. **Key Findings:** 1. **Glucose Uptake and Absorption:** Metformin inhibits sodium-glucose cotransporter 1 (SGLT1) on small intestinal epithelial cells, reducing glucose absorption from the intestinal lumen. It also enhances glucose uptake by increasing the expression of glucose transporter 2 (GLUT2) on the basolateral membrane of enterocytes. 2. **Increased GLP-1 Secretion:** Metformin promotes GLP-1 secretion from L cells in the intestines through several mechanisms, including enhancing glucose transporter protein expression, inhibiting dipeptidyl peptidase-4 (DPP4) activation, regulating bile acid concentration, and mediating PEN2 protein, M3 cholinergic receptors, and GRP receptors. 3. **Alteration of the Gut Microbiota:** Metformin alters the gut microbiota composition, leading to increased short-chain fatty acids (SCFAs) and changes in gut bacteria such as *Akkermansia muciniphila* and *Lactobacillus* spp., which improve metabolic health and reduce inflammation. 4. **Modulation of Immune Response:** Metformin modulates the immune response by altering gut microbiota composition, suppressing pro-inflammatory cytokines, and downregulating the NF-κB signaling pathway. **Adverse Effects:** - **Gastrointestinal Effects:** Metformin can cause gastrointestinal side effects such as nausea, vomiting, diarrhea, and bloating in about 20% of patients. These effects are often related to high local concentrations of metformin and changes in gut microbiota. - **Lactic Acidosis:** Metformin can lead to lactic acidosis, particularly in patients with risk factors, due to enhanced glucose uptake and lactate production in the intestines. - **Vitamin B12 Deficiency:** Metformin can cause vitamin B12 malabsorption, which can lead to neuropathy in diabetic patients. **Conclusion:** Metformin's therapeutic actions in T2DM are multifaceted, involving the gastrointestinal tract, liver, and brain. The gastrointestinal tract is the primary site of metformin's action, influencing glucose metabolism, GLThe article "Understanding the Action Mechanisms of Metformin in the Gastrointestinal Tract" by Cheng et al. (2024) reviews the mechanisms by which metformin, a widely used medication for treating type 2 diabetes (T2DM), operates in the gastrointestinal tract. Metformin, derived from *Galega officinalis*, was first identified in the early 1900s and has since been recognized for its glucose-lowering properties. The primary liver-centric view of metformin's action has evolved to include significant gastrointestinal effects, particularly in glucose uptake and absorption, GLP-1 secretion, gut microbiota modulation, and immune response modulation. **Key Findings:** 1. **Glucose Uptake and Absorption:** Metformin inhibits sodium-glucose cotransporter 1 (SGLT1) on small intestinal epithelial cells, reducing glucose absorption from the intestinal lumen. It also enhances glucose uptake by increasing the expression of glucose transporter 2 (GLUT2) on the basolateral membrane of enterocytes. 2. **Increased GLP-1 Secretion:** Metformin promotes GLP-1 secretion from L cells in the intestines through several mechanisms, including enhancing glucose transporter protein expression, inhibiting dipeptidyl peptidase-4 (DPP4) activation, regulating bile acid concentration, and mediating PEN2 protein, M3 cholinergic receptors, and GRP receptors. 3. **Alteration of the Gut Microbiota:** Metformin alters the gut microbiota composition, leading to increased short-chain fatty acids (SCFAs) and changes in gut bacteria such as *Akkermansia muciniphila* and *Lactobacillus* spp., which improve metabolic health and reduce inflammation. 4. **Modulation of Immune Response:** Metformin modulates the immune response by altering gut microbiota composition, suppressing pro-inflammatory cytokines, and downregulating the NF-κB signaling pathway. **Adverse Effects:** - **Gastrointestinal Effects:** Metformin can cause gastrointestinal side effects such as nausea, vomiting, diarrhea, and bloating in about 20% of patients. These effects are often related to high local concentrations of metformin and changes in gut microbiota. - **Lactic Acidosis:** Metformin can lead to lactic acidosis, particularly in patients with risk factors, due to enhanced glucose uptake and lactate production in the intestines. - **Vitamin B12 Deficiency:** Metformin can cause vitamin B12 malabsorption, which can lead to neuropathy in diabetic patients. **Conclusion:** Metformin's therapeutic actions in T2DM are multifaceted, involving the gastrointestinal tract, liver, and brain. The gastrointestinal tract is the primary site of metformin's action, influencing glucose metabolism, GL