From the Guidelines
Metformin works primarily by reducing glucose production in the liver and improving insulin sensitivity in muscle and fat tissue, as evidenced by the most recent study in 2025 1. The mechanism of action of metformin involves several key processes:
- Activating an enzyme called AMP-activated protein kinase (AMPK), which decreases glucose production in the liver
- Inhibiting the mitochondrial respiratory chain, leading to reduced ATP production and increased AMP levels
- Improving insulin receptor sensitivity, allowing cells to better respond to available insulin
- Slowing intestinal absorption of glucose and potentially altering gut microbiota in beneficial ways This multifaceted approach to glucose regulation makes metformin an effective and safe choice for the management of type 2 diabetes, as supported by recent guidelines 1. Key benefits of metformin include:
- Reduction of microvascular and macrovascular diabetes-related outcomes
- Improvement in cardiovascular risk factors
- Weight neutrality and lack of hypoglycemia when used alone
- Low cost and wide availability However, it's essential to consider potential side effects, such as gastrointestinal intolerance and the risk of lactic acidosis, particularly in patients with chronic kidney disease 1. The standard starting dose of metformin is 500 mg once or twice daily with meals, often gradually increased to 1000-2000 mg daily divided into two doses to minimize gastrointestinal side effects, as recommended in recent studies 1. Regular monitoring of kidney function is crucial, as metformin is cleared by the kidneys, and its use may be contraindicated in patients with severe kidney impairment 1. Overall, metformin remains a cornerstone in the management of type 2 diabetes, offering a favorable balance of efficacy, safety, and cost-effectiveness, as supported by the most recent and highest-quality evidence 1.
From the FDA Drug Label
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization
The mechanism of action of metformin (biguanide) is to:
- Decrease hepatic glucose production
- Decrease intestinal absorption of glucose
- Improve insulin sensitivity by increasing peripheral glucose uptake and utilization 2
From the Research
Mechanism of Action of Metformin
The mechanism of action of metformin, a biguanide, is complex and not fully understood. However, several studies have shed light on its possible mechanisms:
- Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes 3.
- Metformin may cause lactic acidosis, even in patients with normal renal function, although this is rare 4.
- Metformin increases glucose uptake and acts renoprotectively by reducing Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) activity 5.
- The gut is likely to represent at least as important a site of metformin action as the liver in the management of type 2 diabetes 6.
- Bile acids play a crucial role in mediating the glucose-lowering effect of metformin, particularly via secretion of the incretin hormone glucagon-like peptide 1 (GLP-1) 7.
Key Findings
- Metformin reduces hepatic glucose production, but the gastrointestinal tract is also crucial in mediating this effect 3, 6, 7.
- Metformin increases basal glucose rate of disappearance (Rd) and endogenous glucose production (EGP) in individuals with recent-onset type 2 diabetes and non-diabetic control individuals 3.
- SHIP2 activity is elevated in glomeruli of patients with type 2 diabetes receiving nonmetformin medication, but not in patients receiving metformin 5.
- Metformin reduces intestinal bile acid resorption, which may account for its glucose-lowering effect 7.