From the Guidelines
Metformin works by decreasing hepatic glucose production and increasing peripheral insulin sensitivity, leading to a reduction in hyperglycemia in adults with type 2 diabetes mellitus (T2DM) 1. The mechanism of action of metformin involves the activation of AMP-activated protein kinase (AMPK), an enzyme that regulates cellular energy metabolism. This activation leads to decreased gluconeogenesis in the liver, meaning less glucose is produced and released into the bloodstream.
Key Mechanisms
- Decreased hepatic glucose production
- Increased peripheral insulin sensitivity
- Decreased intestinal glucose absorption Additionally, metformin enhances insulin-mediated glucose uptake in skeletal muscle and fat tissue by increasing the activity of glucose transporters.
Benefits
- Promotes modest weight loss
- Does not cause hypoglycemia when used alone
- Reduces the risk of microvascular complications, cardiovascular events, and death 1 The drug is typically started at 500 mg once or twice daily with meals, gradually increasing to an effective dose (usually 1000-2000 mg daily in divided doses) to minimize gastrointestinal side effects like diarrhea and nausea.
Important Considerations
- Metformin carries a small risk of lactic acidosis and must be used with caution in patients with chronic kidney disease (CKD) 1
- The estimated glomerular filtration rate (eGFR) should be ≥30 mL/min/1.73 m² for safe use of metformin 1
- Periodic testing of vitamin B12 levels is recommended due to the increased risk of vitamin B12 deficiency associated with metformin use 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 potential mechanisms:
- Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production 3.
- The discovery that metformin inhibits the mitochondrial respiratory chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the centre of its proposed mechanism of action 3.
- Metformin may also improve obesity-induced meta-inflammation via direct and indirect effects on tissue-resident immune cells in metabolic organs 3.
- The gastrointestinal tract has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide 1 and the intestinal bile acid pool and alterations in gut microbiota composition 3.
Molecular Mechanisms
At the molecular level, metformin's mechanisms of action vary depending on the dose and duration of treatment:
- Metformin targets hepatic mitochondria, and its inhibition of mitochondrial respiratory chain complex 1 leads to the activation of AMPK 3.
- A novel target of metformin at low concentrations has been identified at the lysosome surface, which may reveal a new mechanism of action 4.
- Metformin alters cellular redox balance, and a redox-dependent mechanism of action has been described 5.
- Metformin inhibits hepatic gluconeogenesis in a substrate-selective manner, supporting a redox-dependent mechanism of metformin action 5.
Key Enzymes and Pathways
Several key enzymes and pathways have been identified as playing a crucial role in metformin's mechanism of action: