What is the mechanism of action of metformin (biguanide oral hypoglycemic agent)?

Mechanism of Action of Metformin

Metformin primarily works by reducing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization. 1

Primary Mechanisms of Action

Metformin, a biguanide, exerts its antihyperglycemic effects through several key mechanisms:

1. Reduction of Hepatic Glucose Production:

   • This is the predominant mechanism of action 2
   • Inhibits gluconeogenesis in the liver 1
   • Specifically inhibits the enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis 3
   • Non-competitively inhibits mitochondrial glycerophosphate dehydrogenase, altering hepatocellular redox state 4

2. Improvement of Insulin Sensitivity:

   • Enhances primarily hepatic and peripheral (muscle) insulin sensitivity 1
   • Increases peripheral glucose uptake and utilization 1

3. Decreased Intestinal Glucose Absorption:

   • Reduces glucose absorption from the gastrointestinal tract 1
   • The gut is increasingly recognized as an important site of metformin action 5

Molecular Mechanisms

At the molecular level, metformin's actions include:

• Mitochondrial Effects: Targets hepatic mitochondria, particularly respiratory complex I 4
• AMP-Related Actions: Elevates 5'-adenosine monophosphate (AMP) levels, which inhibits FBP1 3
• Redox State Alteration: Increases cytosolic redox and decreases mitochondrial redox states 4

Clinical Pharmacology

When metformin is administered:

• Insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease 1
• It does not cause hypoglycemia when used alone 2
• It is generally weight-neutral or may cause modest weight loss 2
• Bioavailability is approximately 50-60% under fasting conditions 1
• Steady-state plasma concentrations are reached within 24-48 hours 1

Important Clinical Considerations

• Metformin remains the most widely used first-line therapy for type 2 diabetes 2
• Unlike sulfonylureas, metformin does not stimulate insulin release 2
• Main adverse effects are gastrointestinal (bloating, abdominal discomfort, diarrhea) 2
• Contraindicated in advanced renal insufficiency due to risk of lactic acidosis 2
• Long-term use may be associated with vitamin B12 deficiency 2

Recent research suggests that metformin's mechanisms are more complex than initially thought, with multiple sites of action including the liver, gastrointestinal tract, and potentially immune cells 6. The dose and duration of treatment may also influence which mechanisms predominate 6.

In summary, metformin's unique mechanism of action makes it particularly valuable in type 2 diabetes management as it effectively lowers blood glucose without causing hypoglycemia or weight gain, while potentially offering cardiovascular benefits.