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

Mechanism of Action of Metformin

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

Primary Mechanisms

Metformin's antihyperglycemic effects operate through several pathways:

1. Reduction of Hepatic Glucose Production:

   • Inhibits hepatic gluconeogenesis 2, 1
   • Inhibits fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis 3
   • Suppresses glycogenolysis 4

2. Improvement of Insulin Sensitivity:

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

3. Decreased Intestinal Glucose Absorption:

   • Reduces glucose absorption from the gastrointestinal tract 1

Molecular Targets and Pathways

• Mitochondrial Complex I Inhibition: Metformin inhibits mitochondrial respiratory complex I, leading to:

  • Elevation of AMP (adenosine monophosphate) levels 3, 5
  • Alteration of cellular energy metabolism 5

• AMP-Activated Protein Kinase (AMPK):

  • While metformin activates AMPK, this pathway is considered dispensable for its glucose-lowering effects 5
  • AMPK activation contributes to improved insulin sensitivity, mainly through modulation of lipid metabolism 5

• cAMP Signaling Disruption:

  • Defective cAMP and protein kinase A signaling in response to glucagon 5
  • Opposes the action of glucagon 5

Effects on Insulin

• Insulin secretion remains unchanged with metformin therapy 1
• Fasting insulin levels and day-long plasma insulin response may decrease 1
• Due to the reduction in insulin levels, metformin is often termed an "insulin sensitizer" 6

Clinical Implications

• Metformin typically reduces HbA1c levels by approximately 1 percentage point 7
• It has a low risk of hypoglycemia when used alone 2, 7
• Weight effects are neutral to modest weight loss 7
• Possible cardiovascular benefits have been observed 7, 6

Important Considerations

• Metformin is contraindicated in patients with:

  • Severe renal impairment (eGFR <30 mL/min/1.73m²) 7
  • Liver dysfunction 2
  • Severe infection or hypoxia 2
  • Heart failure with hemodynamic instability 7

• Long-term use may cause vitamin B12 deficiency 2, 7

• Gastrointestinal side effects are common but can be minimized by starting with a low dose and gradually increasing 2

Understanding metformin's mechanism of action has led to its application beyond diabetes management, including potential uses in obesity, polycystic ovary syndrome, and investigations into its effects on cancer metabolism 6, 8.