Mechanism of Action of Metformin
Primary Mechanism
Metformin works primarily by decreasing hepatic glucose production through inhibition of gluconeogenesis, while also increasing peripheral glucose uptake and improving insulin sensitivity. 1
Hepatic Effects
Metformin's antihyperglycemic action occurs predominantly in the liver through multiple interconnected pathways:
- Decreases hepatic glucose production by inhibiting gluconeogenesis and reducing glucose output from the liver 1
- Inhibits fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, through AMP-mediated mechanisms 2
- Alters the cytosolic redox state (increases NADH/NAD+ ratio), which inhibits gluconeogenesis from lactate and glycerol but not from pyruvate and alanine 3
- Reduces hepatic energy state by decreasing intracellular ATP content, which is crucial for glucose production 4
Peripheral Effects
Beyond the liver, metformin acts on multiple tissues:
- Increases peripheral glucose uptake and utilization in skeletal muscle and adipocytes, improving insulin sensitivity 1
- Decreases intestinal absorption of glucose 1
- Increases peripheral fatty acid uptake while inhibiting lipogenesis 5
Molecular Mechanisms
The precise molecular mechanism remains incompletely understood, but multiple pathways contribute:
- Mild inhibition of mitochondrial respiratory complex I, though this is not the sole mechanism 2, 6
- Generation of reactive nitrogen species (RNS), specifically peroxynitrite, which requires endothelial nitric oxide synthase (eNOS) for AMPK activation 7
- AMPK-independent pathways also contribute significantly, as metformin maintains efficacy in mice lacking hepatic AMPK 4
- Corrects abnormalities of intracellular calcium metabolism in insulin-sensitive tissues 6
Insulin Secretion
Metformin does not stimulate insulin secretion, which explains why it rarely causes hypoglycemia when used as monotherapy 8:
- Insulin secretion remains unchanged with metformin therapy 1
- Fasting insulin levels and day-long plasma insulin response may actually decrease 1
Clinical Implications
The American Association of Clinical Endocrinologists considers metformin a "metabolic promoter" that improves cellular metabolism in a blood glucose-independent way 8, which explains its broader metabolic benefits beyond glucose lowering, including:
- Weight neutrality or slight weight loss 8
- Applications in polycystic ovary syndrome (PCOS) through normalization of ovulatory abnormalities 8
- Potential reduction in cardiovascular events and mortality 5
Important Caveats
The mechanism involves multiple redundant pathways rather than a single target, which may explain why different experimental models show varying results regarding AMPK dependence 2, 4. The therapeutic effect likely results from the combined impact on hepatic energy state, redox balance, and direct enzyme inhibition rather than any single mechanism.