From the Guidelines
Metformin's mechanism of action is primarily through reducing hepatic glucose production and increasing peripheral insulin sensitivity.
Key Mechanisms
- Reduces hepatic glucose production: Metformin decreases the amount of glucose produced by the liver, which in turn lowers blood glucose levels 1.
- Increases peripheral insulin sensitivity: Metformin improves the body's ability to use insulin, allowing glucose to enter cells more effectively, thereby reducing blood glucose levels 2.
Additional Effects
- Weight-neutral: Metformin does not typically cause weight gain and may even lead to weight loss in some individuals 3, 2.
- Low risk of hypoglycemia: Metformin does not increase the risk of hypoglycemia, making it a safe choice for many patients 3, 2.
Important Considerations
- Gastrointestinal side effects: Metformin can cause gastrointestinal side effects such as bloating, abdominal discomfort, and diarrhea, which can be mitigated by gradual dose titration and/or using extended-release formulation 3.
- Lactic acidosis risk: Metformin may be associated with a small risk of lactic acidosis, particularly in patients with kidney disease or other contraindications 3, 1, 4.
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 With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.
The mechanism of action of Metformin (metformin hydrochloride) is to:
- Decrease hepatic glucose production
- Decrease intestinal absorption of glucose
- Improve insulin sensitivity by increasing peripheral glucose uptake and utilization 5
From the Research
Mechanism of Action of Metformin
The mechanism of action of metformin is complex and not fully understood, with multiple pathways and targets involved 6, 7, 8, 9, 10. The main effect of metformin is to decrease hepatic glucose production, which is achieved through several mechanisms, including:
- Inhibition of mitochondrial respiratory chain complex I, leading to a decrease in hepatic energy status and activation of AMPK (AMP-activated protein kinase) 7, 9
- Alteration of cellular redox balance, leading to a redox-dependent mechanism of action 9
- Modulation of gut microbiome and regulation of several other signals, such as FBP1, PP2A, FGF21, SIRT1, and mTOR 8
- Perturbation of the cytosolic and mitochondrial NAD/NADH ratio and the ATP/AMP ratio within cells, affecting enzymatic activities and metabolic and signaling pathways 10
Targets of Metformin Action
Metformin targets multiple tissues and cell types, including:
- Hepatic mitochondria, where it inhibits complex I and alters energy metabolism 7, 9
- Gut microbiome, where it modulates the composition and activity of microbial communities 8
- Tissue-resident immune cells, where it regulates inflammatory responses and immune function 6
- Lysosome surface, where it may have a novel mechanism of action at low concentrations 6
Dose-Dependent Effects of Metformin
The mechanisms of action of metformin vary depending on the dose and duration of treatment, with different effects observed at clinically relevant concentrations (50-100 μM) versus supra-pharmacological concentrations (>1 mM) 9. The dose of metformin used in most studies is often higher than the clinically relevant dose, which may cast doubt on the actual effects of metformin on various diseases in the clinic 8.