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
Hepatic Effects
- Inhibits hepatic gluconeogenesis through:
- Activation of AMP-activated protein kinase (AMPK), which acts as a cellular energy sensor 2
- Direct inhibition of fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis 3
- Inhibition of mitochondrial respiratory complex I, leading to altered energy metabolism 4
- Disruption of glucagon signaling pathways by interfering with cAMP and protein kinase A signaling 4
Peripheral Effects
- Improves insulin sensitivity in peripheral tissues (primarily muscle) 1
- Enhances glucose uptake in skeletal muscle through AMPK-dependent pathways 2
- Does not directly affect pancreatic β-cell function or insulin secretion 1
Intestinal Effects
- Decreases glucose absorption in the intestine 1
- May increase GLP-1 levels and alter the gut microbiome 5
Metabolic Consequences
Glucose Metabolism
- Reduces both fasting and postprandial plasma glucose levels 1
- Unlike insulin and sulfonylureas, metformin does not increase insulin secretion 1
- Fasting insulin levels and day-long plasma insulin response may actually decrease with metformin therapy 1
Lipid Metabolism
- Improves lipid profiles through AMPK activation 6
- Can lead to modest weight loss or weight neutrality, unlike insulin and sulfonylureas 2
Clinical Implications
Diabetes Management
- First-line therapy for type 2 diabetes due to its effectiveness in reducing hyperglycemia 5
- In the UKPDS study, metformin reduced microvascular and macrovascular diabetes-related outcomes by 32%, MI by 39%, and all-cause mortality by 36% 5
- Works well in combination with other antidiabetic medications due to its complementary mechanism of action
Beyond Glycemic Control
- May have beneficial effects on cardiovascular outcomes 5
- Potential benefits in non-alcoholic fatty liver disease by improving hepatic steatosis and suppressing liver inflammation 6
- May influence tumor development through both direct (energetic stress) and indirect (insulin reduction) mechanisms 4
Important Considerations
- Metformin's glucose-lowering effect occurs without causing hypoglycemia when used as monotherapy 1
- Contraindicated in severe renal impairment (eGFR <30 mL/min/1.73m²) due to risk of lactic acidosis 2
- Regular monitoring of renal function and vitamin B12 levels is recommended with long-term use 2
- Gastrointestinal side effects are common but can be minimized with gradual dose titration
Understanding metformin's complex mechanism of action helps explain its beneficial effects beyond glycemic control and its favorable safety profile compared to many other antidiabetic medications.