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, all while maintaining unchanged insulin secretion. 1
Primary Mechanisms
Hepatic Effects: Metformin decreases hepatic glucose production by:
- Inhibiting gluconeogenesis through suppression of fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in the gluconeogenesis pathway 2
- Inhibiting mitochondrial respiratory complex I, leading to elevation of AMP levels and subsequent inhibition of gluconeogenic pathways 3
- Activating AMP-activated protein kinase (AMPK), which improves insulin sensitivity and modulates lipid metabolism 4, 3
Intestinal Effects: Metformin decreases glucose absorption in the intestines, contributing to its glucose-lowering effect 1
Peripheral Effects: Metformin increases peripheral glucose uptake and utilization in muscle and adipose tissue, improving insulin sensitivity 1, 5
Molecular Pathways
Mitochondrial Inhibition: Metformin inhibits mitochondrial complex I, resulting in defective cAMP and protein kinase A signaling in response to glucagon 3
AMPK Activation: While not essential for glucose-lowering effects, AMPK activation by metformin:
Direct Enzyme Inhibition: Recent research shows metformin directly inhibits FBP1, which is AMP-inhibited and plays a crucial role in gluconeogenesis 2
Clinical Effects
Glycemic Control: Metformin lowers both basal and postprandial plasma glucose levels 1
Insulin Response: With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease 1
Weight Effects: Unlike many diabetes medications, metformin is weight neutral or may cause slight weight loss 6
Lipid Metabolism: Metformin improves dyslipidemia in patients with type 2 diabetes 5
Unique Aspects
Metformin does not undergo hepatic metabolism and is excreted unchanged in the urine 1
Unlike sulfonylureas, metformin does not stimulate insulin secretion and thus rarely causes hypoglycemia when used as monotherapy 4
Metformin is considered a "metabolic promoter" that improves cellular metabolism in a blood glucose-independent way 4
Clinical Applications Beyond Diabetes
Metformin has shown benefits in non-alcoholic fatty liver disease by improving hepatic steatosis and suppressing liver inflammation 5
It has applications in polycystic ovary syndrome (PCOS) due to its ability to normalize ovulatory abnormalities 4
Metformin may have potential anti-cancer effects through both systemic reduction of insulin levels and direct induction of energetic stress in cells 3
Understanding metformin's complex mechanism of action explains its effectiveness as a first-line agent for type 2 diabetes and its expanding role in treating other metabolic conditions.