From the Guidelines
Metformin works by decreasing hepatic glucose production and increasing peripheral insulin sensitivity, leading to a reduction in hyperglycemia in adults with type 2 diabetes mellitus (T2DM) 1. The mechanism of action of metformin is multifaceted, involving the reduction of glucose production in the liver, improvement of insulin sensitivity in peripheral tissues, and decrease of intestinal glucose absorption.
- Metformin activates AMP-activated protein kinase (AMPK), an enzyme that regulates cellular energy metabolism, leading to decreased hepatic gluconeogenesis and increased glucose uptake in skeletal muscle.
- It also inhibits the mitochondrial respiratory chain complex I, altering cellular energy status and reducing ATP production, which signals the cell to decrease glucose production.
- Additionally, metformin enhances GLP-1 secretion and modifies the gut microbiome, contributing to improved glucose homeostasis 1. The standard dosing of metformin begins at 500 mg once or twice daily with meals, gradually increasing to a maximum of 2000-2550 mg daily divided into 2-3 doses to minimize gastrointestinal side effects.
- Metformin is typically the first-line medication for type 2 diabetes due to its efficacy in lowering blood glucose, neutral effect on weight, low risk of hypoglycemia, and potential cardiovascular benefits, as supported by recent guidelines 1.
- The drug's multiple mechanisms make it effective at addressing several aspects of type 2 diabetes pathophysiology simultaneously, and its use is recommended unless there are contraindications, with a recent study confirming its safety in patients with reduced estimated glomerular filtration rates (eGFR) 1.
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 is to:
- Decrease hepatic glucose production
- Decrease intestinal absorption of glucose
- Improve insulin sensitivity by increasing peripheral glucose uptake and utilization 2
From the Research
Mechanism of Action of Metformin
The mechanism of action of metformin is complex and involves several therapeutic effects, including:
- Reduction of hepatic glucose production through suppression of gluconeogenesis, mainly by potentiating the effect of insulin, reducing hepatic extraction of certain substrates, and opposing the effects of glucagon 3
- Increase in insulin-stimulated glucose uptake into skeletal muscle, attributed in part to increased movement of insulin-sensitive glucose transporters into the cell membrane 3
- Increase in the functional properties of insulin- and glucose-sensitive transporters, leading to increased cellular uptake of glucose and glycogen storage 3
- Insulin-independent suppression of fatty acid oxidation and reduction in hypertriglyceridaemia, which reduces the energy supply for gluconeogenesis and balances the glucose-fatty acid cycle 3
Key Targets of Metformin
Metformin has been shown to target several key enzymes and pathways, including:
- Mitochondrial glycerophosphate dehydrogenase, which is non-competitively inhibited by metformin, resulting in an altered hepatocellular redox state and reduced hepatic gluconeogenesis 4
- Mitochondrial complex I, which is inhibited by metformin, resulting in defective cAMP and protein kinase A signalling in response to glucagon 5
- 5'-AMP-activated protein kinase (AMPK), which is stimulated by metformin, conferring insulin sensitivity mainly by modulating lipid metabolism 5
Clinical Implications
The mechanism of action of metformin has significant implications for its use in the management of type 2 diabetes, including: