From the Guidelines
Metformin works primarily by reducing glucose production in the liver, improving insulin sensitivity in muscle and fat tissues, and decreasing intestinal absorption of glucose, as evidenced by the most recent study in 2025 1. This is achieved through the activation of AMP-activated protein kinase (AMPK), an enzyme that regulates cellular energy metabolism, leading to decreased gluconeogenesis in the liver and reducing the amount of glucose released into the bloodstream. Additionally, metformin enhances peripheral glucose uptake by increasing insulin receptor sensitivity and GLUT4 transporter activity in muscle cells. It also alters the gut microbiome and increases GLP-1 levels, which improves insulin secretion and reduces appetite. Unlike many other diabetes medications, metformin does not cause hypoglycemia when used alone because it doesn't stimulate insulin release. Instead, it works by addressing insulin resistance, making the body's existing insulin more effective. Some of the key benefits of metformin include:
- Reducing triglycerides and LDL cholesterol while slightly increasing HDL cholesterol, which contributes to its cardiovascular benefits in type 2 diabetes patients
- Being effective and safe, inexpensive, and widely available
- Reducing the risk of microvascular complications, cardiovascular events, and death
- Having a low risk of lactic acidosis, especially when used in patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m²
- Being a suitable treatment option for older adults with type 2 diabetes if prescription guidelines are followed carefully, as stated in the 2025 standards of care in diabetes 1. However, metformin may cause gastrointestinal side effects, and long-term use may be associated with vitamin B12 deficiency, as noted in the 2024 standards of care in diabetes 1. Overall, metformin is a highly effective and recommended treatment for type 2 diabetes, with a strong evidence base supporting its use, including studies from 2019 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 Metformin does not cause the body to make more insulin, but rather helps the body respond better to the insulin it makes naturally 2.
From the Research
Mechanism of Action of Metformin
The mechanism of action of metformin is complex and not fully understood. However, several studies have proposed the following mechanisms:
- Reduction of hepatic glucose production: Metformin has been shown to decrease hepatic glucose output, which contributes to its glucose-lowering effect 3, 4, 5.
- Increase in insulin sensitivity: Metformin enhances insulin sensitivity, allowing glucose to enter cells more efficiently 3, 5.
- Activation of AMP-activated protein kinase (AMPK): Metformin activates AMPK, which regulates lipid and glucose metabolism, and has been linked to its beneficial effects on circulating lipids and glucose utilization 6, 7.
- Modulation of the cellular redox state: Metformin may inhibit mitochondrial glycerol-3-phosphate dehydrogenase, leading to alterations in the cellular redox state and contributing to its glucose-lowering effect 7.
- Effects on the gastrointestinal tract: Metformin may modulate the release of glucose-lowering hormones, such as glucagon-like peptide 1, and alter the composition of the gut microbiota, contributing to its glucose-lowering effect 7.
Key Findings
- Metformin reduces post-prandial plasma glucose by facilitating glucose storage as hepatic glycogen after meals 3.
- Metformin decreases fasting hyperglycemia by reducing hepatic glucose production 3, 4.
- The molecular basis of metformin action remains unknown, and several mechanisms have been proposed to explain its effects 3, 4, 7.
- Clinically relevant concentrations of metformin inhibit hepatic gluconeogenesis in a substrate-selective manner, supporting a redox-dependent mechanism of action 4.