From the Guidelines
Metformin works by reducing glucose production in the liver, improving insulin sensitivity in peripheral tissues, and decreasing intestinal glucose absorption, making it the preferred initial pharmacologic agent for the treatment of type 2 diabetes. As the first-line medication for type 2 diabetes, metformin activates AMP-activated protein kinase (AMPK), which inhibits hepatic gluconeogenesis and glycogenolysis, thereby reducing the liver's glucose output 1. It also enhances insulin-mediated glucose uptake in skeletal muscle and fat tissue by increasing the activity of glucose transporters. Additionally, metformin slows intestinal absorption of glucose, which helps reduce post-meal blood sugar spikes.
The standard starting dose is 500 mg once or twice daily with meals, gradually increasing to a typical maintenance dose of 1000-2000 mg daily (maximum 2550 mg) divided into two or three doses to minimize gastrointestinal side effects 1. Unlike insulin secretagogues, metformin does not cause hypoglycemia when used alone and often leads to modest weight loss rather than weight gain, making it particularly beneficial for overweight patients with type 2 diabetes. Key considerations for metformin use include:
- Monitoring for gastrointestinal side effects, such as bloating, abdominal discomfort, and diarrhea, which can be mitigated by gradual dose titration 1
- Risk of lactic acidosis, although very rare, particularly in patients with estimated glomerular filtration rate <30 mL/min/1.73 m² 1
- Association with vitamin B12 deficiency and worsening of symptoms of neuropathy, suggesting periodic testing of vitamin B12 levels 1
Overall, metformin is a safe and effective medication for the treatment of type 2 diabetes, with a long history of use and a strong evidence base supporting its benefits, including reduced risks of microvascular complications, cardiovascular events, and death 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 Metformin hydrochloride tablets help control your blood sugar in a number of ways. These include helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb.
Mechanism of Action of Metformin:
- Decreases hepatic glucose production
- Decreases intestinal absorption of glucose
- Improves insulin sensitivity by increasing peripheral glucose uptake and utilization
- Helps the body respond better to the insulin it makes naturally Metformin does not cause the body to make more insulin 2.
From the Research
Mechanism of Action of Metformin
The mechanism of action of metformin, a biguanide, in treating type 2 diabetes is complex and involves several therapeutic effects. Some of the key effects include:
- Reducing glucose production in the liver by inhibiting gluconeogenesis 3
- Decreasing insulin resistance and increasing insulin sensitivity 4, 5
- Enhancing insulin-stimulated glucose uptake into skeletal muscle 4
- Suppressing fatty acid oxidation and reducing hypertriglyceridaemia 4
- Increasing glucose turnover, particularly in the splanchnic bed 4
Effects on Glucose Metabolism
Metformin has been shown to:
- Lower fasting plasma glucose levels 6, 4
- Increase basal glucose rate of disappearance (Rd) and endogenous glucose production (EGP) 6
- Improve insulin-mediated insulin receptor tyrosine kinase activity, activating post-receptor insulin signalling pathways 4
- Increase glycogen synthase activity and glycogen storage 4
Comparison with Other Antidiabetic Medications
Metformin has been compared with other antidiabetic medications, such as pioglitazone, and has been shown to be equally efficacious in regard to glycemic control, but with differing effects on insulin sensitivity 7. The choice of metformin as a first-line agent in the management of type 2 diabetes may depend on various factors, including the presence of cardio-renal protection 5.
Cellular Mechanisms
The cellular mechanisms of metformin involve the inhibition of mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state and reduced conversion of lactate and glycerol to glucose 3. This leads to a decrease in hepatic gluconeogenesis and an improvement in glycemic control.