How does metformin work to lower glucose levels?

From the Guidelines

Metformin is the preferred initial glucose-lowering medication for most people with type 2 diabetes, and it works by decreasing glucose production in the liver, improving insulin sensitivity, and reducing glucose absorption from the intestines. Metformin lowers glucose levels through several mechanisms that primarily target the liver, muscles, and intestines. It activates an enzyme called AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism and promotes glucose uptake into cells 1. Additionally, metformin enhances the action of insulin without increasing insulin secretion, making it particularly useful for people with insulin resistance. The medication also appears to modify the gut microbiome and may increase GLP-1 levels, which helps regulate blood glucose.

Some of the key benefits of metformin include:

• Reducing risks of microvascular complications, cardiovascular events, and death 1
• Being effective and safe, inexpensive, and widely available 1
• Having beneficial effects on A1C, being weight neutral, and not causing hypoglycemia when used alone 1
• Reducing cardiovascular mortality compared to sulfonylureas 1

Metformin is typically started at 500 mg once or twice daily with meals, and can be gradually increased to a maximum of 2000-2550 mg daily, divided into 2-3 doses to minimize gastrointestinal side effects. The principal side effects of metformin are gastrointestinal intolerance due to bloating, abdominal discomfort, and diarrhea, which can be mitigated by gradual dose titration and/or using extended-release formulation 1. It is essential to note that metformin may be safely used in people with estimated glomerular filtration rate ≥30 mL/min/1.73 m², and very high circulating levels have been associated with lactic acidosis, although this complication is very rare 1.

Overall, metformin's multiple actions make it effective as a first-line treatment for type 2 diabetes, with the added benefits of not causing hypoglycemia when used alone and potentially assisting with modest weight loss, as supported by the most recent and highest quality study 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 works to lower glucose levels by:

• Decreasing hepatic glucose production
• Decreasing intestinal absorption of glucose
• Improving insulin sensitivity by increasing peripheral glucose uptake and utilization 2

From the Research

Mechanism of Metformin in Lowering Glucose Levels

• Metformin is an antihyperglycaemic agent that lowers blood glucose concentrations in type 2 diabetes without causing overt hypoglycaemia 3.
• It acts on the liver to suppress gluconeogenesis mainly by potentiating the effect of insulin, reducing hepatic extraction of certain substrates, and opposing the effects of glucagon 3.
• Metformin also enhances insulin-stimulated glucose uptake into skeletal muscle by increasing the movement of insulin-sensitive glucose transporters into the cell membrane 3.
• Additionally, metformin increases the functional properties of insulin- and glucose-sensitive transporters, leading to increased glycogen synthase activity and glycogen storage 3.

Effects of Metformin on Glucose Metabolism

• Metformin improves insulin sensitivity by increasing insulin-mediated insulin receptor tyrosine kinase activity, which activates post-receptor insulin signalling pathways 3.
• It also exerts effects that are independent of insulin, such as suppressing fatty acid oxidation and reducing hypertriglyceridaemia, which reduce the energy supply for gluconeogenesis and balance the glucose-fatty acid cycle 3.
• However, a study found that metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes, challenging the existing paradigm that metformin primarily acts in the liver by inhibiting endogenous glucose production 4.

Molecular Mechanisms of Metformin

• Metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state and reduced hepatic gluconeogenesis 5.
• Metformin also directly binds to and reduces the catalytic activity of the recombinant Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) phosphatase domain, leading to increased glucose uptake and renoprotective effects 6.
• Furthermore, metformin adjunctive therapy with insulin has been shown to improve glycemic control in patients with type 1 diabetes mellitus by reducing hepatic glucose output and improving insulin sensitivity 7.