Metformin primarily acts by which mechanism?

• A. Inhibits hepatic gluconeogenesis
• B. Stimulates pancreatic insulin release
• C. Inhibits intestinal glucose absorption
• D. Increases hepatic glucose production

Answer: (A)

Metformin’s main action is to lower liver glucose production. It does this by interfering with the liver’s energy metabolism: it inhibits mitochondrial complex I, which raises the AMP to ATP ratio inside liver cells. This activation of AMP-activated protein kinase (AMPK) then lowers the expression and activity of enzymes that drive gluconeogenesis, such as PEPCK and G6Pase, so the liver releases less glucose into the blood. As a result fasting glucose and overall glycemic control improve, without relying on stimulating insulin release.

There can be a small effect on the gut, including a modest reduction in intestinal glucose absorption, and metformin improves insulin sensitivity in muscle, but these are secondary to the dominant effect of reducing hepatic glucose output. Stimulating pancreatic insulin release would come from other types of medications, and increasing hepatic glucose production would worsen blood sugar, which is the opposite of metformin’s therapeutic action.