Metformin primarily lowers fasting glucose by suppressing hepatic gluconeogenesis and increasing insulin sensitivity. Which organ is most directly targeted by metformin's action to reduce hepatic glucose output?

• A. Kidney
• B. Pancreas
• C. Heart
• D. Liver

Answer: (D)

Metformin lowers fasting glucose by acting directly in the liver, the organ responsible for hepatic glucose production. Inside liver cells, it tends to impair mitochondrial function, raising the AMP/ATP ratio and activating AMPK. Activated AMPK then downregulates gluconeogenic enzymes such as PEPCK and G6Pase, reducing glucose produced by the liver. Because the main bottleneck for fasting glucose is hepatic gluconeogenesis, this hepatic action directly lowers fasting blood sugar. Other organs aren’t the primary site for this glucose output control—kidneys deal with drug handling, and the pancreas isn’t the main target for metformin’s glucose-lowering effect.