Metformin
USMLE Step 1Difficulty: easyLast updated:
A 54-year-old man with newly diagnosed type 2 diabetes mellitus (HbA1c 7.9%) and a BMI of 33 kg/m2 is started on an oral agent. The prescriber explains that the drug rarely causes hypoglycemia when used alone and may modestly lower lipid levels. Long-term use can cause vitamin B12 malabsorption, and the drug should be avoided in patients at risk of acidemia, such as those with significant kidney disease or severe hypoxia.
Which of the following is the primary mechanism by which this drug lowers plasma glucose?
Answer and explanation
Correct answer: A. Decrease in hepatic glucose production
The described drug is metformin, a biguanide. It rarely causes hypoglycemia on its own, can cause vitamin B12 malabsorption, and is contraindicated in patients at risk of acidemia because of the very rare risk of lactic acidosis. The source states that biguanides lower plasma glucose by decreasing hepatic glucose production through gluconeogenesis and glycogenolysis. It adds that they also lower lipid levels and may decrease gastrointestinal nutrient absorption and increase beta-cell sensitivity to circulating glucose. Metformin does not stimulate insulin secretion directly, which is why hypoglycemia is uncommon when it is used alone. The listed conditions that contraindicate it are significant kidney disease, hypoxia or severe respiratory disease, alcohol use disorder, other metabolic acidosis, and dehydration.
Each option explained
- A. Decrease in hepatic glucose productionCorrect. Metformin lowers glucose mainly by decreasing hepatic glucose production (gluconeogenesis and glycogenolysis).
- B. Inhibition of sodium-glucose cotransporter 2 in the proximal tubuleIncorrect. SGLT2 inhibition (e.g., empagliflozin) increases urinary glucose excretion and is not associated with B12 malabsorption.
- C. Activation of peroxisome proliferator-activated receptor gamma in adipose tissueIncorrect. PPAR-gamma activation is the mechanism of thiazolidinediones, which cause weight gain and fluid retention.
- D. Inhibition of dipeptidyl peptidase-4Incorrect. DPP-4 inhibitors (gliptins) prolong incretin action; they do not carry the B12 or acidemia warnings described.
- E. Closure of ATP-sensitive potassium channels in pancreatic beta cellsIncorrect. Closing beta-cell K-ATP channels is the mechanism of sulfonylureas, which commonly cause hypoglycemia.
Key point
Metformin lowers glucose mainly by decreasing hepatic glucose production and is avoided in patients at risk of acidemia.
From the source
“Biguanides ( metformin) lower plasma glucose by decreasing hepatic glucose production (gluconeogenesis and glycogenolysis).”