Metformin is a biguanide used in the treatment of type 2 diabetes mellitus and obesity. The
main mechanism of action is to decrease the intestinal glucose absorption and the hepatic glucose
production, however, it does not influence insulin secretion. Metformin also increases the affinity of the
insulin receptor, reduces high insulin levels and improves insulin resistance. Additionally, it promotes
weight loss. Metformin is a pleiotropic compound but acts, largely, by activating 5' adenosine
monophosphate (AMP)-activated protein kinase (AMPK). Data suggest that the therapeutic effects of this
compound are mediated, at least in part, through an upregulation of paraoxonase-1 (PON1) synthesis.
PON1 is a thiolactonase that degrades lipid peroxides, and downregulates the chemokine (C-C motif)
ligand 2 (CCL2) which is a pro-inflammatory chemokine that stimulates the migration of monocytes to
areas of inflammation where they differentiate into macrophages. However, the prescription of metformin
in patients with liver disease is controversial since, in some cases, this drug causes worsening of liver
function. Patients with chronic liver disease have decreased hepatic PON1 activity. A study in mice
deficient in PON1 showed that in this experimental model, metformin administration increased the severity
of steatosis, increased CCL2 expression, did not activate AMPK, and increased the expression of the
apoptosis marker caspase-9. These results suggest that PON1 is essential for the successful activation of
AMPK in the liver, and for metformin to demonstrate its therapeutic function.