Metformin is associated with the suppression of the TNF-α/iNOS/TIMP-1 axis-mediated liver injury and fibrosis secondary to diabetes.

Excessive production of nitric oxide by inducible nitric oxide synthase (iNOS) contributes to liver injury. Diabetes can lead to liver injury and fibrosis, through episodes of nitrosative stress, driven by activation of the inflammation/iNOS pathway. In this study, type 2 diabetes mellitus (T2DM) was induced in rats while another group started the treatment with the antidiabetic drug metformin (200 mg/kg) starting two weeks prior to diabetes induction and continuing until the animals were culled at week 12. Liver injury secondary to T2DM was confirmed 10 weeks after the induction of hyperglycemia as demonstrated by a significant (P < 0.0001) increase in blood and hepatic tissue levels of liver injury biomarkers, tumor necrosis factor-alpha (TNF-α), iNOS, and tissue inhibitor of metalloproteinases-1 (TIMP-1). Glycemia also caused profound liver tissue damage, depletion of glycogen and deposition of collagen. However, these pathological changes and markers of hepatic injury were markedly attenuated in the metformin-treated group. In addition, a significant correlation between nitrosative stress, glycemia, inflammation, glycogen depletion, TIMP-1, and collagen deposition (fibrosis) was observed. These findings demonstrate that diabetes adversely affects hepatic glycogen stores and causes liver tissue injury, as well as upregulating the TNF-α/iNOS/TIMP-1 fibrosis axis while being protected by metformin.