Coffee improves the antidiabetic and hepatoprotective activities of metformin: an <i>in vitro</i>, <i>ex vivo</i>, and computational study

Abstract Liver disorders associated with type 2 diabetes (T2D) are among the primary contributors to mortality in diabetic patients, with oxidative stress being a critical factor driving their development and progression. Metformin remains the first-line treatment for T2D, while coffee consumption has shown promising effects in reducing hyperglycemia and mitigating T2D-related hepatic disease. The present study investigated the anti-diabetic and antioxidant effects of Brazilian coffee beans (Coffea arabica) and metformin, as well as the effect of their synergism employing in vitro, ex vivo, and computational approaches. Liver tissue from male Sprague–Dawley rats was exposed to oxidative injury induced by iron and treated with varying concentrations of coffee, metformin, and their combination. Iron-induced oxidative stress significantly reduced the levels of measured reduced glutathione, superoxide dismutase, and catalase while increasing malondialdehyde, glycogen phosphorylase, and fructose-1,6-bisphosphatase levels. Treatments with coffee, metformin, and their combination restored these biomarkers. Notably, the coffee-metformin combination exhibited a superior inhibitory action on α-glucosidase and α-amylase activities. Liquid chromatography-mass spectrometry (LC-MS) analysis of the coffee extract revealed the presence of chlorogenic acid, caffeine, quinic acid, caffeic acid, protocatechuic acid, and gallic acid. Molecular docking identified chlorogenic acid as the compound with the strongest molecular interactions with α-glucosidase and α-amylase. This was further supported by molecular dynamics simulations, demonstrating its potential to stabilise enzyme complexes. These findings suggest that Brazilian coffee and metformin synergistically (combination index &amp;lt; 1) exhibit potent hepatoprotective and anti-diabetic effects. Therefore, consuming coffee alongside metformin may enhance the anti-diabetic and antioxidant activities of the anti-diabetic drug.