Effect of metformin on fatty acid and glucose metabolism in freshly isolated hepatocytes and on specific gene expression in cultured hepatocytes

The short-term effect of metformin on fatty acid and glucose metabolism was studied in freshly incubated hepatocytes from 24-hr starved rats. Metformi n (5 or 50 mM) had no effect on oleate or octanoate oxidation rates (CO2+ a cid-soluble products), whatever the concentration used. Similarly, metformi n had no effect on oleate esterification (triglycerides and phospholipid sy nthesis) regardless of whether the hepatocytes were isolated from starved ( low esterification rates) or fed rats (high esterification rates). In contr ast, metformin markedly reduced the rates of glucose production from lactat e/pyruvate, alanine, dihydroxyacetone, and galactose. Using crossover plot experiments, it was shown that the main effect of metformin on hepatic gluc oneogenesis was located upstream of the formation of dihydroxyacetone phosp hate. Increasing the time of exposure to metformin (24 hr instead of 1 hr) led to significant changes in the expression of genes involved in glucose a nd fatty acid metabolism. Indeed, when hepatocytes were cultured in the pre sence of 50 to 500 muM metformin, the expression of genes encoding regulato ry proteins: of fatty acid oxidation (carnitine palmitoyltransferase I), ke togenesis (mitochondrial hydroxymethylgltaryl-CoA synthase), and gluconeoge nesis (glucose 6-phosphatase, phosphoenolpyruvate carboxykinase) was decrea sed by 30 to 60%, whereas expression of genes encoding regulatory proteins involved in glycolysis (glucokinase and liver-type pyruvate kinase) was inc reased by 250%. In conclusion, this work suggests that metformin could redu ce hepatic glucose production through short-term (metabolic) and long-term (genic) effects. (C) 2001 Elsevier Science Inc. All rights reserved.