The effects of phenformin in normal vs. diabetic isolated perfused rat liver

In the isolated perfused liver system high concentrations of phenformin (0.93--1.24 mM) were required to reduce the greater than two-fold elevated rate of gluconeogenesis from L-[U-14C]lactate in acutely alloxan diabetic (48-hour) and chronically alloxan diabetic (7-day) rat livers to the slower rate of normal fed livers. At these phenformin concentrations, other hepatic functions such as substrate uptake and 14CO2 production were also inhibited. The livers were also in a very reduced state under these conditions as indicated by the elevated ratios of the redox couples lactate/pyruvate and 3-hydroxybutyrate/acetoacetic acid. The results are interpreted to indicate that if phenformin functions as an antidiabetic (hypoglycemic) agent by inhibiting hepatic gluconeogenesis to normal levels, it is also generally toxic to the liver under such conditions. The results are discussed in relation to current hypotheses of the mechanism of action of phenformin and to phenformin-associated lactic acidosis.