Following i.v. injection of glucose to rats, blood was collected from the carotid artery and the portal vein, and insulin was determined by radioimmunoassay. Pancreatic insulin release and hepatic insulin extraction were increased following the administration of glucocorticoid drugs and reduced following phenytoin. Hepatic glutathione-insulin transhydrogenase activity (GITA) was measured in each animal and found to be increased after glucocorticoid therapy but unaffected by phenytoin. In alloxan-diabetic rats, GITA was significantly increased following treatment with both methylprednisolone and phenytoin compared with control alloxan-diabetic rats. This is suggestive evidence that both these drugs can initiate an increase in GITA. It is concluded that the markedly raised GITA in steroid-treated non-diabetic rats is the combined result of a drug-induced effect plus the major inducing effect of an increased hepatic uptake of insulin on insulin degradation, whereas the main effect of phenytoin is a reduction of pancreatic insulin release.