Phenytoin-induced insulin insensitivity.

Phenytoin is known to induce hyperglycaemia. The mechanism has generally been considered primarily an inhibition of insulin release. We have recently treated a patient who became hyperglycaemic on phenytoin and whose markedly increased insulin requirements suggested an insulin resistant state. Reduction of the phenytoin dose resulted in amelioration of the hyperglycaemia. In vitro studies of phenytoin in a primary culture system of adipocytes that allowed assessment of both insulin receptor binding and post-binding function showed a 57% reduction in maximum [14C]3-0-methylglucose transport in the presence of phenytoin while having no effect on maximum insulin binding. These results suggest that phenytoin administration can result in insulin insensitivity by inducing a post-binding defect in insulin action.