Insulin resistance and the modulation of rat cardiac K+ currents

K+ currents were measured using a whole cell voltage-clamp method in enzyma tically isolated rat ventricular myocytes obtained from two hyperinsulinemi c, insulin-resistant models. Fructose-fed rats as well as genetically obese rats, both of which are resistant to the metabolic effects of insulin, wer e used. The normal augmentation of a calcium-independent sustained K+ curre nt was reduced or abolished in insulin-resistant states. This resistance ca n be reversed by the insulin-sensitizing drug metformin. Vanadyl sulfate (3 -4 wk treatment or after 5-6 h in vitro) enhanced the sustained K+ current. The in vitro effect of vanadyl was blocked by cycloheximide. Insulin resis tance of the K+ current was not reversed by vanadyl sulfate. The results sh ow that insulin resistance is expressed in terms of insulin actions on ion channels, in addition to its actions on metabolism. This resistance can be reversed by the insulin-sensitizing drug metformin. Vanadate compounds, whi ch mimic the effects of insulin on metabolism, also mimic the augmenting ef fects of insulin on a cardiac K+ current in a manner suggesting synthesis o f new channels.