Insulin resistance and the modulation of rat cardiac K(+) currents.
K(+) currents were measured using a whole cell voltage-clamp method in enzymatically isolated rat ventricular myocytes obtained from two hyperinsulinemic, insulin-resistant models. Fructose-fed rats as well as genetically obese rats, both of which are resistant to the metabolic effects of insulin, were used. The normal augmentation of a calcium-independent sustained K(+) current was reduced or abolished in insulin-resistant states. This resistance can 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 resistance of the K(+) current was not reversed by vanadyl sulfate. The results show 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, which mimic the effects of insulin on metabolism, also mimic the augmenting effects of insulin on a cardiac K(+) current in a manner suggesting synthesis of new channels.
Shimoni
Y
Y
Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1. shimoni@ucalgary.ca
Severson
D
D
Ewart
H S
HS
D000818:Animals; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004040:Dietary Carbohydrates; D005632:Fructose / Q000008:administration & dosage / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles; D006946:Hyperinsulinism / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D017968:Vanadium Compounds / Q000494:pharmacology
D004040:Dietary Carbohydrates; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D017968:Vanadium Compounds; D005632:Fructose; C034028:vanadyl sulfate; D008687:Metformin; D003513:Cycloheximide