Type I and II models of diabetes produce different modifications of K+ currents in rat heart: role of insulin.
1. Several K+ currents were measured and compared in enzymatically dispersed ventricular myocytes from control and diabetic rats. 2. Diabetic conditions were established either with a single intravenous injection of streptozotocin (STZ, 100 mg kg-1; 6-14 days duration) or by feeding with a fructose-enriched diet for 4-10 weeks. Both groups became hyperglycaemic, with the former having decreased and the latter having elevated levels of plasma insulin. These conditions therefore mimic type I (insulin-dependent) and type II (non-insulin-dependent) diabetes mellitus, respectively. 3. As reported previously, a Ca(2+)-independent transient outward K+ current, I(t), was attenuated in the type I model. This was not observed in the type II model. The two models differed greatly in the changes observed in a quasi-steady-state K+ current denoted Iss. In the STZ model Iss was substantially attenuated, whereas in the fructose-fed model it was augmented. In both models, the background inwardly rectifying current, IK1, was unchanged. Concomitantly, there was a substantial prolongation of the action potential in the STZ model but not in the fructose-fed model. 4. Incubation of control myocytes with insulin (100 nM) for 5-9 h caused a significant augmentation of Iss, with no effect on I(t) or on IK1. Incubation of myocytes from STZ-diabetic rats with insulin reversed the attenuation of I(t), but not of Iss. 5. The effect of insulin was not blocked by wortmannin, an inhibitor of phosphatidylinositol 3-kinase. However, inhibition of the mitogen-activated protein kinase pathway with PD98059 prevented restoration of I(t). Insulin action on I(t) may therefore involve changes in transcription or expression of channel proteins, rather than changes in cellular metabolism.
Shimoni
Y
Y
Department of Physiology and Biophysics, University of Calgary, Alberta, Canada. shimoni@cvr.ucalgary.ca
Ewart
H S
HS
Severson
D
D
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000378:metabolism*; D004558:Electric Stimulation; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005632:Fructose; D006321:Heart / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008564:Membrane Potentials / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D000077191:Wortmannin
D000730:Androstadienes; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015221:Potassium Channels; D005632:Fructose; D000077191:Wortmannin