Diabetes mellitus attenuates the repolarization reserve in mammalian heart.
OBJECTIVE
In diabetes mellitus several cardiac electrophysiological parameters are known to be affected. In rodent experimental diabetes models changes in these parameters were reported, but no such data are available in other mammalian species including the dog. The present study was designed to analyse the effects of experimental type 1 diabetes on ventricular repolarization and its underlying transmembrane ionic currents and channel proteins in canine hearts.


RESULTS
Diabetes was induced by a single injection of alloxan, a subgroup of dogs received insulin substitution. After the development of diabetes (8 weeks) electrophysiological studies were performed using conventional microelectrodes, whole cell voltage clamp, and ECG. Expression of ion channel proteins was evaluated by Western blotting. The QTc interval and the ventricular action potential duration in diabetic dogs were moderately prolonged. This was accompanied by significant reduction in the density of the transient outward K+ current (I(to)) and the slow delayed rectifier K+ current (I(Ks)), to 54.6% and 69.3% of control, respectively. No differences were observed in the density of the inward rectifier K+ current (I(K1)), rapid delayed rectifier K+ current (I(Kr)), and L-type Ca2+ current (I(Ca)). Western blot analysis revealed a reduced expression of Kv4.3 and MinK (to 25+/-21% and 48+/-15% of control, respectively) in diabetic dogs, while other channel proteins were unchanged (HERG, MiRP1, alpha(1c)) or increased (Kv1.4, KChIP2, KvLQT1). Insulin substitution fully prevented the diabetes-induced changes in I(Ks), KvLQT1 and MinK, however, the changes in I(to), Kv4.3, and Kv1.4 were only partially diminished by insulin.


CONCLUSIONS
It is concluded that type 1 diabetes mellitus, although only moderately, lengthens ventricular repolarization, attenuates the repolarization reserve by decreasing I(to) and I(Ks) currents, and thereby may markedly enhance the risk of sudden cardiac death.
Lengyel
Csaba
C
Department of Pharmacology and Pharmacotherapy, University of Szeged, Hungary.
Virág
László
L
Bíró
Tamás
T
Jost
Norbert
N
Magyar
János
J
Biliczki
Péter
P
Kocsis
Erzsébet
E
Skoumal
Réka
R
Nánási
Péter P
PP
Tóth
Miklós
M
Kecskeméti
Valéria
V
Papp
Julius Gy
JG
Varró
András
A
D000200:Action Potentials; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D020746:Calcium Channels, L-Type / Q000378:metabolism; D051668:Delayed Rectifier Potassium Channels / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D007328:Insulin / Q000627:therapeutic use; D051657:KCNQ1 Potassium Channel / Q000378:metabolism; D051665:Kv1.4 Potassium Channel / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D051672:Shal Potassium Channels / Q000378:metabolism
D020746:Calcium Channels, L-Type; D051668:Delayed Rectifier Potassium Channels; D007328:Insulin; D051657:KCNQ1 Potassium Channel; D051665:Kv1.4 Potassium Channel; D024661:Potassium Channels, Inwardly Rectifying; D051672:Shal Potassium Channels