The Absence of Insulin Signaling in the Heart Induces Abnormalities in Ventricular Repolarization

Abstract

Diabetes mellitus is associated with cardiac arrhythmias, ventricular fibrillation and sudden death. These cardiac effects may result directly from the absence of insulin signaling in the heart or as in indirect consequence of diabetic sequelae (e.g., hyperlipidemia, hypertension or coronary artery disease). To study the electrical consequences of absent insulin signaling in the heart, we used a cardiac-specific insulin receptor knock-out (CIRKO) mouse model. We recorded action potentials and K+ currents in myocytes isolated from CIRKO mice and their control littermates. Action potential duration at 90% (APD90) was significantly prolonged in left ventricle, apex and septum from CIRKO mice compared to WT. Conversely, no differences in APD90 were observed in right ventricular myocytes. Outward potassium currents recorded using whole-cell voltage clamp method showed a reduction in both peak and sustained current in CIRKO mice. Neither the voltage dependence of steady-state inactivation nor recovery from inactivation of the rapidly inactivating outward K+ current (Ito,f) were affected. In addition, the inward rectifier K+ current (IK1) was not different between both groups. Consistent with the APD prolongation, CIRKO mice showed QT interval prolongation, compared to WT littermates. Western blot and real time q-PCR analyses revealed that the protein levels and mRNA expression of Kv4.2 were significantly reduced in CIRKO hearts. We conclude that the absence of insulin signaling in the heart causes a reduction in Kv4.2 message and protein that in turn, reduces Ito,f, prolongs APD in left ventricle and prolongs the QT interval.