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The absence of insulin signaling in the heart induces changes in potassium channel expression and ventricular repolarization.

Diabetes mellitus increases the risk for cardiac dysfunction, heart failure, and sudden death. The wide array of neurohumoral changes associated with diabetes pose a challenge to understanding the roles of specific pathways that alter cardiac function. Here, we use a mouse model with cardiomyocyte-restricted deletion of insulin receptors (CIRKO, cardiac-specific insulin receptor knockout) to study the specific effects of impaired cardiac insulin signaling on ventricular repolarization, independent of the generalized metabolic derangements associated with diabetes. Impaired insulin action caused a reduction in mRNA and protein expression of several key K(+) channels that dominate ventricular repolarization. Specifically, components of transient outward K(+) current fast component (Ito,fast; Kv4.2 and KChiP2) were reduced, consistent with a reduction in the amplitude of Ito,fast in isolated left ventricular CIRKO myocytes, compared with littermate controls. The reduction in Ito,fast resulted in ventricular action potential prolongation and prolongation of the QT interval on the surface ECG. These results support the notion that the lack of insulin signaling in the heart is sufficient to cause the repolarization abnormalities described in other animal models of diabetes.

Pubmed ID: 24375641 RIS Download

Mesh terms: Action Potentials | Animals | Arrhythmias, Cardiac | Diabetes Complications | Disease Models, Animal | Down-Regulation | Electrocardiography | Heart Rate | Heart Ventricles | Insulin | Kv Channel-Interacting Proteins | Mice | Mice, Knockout | Myocytes, Cardiac | Potassium Channels | RNA, Messenger | Receptor, Insulin | Shal Potassium Channels | Signal Transduction | Time Factors

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Associated grants

  • Agency: NHLBI NIH HHS, Id: K99-HL-111322
  • Agency: NIDDK NIH HHS, Id: R01DK092065
  • Agency: NHLBI NIH HHS, Id: R00 HL111322
  • Agency: NHLBI NIH HHS, Id: T32-HL-007576
  • Agency: NHLBI NIH HHS, Id: T32 HL007576
  • Agency: NHLBI NIH HHS, Id: UO1HL087947

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