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Am J Physiol Heart Circ Physiol. 2014 Mar 1;306(5):H747-54. doi: 10.1152/ajpheart.00849.2013. Epub 2013 Dec 27.

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

Author information

1
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah;

Abstract

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.

KEYWORDS:

cardiac insulin receptor; potassium channels; ventricular repolarization

PMID:
24375641
PMCID:
PMC3949065
DOI:
10.1152/ajpheart.00849.2013
[Indexed for MEDLINE]
Free PMC Article

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