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

Angelica Lopez-Izquierdo1, Renata O Pereira, Adam R Wende

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

American Journal of Physiology. Heart and Circulatory Physiology
|December 31, 2013
PubMed

Insights

Diabetes impairs heart function by reducing key potassium channels, leading to prolonged action potentials and QT intervals. This study clarifies the direct impact of cardiac insulin signaling on heart rhythm.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Endocrinology

Background:

  • Diabetes mellitus is linked to increased risk of cardiac dysfunction, heart failure, and sudden cardiac death.
  • Neurohumoral changes in diabetes complicate understanding of specific pathways affecting cardiac function.
  • Investigating direct effects of impaired cardiac insulin signaling is crucial.

Purpose of the Study:

  • To investigate the specific effects of impaired cardiac insulin signaling on ventricular repolarization.
  • To determine if reduced insulin receptor signaling in cardiomyocytes alone causes repolarization abnormalities.
  • To differentiate these effects from generalized metabolic derangements of diabetes.

Main Methods:

  • Utilized a cardiomyocyte-restricted insulin receptor knockout (CIRKO) mouse model.
  • Assessed mRNA and protein expression of key potassium (K+) channels involved in ventricular repolarization.
  • Measured transient outward K+ current (Ito,fast) amplitude in isolated ventricular myocytes.
  • Analyzed ventricular action potential duration and QT interval on surface ECG.

Main Results:

  • CIRKO mice showed reduced mRNA and protein expression of critical K+ channels (Kv4.2, KChiP2) governing repolarization.
  • A significant reduction in the amplitude of Ito,fast was observed in CIRKO myocytes.
  • Ventricular action potential prolongation and prolonged QT intervals were evident in CIRKO mice.
  • These findings were independent of generalized metabolic changes.

Conclusions:

  • Impaired insulin action specifically in cardiomyocytes is sufficient to cause ventricular repolarization abnormalities.
  • Reduced expression and function of key K+ channels underlie these repolarization defects.
  • Cardiac insulin signaling plays a vital role in maintaining normal heart rhythm and preventing arrhythmias in diabetes.
Keywords:
cardiac insulin receptorpotassium channelsventricular repolarization

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