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Experimental Diabetes Research
Volume 2012, Article ID 654904, 12 pages
Review Article

Cardiac Insulin Resistance and MicroRNA Modulators

1Department of Internal Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA
2Department of Nutrition and Exercise Physiology, School of Medicine, University of Missouri, Columbia, MO 65212, USA
3Diabetes and Cardiovascular Laboratory, School of Medicine, University of Missouri, Columbia, MO 65212, USA
4Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA
5Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, One Hospital Drive, Columbia, MO 65212, USA

Received 8 July 2011; Accepted 22 July 2011

Academic Editor: Jun Ren

Copyright © 2012 Lakshmi Pulakat et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Cardiac insulin resistance is a metabolic and functional disorder that is often associated with obesity and/or the cardiorenal metabolic syndrome (CRS), and this disorder may be accentuated by chronic alcohol consumption. In conditions of over-nutrition, increased insulin (INS) and angiotensin II (Ang II) activate mammalian target for rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2), it also renders cardioprotection via increased Ang II receptor 2 (AT2R) upregulation and adaptive hypertrophy. In the INS-resistant and hyperinsulinemic Zucker obese (ZO) rat, a rodent model for CRS, activation of mTOR/S6K1signaling in cardiac tissue is regulated by protective feed-back mechanisms involving mTOR↔AT2R signaling loop and profile changes of microRNA that target S6K1. Such regulation may play a role in attenuating progressive heart failure. Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy.