Skip Navigation



European Heart Journal Advance Access published online on October 1, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp396
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
31/1/100    most recent
ehp396v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Cook, S. A.
Right arrow Articles by Camici, P. G.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cook, S. A.
Right arrow Articles by Camici, P. G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction

Stuart A. Cook1,2,3,{dagger}, Anabel Varela-Carver2,{dagger}, Marco Mongillo1, Christina Kleinert2, Muhammad T. Khan1, Lucia Leccisotti1, Nicola Strickland3, Takashi Matsui4, Saumya Das4, Anthony Rosenzweig4, Prakash Punjabi3 and Paolo G. Camici1,2,3,*

1 Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital Campus, London W12 0NN, UK
2 National Heart and Lung Institute, Imperial College, London, UK
3 Imperial College NHS Trust, Hammersmith Hospital, London, UK
4 Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA

Received 22 December 2008; revised 5 August 2009; accepted 27 August 2009 * Corresponding author. Tel: +44 208 383 3186, Email: paolo.camici{at}csc.mrc.ac.uk

Aims: Whole body and myocardial insulin resistance are features of non-insulin-dependent diabetes mellitus (NIDDM) and left-ventricular dysfunction (LVD). We determined whether abnormalities of insulin receptor substrate-1 (IRS1), IRS1-associated PI3K (IRS1-PI3K), and glucose transporter 4 (GLUT4) contribute to tissue-specific insulin resistance.

Methods and results: We collected skeletal muscle (n = 27) and myocardial biopsies (n = 24) from control patients (n = 7), patients with NIDDM (n = 9) and patients with LVD (n = 8), who were characterized by euglycaemic–hyperinsulinaemic clamp and positron emission tomography. Comparative studies were carried out in three mouse models. We demonstrate an unrecognized reduction of IRS1 in skeletal muscle of LVD patients and an unexpected increase in cardiac IRS1-PI3K activity in NIDDM and LVD patients. In NIDDM, there was a concomitant reduction in sarcolemmal GLUT4, whereas in patients with LVD sarcolemmal GLUT4 was increased. We confirm activation of IRS1-PI3K and reduction in sarcolemmal GLUT4 in the insulin resistant ob/ob mouse heart where we also demonstrate perturbation of GLUT4 docking and fusion. A direct relationship between PI3K and GLUT4 was demonstrated in mice expressing activated PI3K in the heart and increased GLUT4 at the sarcolemma was confirmed in a mouse model of LVD.

Conclusion: Our data show that the mechanisms of myocardial insulin resistance are different between NIDDM and LVD.

Key Words: Insulin • Congestive heart failure • Diabetes • Imaging

{dagger} Both authors contributed equally to this work.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.