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Received March 6, 2003
Accepted after revision March 9, 2003
1 Turku PET Centre, University of Turku, Turku, Finland
2 Department of Surgical Sciences, Karolinska Hospital, Stockholm, Sweden
3 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
4 Paavo Nurmi Centre, Sports and Exercise Medicine Unit, Department of Physiology, Turku, Finland
5 Turku PET Centre, University of Turku, Turku, Finland, and Department of Medicine, University of Turku, Turku, Finland.
6 Professor of Physiology, Department of Clinical Physiology, Section for Integrative Physiology, Karolinska Institutet, von Eulers väg 4, II, SE-171 77 Stockholm, Sweden
* To whom correspondence should be addressed. E-mail: Juleen.Zierath{at}fyfa.ki.se.
We investigated whether insulin resistance in patients with chronic heart failure (CHF) is associated with impaired insulin signalling in skeletal muscle and whether exercise training would lead to an improvement in insulin signalling, concomitant with enhanced insulin action. Fourteen men with CHF due to idiopathic dilated cardiomyopathy, with mild-to-moderate limitation of physical activity and a left-ventricular ejection fraction of less than 45 %, were studied before and after either a 5 month exercise training programme (n = 7) or standard care (n = 7). Seven healthy men participated as controls. Whole-body insulin-stimulated glucose uptake was determined by the euglycaemic hyperinsulinaemic clamp technique and skeletal muscle biopsy samples were obtained before and after the insulin infusion for insulin signalling measurements. Insulin-stimulated glucose uptake was 20 % lower in CHF patients versus healthy subjects. Physiological hyperinsulinaemia increased tyrosine phosphorylation of insulin receptor substrate (IRS)-1 by ~2.5-fold, IRS-1-associated phosphatidylinositol 3-kinase (PI-3-kinase) activity by ~2-fold and Akt (protein kinase B) phosphorylation by ~3-fold, with similar responses between healthy subjects and CHF patients. Insulin-mediated glucose uptake was not altered in patients after standard care, whereas exercise training elicited a 25 % increase in glucose uptake. Neither standard care nor exercise training altered insulin-stimulated tyrosine phosphorylation of IRS-1, IRS-1-associated PI-3-kinase activity or Akt phosphorylation. In conclusion, the CHF patients demonstrated impaired insulin-stimulated glucose uptake, despite normal signal transduction in skeletal muscle at the level of IRS-1, PI-3-kinase and Akt. Of clinical relevance is the finding that exercise training improves glucose uptake. However, these changes in insulin action after exercise training appear to be independent of enhanced insulin signalling at the level of IRS-1, PI-3-kinase or Akt.
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