Insulin signalling and resistance in patients with chronic heart failure.
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 approximately 2.5-fold, IRS-1-associated phosphatidylinositol 3-kinase (PI-3-kinase) activity by approximately 2-fold and Akt (protein kinase B) phosphorylation by approximately 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.
Turku PET Centre, University of Turku, Turku, Finland and Department of Surgical Sciences, Karolinska Hospital, Stockholm, Sweden.
Jukka
J
Kemppainen
Hiroki
H
Tsuchida
Kira
K
Stolen
Håkan
H
Karlsson
Marie
M
Björnholm
Olli J
OJ
Heinonen
Pirjo
P
Nuutila
Anna
A
Krook
Juhani
J
Knuuti
Juleen R
JR
Zierath
D002303:Cardiac Output, Low / Q000209:etiology / Q000503:physiopathology*; D002311:Cardiomyopathy, Dilated / Q000150:complications; D016022:Case-Control Studies; D002908:Chronic Disease; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply / Q000503:physiopathology*; D010806:Physical Education and Training; D012039:Regional Blood Flow; D015398:Signal Transduction; D013318:Stroke Volume
D007328:Insulin; D005947:Glucose