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Insulin signalling and resistance in patients with chronic heart failure
Jukka Kemppainen1, Hiroki Tsuchida, Kira Stolen
1Turku PET Centre, University of Turku, Turku, Finland and Department of Surgical Sciences, Karolinska Hospital, Stockholm, Sweden.
Insights
Patients with chronic heart failure (CHF) show impaired insulin-stimulated glucose uptake despite normal skeletal muscle insulin signaling. Exercise training significantly improves glucose uptake in CHF patients, independent of enhanced insulin signaling pathways.
Area of Science:
- Cardiology
- Metabolic Physiology
- Exercise Science
Background:
- Chronic heart failure (CHF) is frequently associated with insulin resistance.
- The underlying mechanisms of insulin resistance in CHF, particularly concerning skeletal muscle insulin signaling, remain incompletely understood.
Purpose of the Study:
- To investigate insulin resistance in skeletal muscle of CHF patients.
- To determine if exercise training improves insulin signaling and action in CHF.
- To elucidate the specific molecular pathways involved in insulin action and their response to exercise.
Main Methods:
- Studied 14 men with CHF and 7 healthy controls.
- Utilized the euglycaemic hyperinsulinaemic clamp technique to measure whole-body insulin-stimulated glucose uptake.
- Analyzed skeletal muscle biopsy samples for insulin signaling markers, including insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI-3-kinase), and Akt phosphorylation.
Main Results:
- CHF patients exhibited 20% lower insulin-stimulated glucose uptake compared to controls.
- Insulin signaling pathways (IRS-1, PI-3-kinase, Akt) were similarly activated by insulin in both CHF patients and controls.
- Standard care did not alter glucose uptake, while 5-month exercise training increased glucose uptake by 25% in CHF patients.
- Exercise training did not significantly alter the measured insulin signaling pathway components.
Conclusions:
- CHF patients have impaired insulin-stimulated glucose uptake, not explained by defects in skeletal muscle IRS-1, PI-3-kinase, or Akt signaling.
- Exercise training is a clinically relevant intervention that enhances insulin action and glucose uptake in CHF patients.
- The improvement in insulin action following exercise training in CHF appears to be independent of alterations in the studied insulin signaling cascade.
Abstract:
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.