Insulin resistance in moderate chronic heart failure is related to hyperleptinaemia, but not to norepinephrine or TNF-alpha

Objectives: Chronic heart failure (CHF) has emerged as an insulin-resistant state, independently of ischaemic aetiology. The underlying mechanisms of this finding are not known. Catecholamines, tumor necrosis factor alpha (TNFα) and leptin, the adipocyte specific hormone, have all been implicated as mediators of impaired insulin sensitivity. The purpose of this study was to examine in patients with CHF and in comparison to healthy controls subjects whether norepinephrine, TNFα or leptin relate to insulin sensitivity. Design: 41 patients with CHF (age 60±2 years, NYHA I/II/III/IV 4/12/22/3, peak oxygen consumption 17.6±1.0 ml/kg per min) and 21 healthy controls of similar age and total and regional fat distribution were studied in a cross-sectional study. Insulin sensitivity was assessed by intravenous glucose tolerance testing using the minimal model approach; catecholamines, TNFα and soluble TNF receptors 1 and 2 were also measured. Total and regional body fat mass was assessed by dual energy X-ray absorptiometry. Results: Insulin sensitivity was reduced in CHF patients compared to controls by 31% (P<0.01) and fasting insulin was higher in patients than in controls (79.1±9.7 vs. 41.4±6.0 pmol/l, P<0.01). Patients had, compared to healthy controls, elevated serum leptin levels (8.28±0.84 vs. 4.83±0.68 ng/ml), norepinephrine (3.45±0.34 vs. 1.87±0.16 nmol/l, both P<0.01) and soluble TNF-receptors 1 (1280±141 vs. 639±52 pg/ml) and 2 (2605±184 vs. 1758±221 pg/ml, both P<0.01). Leptin levels corrected for total body fat mass were higher in CHF patients than in controls (41.3±3 vs. 24.3±2 pg/ml per 100 g, P<0.001). TNFα was not significantly different between the groups. In both groups there was an inverse correlation between insulin sensitivity and serum leptin (r=-0.65, P<0.0001 for pooled subjects); in contrast, no significant relation was found between insulin sensitivity and norepinephrine or TNFα. In multivariate regression analysis, leptin emerged as the only significant predictor of insulin sensitivity (standardised coefficient=-0.59, P<0.001), independent of body fat mass, age and peak VO₂. Conclusion: In moderate CHF, elevated leptin levels directly and independently predict insulin resistance. Elevated serum leptin levels could play a role in the impaired regulation of energy metabolism in CHF. In contrast to observations in other conditions, TNFα and norepinephrine are not related to insulin resistance in moderate CHF.