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

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Abstract

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.

Introduction

In recent years neuroendocrine, immune and metabolic systems have been found to contribute to the progression of chronic heart failure (CHF). It has been shown that CHF is a condition of insulin resistance [1], [2] independently of an ischaemic aetiology [3]. The underlying mechanisms of this finding are not fully understood but several hypotheses have been proposed. Catecholamines can induce insulin resistance in humans without heart disease [4], [5]. Increased sympathetic activation is a well established feature in CHF. An inverse correlation between norepinephrine concentrations and insulin sensitivity has been reported in a study of CHF patients [6], but the results have not been confirmed by others [3]. Furthermore, tumor necrosis factor-alpha (TNFα) has been suggested to play a role in the pathogenesis of obesity-related insulin resistance [7]. This has been confirmed in non-obese [8] insulin-resistant subjects. Inflammatory immune activation marked by elevated levels of TNFα and its soluble receptors is an aspect of CHF that has been recognized only in the last decade [9], [10]. If, and to what extent elevated TNFα levels contribute to insulin resistance in CHF patients, is not clear.

Another factor that has been implicated in the pathogenesis of impaired insulin sensitivity is the ob gene product leptin [11]. Initially seen as a mediator of central regulation of food intake and energy expenditure, there is increasing evidence that leptin might also be involved in energy metabolism at a peripheral level [12]. Leptin receptors are expressed in peripheral tissues such as pancreatic islets, liver, kidney, lung and skeletal muscle [13], [14], [15] suggesting that leptin might also have a physiological role in tissues other than the brain. Recent studies demonstrated that leptin might modulate responsiveness to insulin and that elevated leptin levels are related to insulin resistance: Potential mechanisms of how leptin might affect insulin sensitivity have been identified [16] and a dose-dependent inhibiting effect of leptin on insulin-mediated glucose metabolism of the skeletal muscle has been reported [17]. An association between raised leptin levels and insulin resistance, independently of body fat mass, has been reported in obese and lean men [18], [19]. The significance of leptin in regulating energy metabolism in human is, however, poorly understood and further investigation of the regulatory effects of leptin is needed [20]. Previously, we [21] and others [22] reported on elevated leptin levels in non-cachectic CHF patients and it seems possible that hyperleptinaemia may contribute to impaired insulin sensitivity in these patients. The aim of the present study was to analyse the relation of norepinephrine, plasma TNFα and leptin levels to impaired insulin sensitivity in CHF in comparison to healthy control subjects

Section snippets

Patient population

The study group consisted of 41 male patients with CHF due to ischaemic heart disease (n=25) or idiopathic dilated cardiomyopathy (n=16), and 21 healthy control subjects of similar age. The diagnosis of CHF was based on a history of systolic heart failure with symptomatic exercise limitation for at least 6 months. In all patients objective evidence of left ventricular enlargement or functional impairment by radionuclide ventriculography and/or echocardiography was present. All patients were

Results

Clinical characteristics of the patients and the control subjects are given in Table 1. The two groups were similar for age, weight, body mass index and both total, and regional, body fat distribution. CHF patients had compared to control subjects reduced peak oxygen consumption (−51%, P<0.0001) and lower blood pressure (−10%, P<0.01). CHF patients were further characterised by moderate increase in serum creatinine (P=0.001) and reduced sodium levels (P=0.002).

As shown in Table 2, CHF patients

Discussion

In the present study, we found markedly elevated serum leptin levels in patients with CHF compared to healthy control subjects. We also found that leptin independently predicts insulin sensitivity in CHF patients as in healthy subjects. No relation was, however, found between insulin sensitivity and norepinephrine, TNFα or soluble TNF receptors, either in CHF patients or in controls.

Serum leptin levels are closely related to body fat tissue mass [26] and are higher in women than in men,

Acknowledgments

WD is supported by a PhD studentship of the NHLI, London and by the Club of the Friends and Sponsors of the Charité Medical School, Berlin. SDA is supported by a post-graduate fellowship of the Max-Delbrück Centrum, Berlin, Germany.

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