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. 2003 May 9;550(Pt 1):305–315. doi: 10.1113/jphysiol.2003.042648

Insulin signalling and resistance in patients with chronic heart failure

Jukka Kemppainen *, Hiroki Tsuchida †, Kira Stolen *, Håkan Karlsson ‡, Marie Björnholm ‡, Olli J Heinonen §, Pirjo Nuutila *,‖, Anna Krook ‡, Juhani Knuuti *, Juleen R Zierath †
PMCID: PMC2343024  PMID: 12740426

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 ≈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.

Chronic heart failure (CHF) is a complex disorder in which changes in heart function accompany alterations in peripheral perfusion (Wilson et al. 1984b; Sullivan et al. 1989) and glucose metabolism (Massie et al. 1987; Mancini et al. 1988). Whole-body insulin resistance is prevalent in CHF patients with either ischaemic heart failure or idiopathic dilated cardiomyopathy (IDCM; Paolisso et al. 1991; Swan et al. 1997). Even though CHF patients have reduced skeletal muscle blood flow and abnormal sympathetic nervous system activation (Zelis et al. 1974; Cohn et al. 1984; Wilson et al. 1984a; Sullivan et al. 1989), the insulin resistance associated with this disease seems to originate from defects directly at the level of skeletal muscle, rather than from defects in the peripheral circulation or elevated catecholamine levels (Parsonage et al. 2002). Numerous structural and metabolic abnormalities have been described in the skeletal muscle from CHF patients, including fibre-type alterations, decreased oxidative enzyme capacity and excessive intra cellular lipid accumulation (Lipkin et al. 1988; Sullivan et al. 1990; Ralston et al. 1991; Drexler et al. 1992). However, the intracellular mechanisms underlying skeletal muscle insulin resistance in CHF patients have not been fully elucidated. Defects in skeletal muscle glucose uptake could arise from alterations in insulin signal transduction.

Insulin signal transduction in skeletal muscle is mediated by a series of phosphorylation cascades linking initial activation of the insulin receptor (IR) tyrosine kinase to downstream substrates, including the insulin receptor substrates (IRS). Tyrosine phosphorylated IRS-1 recruits signalling molecules with SH2 domains, including the phosphatidylinositol (PI) 3-kinase, into active signalling complexes (White & Yenush, 1998). PI-3-kinase activation is necessary, but not sufficient for the metabolic actions of insulin (Yeh et al. 1995; Krook et al. 1997; Baumann et al. 2000), suggesting that novel cascades contribute to the regulation of glucose transport. Activation of the phosphoinositide-dependent serine/threonine kinase Akt (also known as protein kinase B), a downstream target of PI-3-kinase, has been implicated as a component of the insulin-signalling pathway to glucose transport. Several pathways are likely to converge to elicit translocation of the insulin-sensitive glucose transporter (GLUT4) to the plasma membrane to facilitate glucose transport into the cell. In skeletal muscle from type-2 diabetic patients, whole-body insulin resistance is associated with defects in insulin action on IRS-1 phosphorylation, PI-3-kinase activity (Goodyear et al. 1995; Björnholm et al. 1997; Kim et al. 1999; Cusi et al. 2000; Krook et al. 2000) and glucose transport in isolated skeletal muscle (Goodyear et al. 1995; Björnholm et al. 1997; Krook et al. 2000). However, this is not a universal finding (Meyer et al. 2002), and in one in vitro study (Krook et al. 2000), insulin signalling defects were more profound at pharmacological insulin levels. Nevertheless, insulin signalling defects have also been reported to occur in skeletal muscle from insulin-resistant patients with either polycystic ovary syndrome (Dunaif et al. 2001), gestational diabetes (Friedman et al. 1999; Shao et al. 2000, 2002) or pancreatic cancer (Isaksson et al. 2003). Since IRS-1 and PI-3-kinase have been identified as candidates for defects contributing to peripheral insulin resistance (Goodyear et al. 1995; Björnholm et al. 1997; Friedman et al. 1999; Kim et al. 1999; Cusi et al. 2000; Krook et al. 2000; Shao et al. 2000; Dunaif et al. 2001; Shao et al. 2002; Isaksson et al. 2003), we hypothesised that whole-body insulin resistance in CHF patients may arise from defects in insulin signalling.

Regular moderate exercise is known to improve quality of life, functional capacity, peripheral blood flow and muscular adaptations in patients with CHF (Magnusson et al. 1996; Hambrecht et al. 1997, 1998; Belardinelli et al. 1999). In insulin-resistant humans and rodents, regular exercise enhances insulin sensitivity (Seals et al. 1984; Trovati et al. 1984; Rogers et al. 1988; Cortez et al. 1991; Dela et al. 1992; Hughes et al. 1993; Chibalin et al. 2000). The molecular mechanism for enhanced insulin sensitivity with exercise training may be related to increased expression and/or activation of key proteins that regulate glucose metabolism in skeletal muscle (Houmard et al. 1999; Chibalin et al. 2000; Kirwan et al. 2000). Importantly, insulin-stimulated PI-3-kinase activity is greater in skeletal muscle from young healthy people who participate in regular exercise training compared to sedentary individuals (Kirwan et al. 2000). Thus, enhanced insulin action after exercise training may be due to improvements in insulin signal transduction. Since insulin resistance is associated with CHF, exercise training may improve insulin action through enhanced insulin signal transduction.

The purpose of the present study was to determine whether insulin resistance due to idiopathic dilated cardiomyopathy in CHF patients is associated with impaired insulin signalling in skeletal muscle. Secondly we determined whether a 5 month exercise training programme would enhance insulin signalling in skeletal muscle from CHF patients. We hypothesised that insulin action on several key proteins in the insulin signal transduction cascade in skeletal muscle from CHF patients would be impaired, and that exercise training would lead to an improvement in insulin signalling, concomitant with improved insulin action.

METHODS

Subjects

Fourteen men with CHF due to IDCM with mild-to-moderate limitation of physical activity (New York Heart Association Classification (NYHA) I-III) and a left ventricular ejection fraction (LVEF) of less than 45 % were studied before and after an exercise training programme (n = 7) or standard care (n = 7). Seven healthy men participated as controls. The ethical committee of the University of Turku and Turku University Central Hospital approved the study protocol. The purpose and potential risks of this study were explained to all subjects and informed written consent to participate was obtained from them before enrolment in the study. The investigation was performed according to the principles outlined in the declaration of Helsinki.

The characteristics of the subjects are presented in Table 1. Control subjects were not taking any medication and presented with a normal electrocardiogram (ECG), blood pressure and routine haematological and biochemical blood analyses. Control subjects did not participate in a regular exercise programme. CHF patients had more than an 8 month history of IDCM, had been clinically stable for more than 3 months prior to the onset of the study period and were on optimal medical therapy. The exclusion criteria included decompensated CHF, ischaemic heart disease, unstable angina, diabetes, severe pulmonary disease, severe valvular disease, severe arrhythmia, renal insufficiency, uncontrolled hypertension, orthopaedic limitations and current cigarette smoking. IDCM patients were separated into two groups based on living proximity to the exercise training site, without randomisation. This was based solely on logistical reasons and took place without any prior knowledge of functional capacity, medical status or physical examination results of the participants. One patient in the exercise training group could not complete the glucose uptake study at baseline due to marked dyspnoea related to the supine study position. However, this patient was included in the study since baseline and follow-up muscle biopsy samples were obtained successfully.

Table 1.

Subjects' characteristics

Healthy subjects CHF patients
Age (years) 47 ± 3 54 ± 2
Body weight (kg) 801 ± 3.7 94.0 ± 5.2
BMI (kg m−2) 26.1 ± 0.9 29.9 ± 1.7
Body fat (%) 19.6 ± 1.3 23.1 ± 1.1
Glucose (mM) 5.3 ± 0.2 5.9 ± 1.5
Insulin (mU 1−1) 6.9 ± 1.3 10.2 ± 1.5
Cholesterol (mM) 5.8 ± 0.4 5.5 ± 0.2
peak VO2,max (ml kg−1 min−1) 35.5 ± 1.0 20.1 ± 1.2*
Muscle flow (ml kg−1 min−1) 25.9 ± 3.0 25.2 ± 4.1
LVEF (%) 69.1 ± 1.5 35.0 ± 1.9*
NYHA class 1.4 ± 0.1
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Blood chemistry was determined in fasted subjects. Muscle blood flow was determined under insulin-stimulated conditions. BMI, body mass index; V̇O2, max, maximal O2 uptake; LVEF, left-ventricular ejection fraction, NYHA class, New York Heart Association.

*

P < 0.001 vs. healthy subjects.

Study protocol

CHF patients were studied at baseline and after 5 months participation in an exercise training programme. Control subjects were only studied at baseline. Subjects were instructed to abstain from any kind of strenuous physical activity for at least 48 h before the study and to report to the laboratory after an overnight 12 h fast. Body fat content was estimated using a calliper, from seven skin folds (chest, midaxillary, triceps, subscapular, suprailiac, abdominal and thigh; Jackson & Pollock, 1985). A minimum of three measurements was made at each site. All participants underwent a symptom-limited, incremental cycle ergometer test with continuous respiratory gas exchange analysis at least 3 days before the study day (Vmax, SensorMedics BV, Bilthoven, The Netherlands). LVEF at rest was determined using two-dimensionally guided M-mode echocardiography (Acuson 128XP, Acuson, Mountain View, CA, USA) before the positron emission tomography (PET) study. Skeletal muscle blood flow was measured at baseline using PET and [15O2]-labelled water, as described previously (Ruotsalainen et al. 1997).

The euglycaemic hyperinsulinaemic clamp technique (DeFronzo et al. 1979) was used in conjunction with a needle biopsy technique to obtain basal and insulin-stimulated vastus lateralis skeletal muscle samples. Local anaesthesia (lidocaine (lignocaine) chloride 10 mg ml−1) was administered subcutaneously and around the skeletal muscle fascia, and an incision (about 5 mm long/10 mm deep) was made through the skin and muscle fascia. A percutaneous needle biopsy sample of the vastus lateralis muscle was obtained using a modified Bergström needle with suction. The basal biopsy sample was taken before the onset of the insulin infusion. The insulin-stimulated biopsy sample was obtained 3 cm from the first incision site on the same leg, 160 min after the onset of the infusion. Whole-body glucose uptake was determined as described previously (DeFronzo et al. 1979). Muscle samples were immediately frozen in liquid N2 and stored at −80 °C.

After the baseline investigation, the standard care group continued treatment as advised by a physician, without exercise training, for 5 months. The training group participated in a 5 month exercise programme that included both strength- and endurance-training components. The exercise training programme consisted of three supervised sessions and two home sessions per week. Dynamic exercise was carried out on either a stationary ergometer or a treadmill. The initial dynamic exercise intensity corresponded to 50 % of maximal O2 consumption (V̇O2, max). Exercise intensity and duration progressively increased to reach 70 % of V̇O2, max. A resistance-training programme was added after 4 weeks of endurance training. The resistance programme consisted of nine different exercises for the upper and lower body (leg extension, flexion, biceps, triceps, shoulder press, abdominal curl and back extensions). All studies at baseline and after 5 months were performed under the same conditions and at the same time of day. The subjects were instructed to follow their normal medication routine on the study days. Follow-up investigations were not performed for healthy control subjects.

Skeletal muscle blood flow

For measurement of skeletal muscle blood flow, 1.4 ± 0.1 GBq [15O]H2O was injected intravenously. The dynamic positron-emission tomography (PET) scan, automated blood sampling, measurements of radioactivity concentration and calculation of blood flow were performed as described previously (Raitakari et al. 1996; Ruotsalainen et al. 1997). Regions of interest within the quadriceps femoris were drawn in the middle of the skeletal muscle, between the patella and the spina iliaca anterior superior, onto four adjacent cross-sectional planes. Care was taken to avoid the area of the great vessels.

Blood chemistry

Plasma glucose concentrations were analysed in duplicate by the glucose oxidase method, using an Analox GM7 or GM9 (Analox Instruments, London, UK) glucose analyser. Serum insulin was measured using an automated time-resolved immunofluorometric assay (Autodelfia, Perkin-Elmer, Turku, Finland). Total cholesterol was measured in serum using standard enzymatic methods (Boehringer Mannheim, Mannheim, Germany) with a fully automated analyser (Hitachi 704, Hitachi, Tokyo, Japan).

IRS-1 tyrosine phosphorylation

Muscle specimens were freeze-dried overnight and then dissected to remove blood, fat and connective tissue. Freeze-dried muscle specimens were homogenised in ice-cold buffer A (137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2, 1 % Triton X-100, 10 % glycerol, 20 mM Tris, 10 mM NaF, 1 mM EDTA, 5 mM sodium pyrophosphate, 0.5 mM Na3VO4, 0.2 mM phenylmethylsulphonyl fluoride, 1 μg leupeptin, 1 μg aprotinin, 1 mM dithiothreitol (DTT), 1 mM benzamidine, and 1 mM microcystin) and centrifuged at 12 000 g for 30 min (4 °C). The supernatant was obtained and protein concentration was measured by the Bradford method (Bio-Rad, Richmond, CA, USA). An aliquot of the supernatant (1 mg) was immunoprecipitated overnight (4 °C) with an anti-IRS-1 antibody (JD159 from Drs Morris White and Martin Myers, Joslin Diabetes Center, Boston MA, USA) coupled to protein A-sepharose (Sigma, St Louis, MO, USA). The immunoprecipitates were washed three times with ice-cold buffer A (without DTT and microcystin), twice with buffer B (0.5 M LiCl, 0.1 M Tris, pH 8.0), once with buffer C (0.15 M NaCl, 1 mM EDTA, 10 mM Tris, pH 7.6), and then resuspended in Laemmli sample buffer with 100 mM DTT, and heated at 95 °C for 5 min. Proteins were separated by SDS-PAGE (6 % resolving gel), transferred to nitrocellulose membranes, and blocked with TBS containing 5 % milk. The membranes were incubated with anti-phosphotyrosine antibodies (Upstate, Lake Placid, NY, USA), washed, and then incubated with appropriate secondary antibodies. Immunoreactive proteins were visualised by enhanced chemiluminescence (ECL plus; Amersham, Arlington Heights, IL, USA) and quantified using densitometry.

IRS-1-associated PI-3-kinase activity

An aliquot of the supernatant (800 μg) described above was immunoprecipitated overnight (4 °C) with an anti-IRS-1 antibody coupled to protein A-sepharose. The immune complexes were washed three times with ice-cold buffer A (without DTT and microcystin), twice with buffer B, once with buffer C, once with buffer D (20 mM Hepes, 1 mM DTT, 5 mM MgCl2, pH 7.3), and resuspended in kinase assay buffer (20 mM Hepes, 20 mM β-glycerophosphate, 5 mM sodium pyrophosphate, 30 mM NaCl, 1 mM DTT). PI-3-kinase activity was assessed directly on the protein A-sepharose beads, as reported previously (Krook et al. 1997). Reaction products were resolved by thin-layer chromatography and were quantified using a PhosphorImager (Bio-Rad).

Akt phosphorylation and protein expression

An aliquot (40 μg) of the supernatant was resuspended in Laemmli buffer and heated to 95 °C for 5 min. Proteins were separated by SDS-PAGE (7.5 % resolving gel), transferred to polyvinylidene difluoride membranes, and blocked with TBS containing 7.5 % milk. Membranes were incubated with the anti-phospho-specific Akt (New England BioLabs, Beverly, MA, USA), anti-IR (CT3 from Ken Siddle, Cambridge University, Cambridge, UK), anti-IRS-1 (JD159), and anti-Akt antibodies (New England BioLabs). Membranes were washed and then incubated with appropriate secondary antibodies. Proteins were visualised and quantified as described above.

Statistics

Data are reported as means ±s.e.m. Student's paired or unpaired t test was used to assess differences within groups (basal and insulin-stimulated conditions) or between groups, respectively. Other differences were determined by one-way ANOVA. Fisher's least significant difference post hoc analysis was used to identify significant differences. Differences were considered significant at P < 0.05.

RESULTS

Subject characteristics

Age, body weight, body mass index (BMI), percentage body fat, and fasting plasma glucose serum insulin, and total cholesterol concentration were not significantly different in CHF patients compared to control subjects (Table 1). V̇O2, max was 43 % lower in CHF subjects (P < 0.001 versus control subjects). LVEF was markedly impaired in CHF patients (P < 0.001 versus control subjects). Baseline measurements of the different anthropometrical, biochemical, and physiological parameters were similar between CHF subjects undergoing standard care versus an exercise training programme (Table 2). Standard care was not associated with changes in any of the physiological parameters studied. Exercise training in CHF patients did not lead to changes in body weight, BMI or body fat. The slight reduction in insulin levels observed after exercise training did not reach statistical significance (P = 0.3). However, V̇O2, max was 20 % greater (P < 0.001) and LVEF was modestly enhanced (P < 0.05) after exercise training.

Table 2.

Anthropometric, biochemical and physiological parameters before and after treatment with standard care or an exercise training programme in CHF subjects

Standard care Exercise trainig
Baseline 5 months Baseline 5 months
Body weight (kg) 93.5 ± 4.2 947.7 ± 4.1 94.5 ± 9.9 95.6 ± 10.8
BMI (kg m−2) 30.0 ± 1.3 30.3 ± 1.3 29.9 ± 3.3 30.2 ± 3.6
Body fat (%) 24.4 ± 1.4 24.4 ± 1.5 21.8 ± 1.6 20.8 ± 2.0
Glucose (mM) 5.8 ± 0.2 5.5 ± 0.2 6.0 ± 0.5 6.1 ± 0.4
Insulin (mU I−1) 11.1 ± 2.4 12.6 ± 3.7 9.2 ± 1.9 7.0 ± 0.9
Cholesterol (mM) 5.1 ± 0.2 5.1 ± 0.3 5.8 ± 0.3 5.8 ± 0.4
peak V̇O2, max (ml kg−1 min−1) 20.6 ± 1.6 21.2 ± 1.1 19.7 ± 1.8 24.5 ± 2.3**
LVEF (%) 36.1 ± 2.3 37.1 ± 2.3 33.9 ± 3.1 38.1 ± 3.5*
NYHA class 1.2 ± 0.2 1.1 ± 0.1 1.6 ± 0.2 1.3 ± 0.2
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*

P < 0.005

**

P < 0.001 vs. baseline value.

Blood flow, glucose uptake and insulin signalling in CHF patients versus healthy subjects

Whole body insulin-stimulated glucose uptake was 20 % lower (P < 0.05) in CHF patients versus healthy subjects (Fig. 1A). Insulin-stimulated skeletal muscle blood flow was similar in CHF patients and healthy control subjects (Table 1). We next determined whether reduced whole-body glucose uptake was associated with impaired insulin signalling in the vastus lateralis skeletal muscle. Serum insulin levels at the time of muscle biopsy sampling were 6.9 ± 1.3 and 10.2 ± 1.5 mU l−1 under basal conditions (NS) and 68.4 ± 4.0 and 81.4 ± 5.8 mU l−1 under insulin-stimulated conditions (n.s.) for control subjects and CHF patients, respectively. Physiological hyperinsulinaemia increased the tyrosine phosphorylation of IRS-1 in skeletal muscle ≈2.5-fold, with similar responses noted between healthy subjects and CHF patients (Fig. 1B). PI-3-kinase activity was assessed in IRS-1 immunoprecipitates of basal and insulin-stimulated skeletal muscle. Insulin infusion led to a ≈2-fold increase in IRS-1-associated PI-3-kinase activity, with similar responses noted between healthy subjects and CHF patients (Fig. 1C). Insulin-stimulated Akt phosphorylation was increased ≈3-fold in skeletal muscle, with similar responses noted between healthy subjects and CHF patients. Protein expression of the insulin receptor, IRS-1 and Akt was similar between healthy subjects and CHF patients (data not shown). Thus, reduced whole-body insulin-stimulated glucose uptake in CHF patients was not associated with impaired skeletal muscle insulin signalling at the level of IRS-1, PI-3-kinase or Akt.

Figure 1. Insulin action on glucose uptake and signal transduction in healthy subjects and CHF patients.

Figure 1

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Whole-body insulin-mediated glucose uptake (A) was determined by means of the euglycaemic-hyperinsulinaemic clamp technique. Signal transduction was assessed in samples of the vastus lateralis skeletal muscle before and 160 min after the onset of insulin infusion; tyrosine phosphorylation of IRS-1 (B), IRS-1-associated PI-3-kinase activity (C), and Akt phosphorylation (D) were assessed. Results are presented as means ±s.e.m. *P < 0.05 for differences between healthy subjects and CHF patients (A) or between basal and insulin-stimulated conditions (B, C and D).

Effects of exercise training on glucose uptake and insulin signalling in CHF patients

Whole-body insulin-mediated glucose uptake was not altered in patients undergoing standard care (Fig. 2A). In contrast, exercise training elicited a 25 % (P < 0.05) increase in whole-body insulin-stimulated glucose uptake (Fig. 2B) over pre-training baseline levels. This change was significantly different compared to the standard care group (P < 0.05 for both the absolute and relative change). Importantly, exercise training improved whole-body insulin-mediated glucose uptake to levels comparable with control subjects (16.5 ± 2.8 versus 16.8 ± 1.1 μmol kg−1 min−1 for exercise-trained CHF patients versus healthy control subjects; n.s.). We next compared the effects of standard care versus exercise training on insulin signalling at the level of IRS-1, PI-3-kinase and Akt in skeletal muscle from CHF patients. Before participating in the treatment studies, serum insulin levels at the time of muscle biopsy sampling were 9.2 ± 1.9 and 11.1 ± 2.4 mU l−1 under basal conditions (NS) and 80.3 ± 3.1 and 82.7 ± 11.8 mU l−1 under insulin-stimulated conditions (n.s.) for patients assigned to either the exercise training programme and standard care, respectively. After the 5 month treatment period, serum insulin levels at the time of muscle biopsy sampling were 7.0 ± 0.9 and 12.6 ± 3.7 mU l−1 under basal conditions (n.s.) and 84.2 ± 4.7 and 92.7 ± 3.9 mU l−1 under insulin-stimulated conditions (n.s.) for patients treated with exercise training and standard care, respectively. Insulin increased IRS-1 tyrosine phosphorylation 2.8-fold (P < 0.05) in both standard care and exercise-trained subjects (Fig. 3). Neither standard care nor exercise training altered insulin-stimulated tyrosine phosphorylation of IRS-1. Consistent with our findings for IRS-1 tyrosine phosphorylation, the approximately 2.0-fold increase in IRS-1-associated PI-3-kinase activity after in vivo insulin exposure (P < 0.05) was not altered after standard care or exercise training (Fig. 4). Furthermore, the 3-fold increase in insulin-stimulated Akt phosphorylation observed in CHF patients was not altered after standard care or exercise training (Fig. 5). Neither standard care nor exercise training had any effect on protein expression of the insulin receptor IRS-1 and Akt in skeletal muscle (data not shown). Thus, the exercise-training-induced improvement in whole-body insulin-mediated glucose uptake was not associated with changes in insulin signalling at the level of IRS-1, PI-3-kinase or Akt.

Figure 2. Whole-body glucose uptake in CHF patients before or after 5 months of either standard care or exercise training.

Figure 2

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*P < 0.05 compared with pre-treatment.

Figure 3. Tyrosine phosphorylation of IRS-1 in skeletal muscle from CHF patients before (Pre) and after (Post) 5 months of either standard care or exercise training.

Figure 3

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Skeletal muscle biopsy samples were obtained as described in Fig. 1. *P < 0.05 for differences between basal and insulin-stimulated conditions.

Figure 4. IRS-1-associated PI-3-kinase activity in skeletal muscle from CHF patients before or after 5 months of either standard care or exercise training.

Figure 4

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Skeletal muscle biopsy samples were obtained as described in Fig. 1. *P < 0.05 for differences between basal and insulin-stimulated conditions.

Figure 5. Akt phosphorylation in skeletal muscle from CHF patients before or after 5 months of either standard care or exercise training.

Figure 5

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Skeletal muscle biopsy samples were obtained as described in Fig. 1. *P < 0.05 for differences between basal and insulin-stimulated conditions.

DISCUSSION

CHF is characterised by muscle weakness, dyspnoea, limited exercise capacity and decreased quality of life. Progression of CHF affects both the central and peripheral circulatory systems, causing skeletal muscle atrophy, increased vascular resistance, and metabolic abnormalities (Hanson, 1994). Skeletal muscle insulin resistance in CHF may be attributed to a local defect at the level of the myocyte, rather than from a failure of insulin-mediated vasodilatation or sympathetic nervous system activity (Parsonage et al. 2002). To date, the molecular mechanisms underlying skeletal muscle insulin resistance in CHF have not been elucidated. A growing body of evidence suggests that insulin signalling defects at the level of IRS-1 and PI-3-kinase contribute to insulin resistance in skeletal muscle from type-2 diabetic patients (Goodyear et al. 1995; Björnholm et al. 1997; Kim et al. 1999; Cusi et al. 2000; Krook et al. 2000), as well as the immediate relatives of patients with type 2 diabetes mellitus (Pratipanawatr et al. 2001). However, this is not a universal finding for all studies of type 2 diabetic subjects (Meyer et al. 2002) or their immediate relatives (Storgaard et al. 2001). Here we report that impaired whole-body insulin-mediated glucose uptake in CHF patients is not associated with impaired tyrosine phosphorylation of IRS-1, PI-3-kinase activation or Akt phosphorylation in skeletal muscle. Thus, while several insulin-resistant states including type 2 diabetes, obesity, glucose intolerance, polycystic ovary syndrome, gestational diabetes and pancreatic cancer have been reported to be associated with insulin signalling defects in skeletal muscle (Goodyear et al. 1995; Björnholm et al. 1997; Friedman et al. 1999; Kim et al. 1999; Cusi et al. 2000; Krook et al. 2000; Shao et al. 2000, 2002; Dunaif et al. 2001; Pratipanawatr et al. 2001; Shao et al.; Isaksson et al. 2003), insulin resistance in this cohort of CHF patients does not seem to be explained by impaired insulin action at the level of IRS-1/PI-3-kinase/Akt.

As we have reported earlier for healthy control subjects (Björnholm et al. 1997), in vivo infusion of insulin is associated with an increase in tyrosine phosphorylation of IRS-1, activation of PI-3-kinase and Akt phosphorylation. However, the increase in IRS-1 tyrosine phosphorylation and PI-3-kinase activity measured in the present group of control subjects was somewhat lower than in our earlier studies (Björnholm et al. 1997), and may be consistent with the mild reduction in whole-body insulin-mediated glucose uptake in this control group. Although insulin-mediated whole-body glucose uptake was 20 % lower in CHF patients as compared to healthy subjects, the level of insulin resistance in this cohort appears to be less severe than reported by others (Swan et al. 1997; Doehner et al. 2002). This may be due to the mild-to-moderate state of CHF, as compared to the more advanced state of the disease as reported for other cohorts (Swan et al. 1997; Doehner et al. 2002), since decreased insulin sensitivity is associated with the progression and degree of heart failure (Suskin et al. 2000). Thus, our results suggest that defective insulin signalling at the level of IRS-1/PI-3-kinase/Akt in skeletal muscle does not appear to be a primary cause of whole-body insulin resistance in patients with CHF.

There is considerable doubt as to whether insulin sensitivity is coupled to blood flow (Bonadonna et al. 1998; Yki-Jarvinen & Utriainen, 1998; Baron, 2002). Blood flow appears to be a rate-limiting step for glucose uptake only in insulin-sensitive subjects, not in insulin-resistant patients (Baron et al. 2000). In the present study, blood flow did not seem to be a rate-limiting factor for glucose uptake in CHF patients, since insulin-stimulated muscle blood flow at rest was similar to that of healthy control subjects, despite the 20 % reduction in whole-body glucose uptake. Thus, blood flow alone does not appear to explain the reduced insulin-stimulated glucose uptake in CHF patients. Consistent with this, an earlier study performed in a smaller group of CHF patients provided evidence that insulin resistance on whole-body glucose uptake was secondary to the failure of insulin-mediated vasodilatation or sympathetic nervous system activity (Parsonage et al. 2002). Thus, metabolic defects are probably due to abnormalities at the level of skeletal muscle. Nevertheless, our present results cannot exclude the possibility that blood flow distribution in the capillary network may have been different between the groups, and this may have influenced glucose uptake. Furthermore, the metabolic effects of insulin may also depend upon the blood flow distribution between the nutritive and non-nutritive compartments, as has been shown in experimental animal studies (Clark et al. 2003).

Since skeletal muscle blood flow was not diminished in these patients, specific biochemical and metabolic defects in the skeletal muscle itself could account for the reduced insulin action on whole-body glucose uptake. The regulation of insulin action on glucose uptake is a complex process, involving parallel pathways that converge and function in tandem, to recruit GLUT4 to the plasma membrane to facilitate glucose transport. Novel insulin signalling cascades may contribute to the regulation of glucose transport since PI-3-kinase activation is necessary, but not sufficient, for all metabolic actions of insulin (Krook et al. 1997; Baumann et al. 2000). However, the physiological nature of alternative insulin signalling pathways in the regulation of glucose transport in skeletal muscle has not been resolved. The discrepancy between our findings of impaired insulin-mediated whole-body glucose uptake, despite normal IRS-1/PI-3-kinase/Akt signalling in CHF patients may be explained by a defect at a later (yet to be identified) stage in the insulin signalling cascade, or from a direct impairment at the level of GLUT4 translocation. In healthy subjects and type 2 diabetic patients, insulin-mediated whole-body glucose uptake, as assessed by the euglycaemic hyperinsulinaemic clamp, is tightly correlated with the insulin-stimulated 3-O-methylglucose transport measured in isolated skeletal muscle (Galuska et al. 1994; Zierath et al. 1994). Furthermore, rates of insulin-stimulated 3-O-methylglucose transport are correlated with the amount of cell surface GLUT4 content (Lund et al. 1997; Ryder et al. 2000), with reductions in both parameters noted in skeletal muscle from type 2 diabetic subjects (Ryder et al. 2000). Whether defects at the level of GLUT4 translocation account for the reduction in insulin-mediated whole-body glucose uptake in CHF patients has yet to be determined.

The metabolic abnormalities in skeletal muscle from CHF patients may result from alterations in fibre-type composition or changes in the oxidative enzyme capacity (Lipkin et al. 1988; Ralston et al. 1991; Drexler et al. 1992; Hambrecht et al. 1997, 1998), converting the muscle to a more insulin-resistant phenotype. In humans, whole-body glucose uptake and cellular glucose transport are positively correlated with the percentage of type I fibres, and negatively correlated with the percentage of type IIB fibres (Hickey et al. 1995; Zierath et al. 1996; Nyholm et al. 1997). Likewise in rodents, insulin-stimulated tyrosine phosphorylation of IR and IRS-1, phosphotyrosine-associated PI-3-kinase activity and Akt phosphorylation is increased in skeletal muscle enriched in predominantly oxidative (type I fibres) versus glycolytic (type II) fibres (Song et al. 1999). Total GLUT4 protein content is also greater in oxidative (type I) skeletal muscle fibres, and this is coupled to increased insulin-stimulated glucose transport (Henriksen et al. 1990). Clinical evidence also suggests that skeletal muscle fibre type composition can influence insulin action. In insulin-resistant states due to morbid obesity (Hickey et al. 1995), or with forced inactivity due to spinal cord injury (Hjeltnes et al. 1998), the percentage of type I skeletal muscle fibres is reduced, concomitant with reduced insulin action on glucose uptake. Of particular relevance for the present study, in a small group of CHF patients, exercise training was reported to convert skeletal muscle fibre type distribution from glycolytic (type II) to oxidative (type I) fibres (Hambrecht et al. 1997).

In the past, CHF patients were advised to avoid physical exercise. However, these patients are now encouraged to participate in cardiac rehabilitation programmes, as exercise training is widely recognised as a suitable treatment strategy (Magnusson et al. 1996; Hambrecht et al. 1997, 1998). We have recent evidence to suggest that improvements in insulin-stimulated glucose uptake are independent of changes in peripheral perfusion in CHF patients after exercise training (Kemppainen et al. 2003), indicating that the improvement in whole-body glucose uptake is directly related to metabolic changes in skeletal muscle. Insulin-stimulated IRS-1-associated PI-3-kinase activity is enhanced in skeletal muscle from healthy subjects engaged in habitual exercise training programmes (Kirwan et al. 2000). Furthermore, in healthy young (22 ± 1 years) but sedentary men, 7 days of exercise training (60 min day−1 at 75 % V̇O2, max) is associated with enhanced insulin-mediated whole-body glucose uptake and phosphotyrosine-associated PI-3-kinase activity in skeletal muscle (Houmard et al. 1999). Here we provide evidence that exercise training improved whole-body insulin-mediated glucose uptake in CHF patients. However, the improvements in whole-body glucose uptake were not coupled to enhanced insulin signalling, suggesting that improved insulin action is enhanced distal to IRS-1/PI3-kinase/Akt. Interestingly, while short-term exercise training increased insulin signalling in skeletal muscle from young men (Houmard et al. 1999), these changes did not occur in middle-aged (58 ± 2 years) men (Tanner et al. 2002), consistent with our present observations in CHF patients. Thus, improvements in insulin-mediated glucose uptake after exercise training can occur independently of enhanced PI-3-kinase/Akt activity. While the mechanism for the apparent differential adaptive response of the insulin signalling cascade to exercise training between young and middle-age subjects is unknown, our study highlights the finding that CHF patients retain the ability to adapt to exercise training through positive changes in insulin-mediated whole-body glucose uptake, independently of changes in insulin signalling at the level of IRS-1/PI-3-kinase/Akt.

In conclusion, CHF patients demonstrate impaired insulin-stimulated whole-body glucose uptake, despite normal insulin signalling in skeletal muscle at the level of IRS-1, PI-3-kinase or Akt. Thus, insulin signalling defects are not a primary cause of impaired whole-body insulin-mediated glucose uptake in CHF. Exercise training is beneficial to treat the metabolic abnormalities associated with CHF and improves insulin action on whole-body glucose uptake independently of enhanced insulin signal transduction. Thus, altered insulin action on glucose uptake in CHF patients occurs at a distal component of the insulin signal transduction pathway regulating glucose uptake.

Acknowledgments

This study was supported by grants from the Swedish Medical Research Council, the Swedish Diabetes Association, Torsten and Ragnar Söderbergs Foundation, the Foundation for Scientific Studies of Diabetology, the Karolinska Institutet Foundation and Novo-Nordisk Research Foundation. Funding was also received from the Finnish Ministry of Education, the Aarne Koskelo Foundation, the Research Foundation of Orion Corporation and the Finnish Cardiovascular Foundation. We thank Drs Morris F. White and Martin G. Myers Jr (Joslin Diabetes Center, Boston, USA) for the generous gifts of IRS-1 antiserum.

Jukka Kemppainen and Hiroki Tsuchida contributed equally to this work.

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