Insulin: an anti-inflammatory hormone?

Recent observations in in vitro studies have proposed a pro-inflammatory effect of glucose and an anti-inflammatory action of insulin⁽Reference Hotamisligil^1, Reference Kahn, Hull and Utzschneider^2, Reference Gustafson, Hammarstedt and Andersson¹²⁾. These observations have led to a working hypothesis explaining how the pro-inflammatory state that accompanies the metabolic syndrome associates with both insulin resistance and endothelial dysfunction, via the connection between inflammation and metabolic processes. This hypothesis would also explain why insulin-resistant states (like obesity and type-II diabetes) are associated with oxidative stress, inflammation and atherosclerosis.

Acute v. regular exercise

IL-6 and other cytokines which are produced and released by skeletal muscles have been suggested to be involved in mediating the health-beneficial effects of exercise and play important roles in the protection against diseases associated with low-grade inflammation. The following hypothesis is based on years of observation by Pedersen and co-workers⁽Reference Pedersen, Steensberg and Fischer^22–Reference Fischer, Berntsen and Perstrup²⁴⁾: plasma IL-6 increases in an exponential fashion with exercise and is related to exercise intensity, duration, the mass of muscle recruited and one's endurance capacity. Consequently, the contracting skeletal muscle is a major source of circulating IL-6 in response to acute exercise. During heavy exercise, such as a marathon, there is up to a 60-fold increase in the IL-6 plasma levels⁽Reference Ostrowski, Rohde and Zacho²⁵⁾ with the duration of the event explaining more than 50% of the variation⁽Reference Fischer²⁶⁾. The mentioned plasma IL-6 increase supports the hypothesis that the post-exercise cytokine production is related to skeletal muscle damage with an acute inflammatory response⁽Reference Philippou, Bogdanis and Maridaki²⁷⁾.

Interestingly, IL-6 shows a markedly lower response to acute exercise in trained subjects. The health benefits of long-term regular exercise are ascribed to the anti-inflammatory response elicited by an acute bout of exercise, which is partly mediated by muscle-derived IL-6. Physiological concentrations of IL-6 stimulate the appearance in the circulation of the anti-inflammatory cytokines IL-1ra and IL-10, and inhibit the production of the pro-inflammatory cytokine TNFα. The anti-inflammatory effects of exercise may therefore offer protection against TNF-induced insulin resistance. Moreover, IL-6 stimulates lipolysis as well as fat oxidation. The increase of IL-6 at the end of acute exercise is responsible for the increased CRP levels during late recovery. In response to regular physical activity, basal as well as post-exercise plasma levels of IL-6 decreases by mechanisms that might include increased glycogen content, improved anti-oxidative capacity and improved insulin sensitivity. The lower levels of IL-6 in circulation will subsequently result in lower CRP levels. When untrained, basal plasma IL-6 and CRP levels are elevated via mechanisms that may involve impaired insulin sensitivity and/or increased oxidative stress⁽Reference Pedersen, Steensberg and Fischer^22, Reference Pedersen²³⁾.

Few studies have prospectively examined the effect of exercise training on low-grade inflammatory status, and the data obtained from intervention studies are less consistent when compared with cross-sectional population studies or with clinical experiments. A lower number of subjects or a good physical condition at the start of some intervention studies may explain a part of this inconsistency. Nevertheless, two longitudinal studies in athletes show that regular training induces a reduction in the CRP level⁽Reference Fallon, Fallon and Boston^28, Reference Mattusch, Dufaux and Heine²⁹⁾.

Physical activity-based lifestyle change appears to be the most variable component of energy expenditure and therefore has been the target of behavioural interventions to modify body weight. However, combined dietary and exercise interventions do not provide consistent evidence that exercise per se and not weight loss is more important for reducing inflammatory factors, and it is beyond this summary and can be reviewed elsewhere⁽Reference Nicklas, You and Pahor³⁰⁾.

Conflicting findings exist in clinical trials that have involved exercise only. Several training interventions have not produced changes in the basal IL-6 or CRP⁽Reference Hammett, Prapavessis and Baldi^31–Reference Marcell, McAuley and Traustadottir³⁴⁾, while significant reductions in inflammatory markers have been observed following training without changes in BMI or body fat in elderly participants⁽Reference Kohut, McCann and Russell^35, Reference Stewart, Flynn and Campbell³⁶⁾. The biggest trial with exercise training on inflammation was performed in 652 sedentary healthy, young and middle-aged, white and black women and men in the HERITAGE Family Study after a 20-week training intervention⁽Reference Lakka, Lakka and Rankinen³⁷⁾. There was no control group to compare with, and every subject served as his/her own control. A non-significant reduction was consistent across all population groups and varied between 1·2 and 2·2 mg/l. Considering that the variation over time in CRP in healthy individuals with stable lifestyles is small⁽Reference Pearson, Mensah and Alexander⁸⁾, the reduction, although non-significant, could nevertheless reflect the true effect of exercise training. Further stratification according to basal CRP levels showed a reduction by about 1·3 mg/l in subjects with initial CRP levels above 3·0 mg/l. This observation is potentially important from a public health and clinical point of view by decreasing the risk of CVD in individuals with high CRP. Thus, baseline levels may be an important factor.

Elderly people and disease states

Elderly people have higher basal levels of inflammation independent of disease status, and a considerable number of studies have been carried out in this population to assess the associations between physical activity and inflammatory markers⁽Reference Elosua, Bartali and Ordovas^38–Reference Jankord and Jemiolo⁴³⁾. Rather consistent inverse BMI independent associations are found and the associations are suggested to be dose-dependent; the more physically active the person, the lower the inflammatory markers⁽Reference Fischer, Berntsen and Perstrup^24, Reference Colbert, Visser and Simonsick⁴⁴⁾. Also, subjects over 80 years show consistent inverse associations between inflammation and physical activity⁽Reference Bruunsgaard, Ladelund and Pedersen⁴⁵⁾. A mean score of functional fitness was associated with IL-6, and IL-1RA (but not CRP, TNFα, IL-10 or IL-1β) in a prospective population-based study of 1020 participants aged 65 years and above⁽Reference Elosua, Bartali and Ordovas^38, Reference Cesari, Penninx and Pahor⁴⁶⁾. Muscle strength was also evaluated in this study and low hand-grip strength was associated with high levels of CRP (P<0·001) and IL-6 (P<0·001)⁽Reference Cesari, Penninx and Pahor⁴⁶⁾. A few more studies have shown a negative association of CRP, IL-6 and TNFα with muscle strength⁽Reference Taaffe, Harris and Ferrucci^41, Reference Visser, Pahor and Taaffe⁴⁷⁾.

Exercise intervention in elderly people or patients with CVD shows more consistent results of an anti-inflammatory effect. After a 6-month individualised, supervised exercise programme for 43 subjects at a high risk of IHD, a trend towards reduced CRP levels (35%) was observed. The subjects exercised for a mean of 2·5 (range, 0·3–7·4) h per week⁽Reference Smith, Dykes and Douglas⁴⁸⁾. Another study has reported a decrease of basal plasma IL-6 after aerobic training in patients with coronary artery disease⁽Reference Goldhammer, Tanchilevitch and Maor⁴⁹⁾. A randomised trial of 39 patients with intermittent claudication demonstrated that both serum CRP and amyloid-A levels were significantly reduced after 3 and 6 months of supervised exercise compared with controls⁽Reference Tisi, Hulse and Chulakadabba⁵⁰⁾. In a relatively large intervention study of exercise training on cardiac rehabilitation patients, the median CRP concentrations were significantly reduced by 41% (mean change from 5·9 (sd 7·7) mg/l to 3·8 (sd 5·8) mg/l; median change from 3·4 to 2·0 mg/l) in 235 patients with coronary artery disease, while CRP concentration did not change in 42 subjects who did not exercise⁽Reference Milani, Lavie and Mehra⁵¹⁾. Again, the exercise training seemed to be more effective in those with the highest CRP concentration, independent of changes in body weight or percentage of body fat⁽Reference Milani, Lavie and Mehra⁵¹⁾ indicating that baseline levels of low-grade inflammation may be an important factor.

In disease states such as symptomatic CVD or in patients with the metabolic syndrome, as well as in elderly people, levels of inflammatory markers are generally higher than in healthy young adults. Evidence points out that higher basal low-grade inflammation may be a factor in determining the relative contribution of fitness. Studies in patients with diabetes⁽Reference McGavock, Mandic and Vonder Muhll⁵²⁾ and metabolic syndrome⁽Reference Aronson, Sheikh-Ahmad and Avizohar^53, Reference Aronson, Sella and Sheikh-Ahmad⁵⁴⁾ have consistently demonstrated inverse associations between fitness and inflammation independent of fatness. In one study, the independent associations of fitness were in fact more prominent among metabolic syndrome patients compared with healthy participants⁽Reference Aronson, Sheikh-Ahmad and Avizohar^53, Reference Aronson, Sella and Sheikh-Ahmad⁵⁴⁾.

Middle-aged, younger adults and children

Several studies of large population cohorts, such as the British Regional Heart Study⁽Reference Wannamethee, Lowe and Whincup⁴⁰⁾, the ATTICA study⁽Reference Panagiotakos, Pitsavos and Chrysohoou⁵⁵⁾, the Third National Health and Nutrition Examination Survey⁽Reference Abramson and Vaccarino^56, Reference King, Carek and Mainous⁵⁷⁾, the men's Health Professionals Follow-up Study⁽Reference Pischon, Hankinson and Hotamisligil⁵⁸⁾, the Nurses' Health Study II⁽Reference Pischon, Hankinson and Hotamisligil⁵⁸⁾ and the Women's Health Study⁽Reference Mora, Lee and Buring⁵⁹⁾, provide evidence for an inverse, independent dose–response relationship between plasma CRP concentration and level of physical activity in both men and women, but the consistency is less than in elderly subjects, or in disease states.

On the contrary, the associations found between self-reported physical activity, and soluble receptor of TNF-R1 and TNF-R2, serum IL-6 and CRP in a study including healthy men from The Men's Health Professionals Follow-up Study and healthy women from the Nurses' Health Study II⁽Reference Pischon, Hankinson and Hotamisligil⁵⁸⁾ were no longer significant when adjusting for BMI and leptin, suggesting that inflammation does not directly account for the beneficial effects of physical activity. The effects in healthy men and women of BMI, CRP and physical activity were measured longitudinally over 1 year and retrospectively for physical activity the previous year, concluding that BMI, but not previous year or current physical activity, predicts CRP⁽Reference Rawson, Freedson and Osganian⁶⁰⁾. A univariate analysis of CRP levels in 2120 Finns showed that CRP was associated with obesity indices and physical activity among both sexes⁽Reference Raitakari, Mansikkaniemi and Marniemi⁶¹⁾. In multivariate correlates, however, the determinants of CRP levels include obesity and smoking in men and obesity, oral contraceptives use and physical activity in women. The study showed that about one in three healthy women who used oral contraceptives had CRP concentration exceeding 3 mg/l, which should be taken into account when studying younger females. In a longitudinal study⁽Reference Rawson, Freedson and Osganian⁶⁰⁾ of healthy men and women, BMI, but not current- or previous-year physical activity, was significantly related to CRP. Similarly, a cross-sectional study⁽Reference Verdaet, Dendale and De Bacquer⁶²⁾ in men found no relationship between leisure time, physical activity and CRP, fibrinogen and serum amyloid A, after correction for BMI and current smoking status.

Cross-sectional studies in men from the Aerobics Center Longitudinal Study have demonstrated that cardiorespiratory fitness levels are inversely associated with CRP values and also the prevalence of elevated CRP values⁽Reference Church, Barlow and Earnest⁶³⁾. Analyses with fibrinogen and leucocyte count showed similar results⁽Reference Church, Finley and Earnest⁶⁴⁾. The competing effect of weight and fitness (assessed by submaximal graded exercise treadmill testing) on cardiorespiratory fitness levels was studied in the NHANES (1999–2002) which included 2112 US adults without previously diagnosed CVD⁽Reference Diaz, Player and Mainous⁶⁵⁾. Both fitness and BMI were independently associated with increased fasting insulin and CRP. However, when patients with low, moderate and high fitness were further stratified as normal, overweight, or obese, weight remained significantly associated with CRP, but fitness did not.

Disease-free young population studies have assessed the interaction between inflammatory markers (CRP, IL-6 and TNFα), physical activity or cardiorespiratory fitness and fatness⁽Reference Cook, Mendall and Whincup^66–Reference Ruiz, Ortega and Warnberg⁷⁴⁾. Organised leisure time exercise (assessed by questionnaire) in children has shown negative correlations with serum IL-6 concentrations, independent of adiposity and fat localisation⁽Reference Platat, Wagner and Klumpp⁶⁸⁾, and in 10-year-old children, a borderline significant negative association was observed between CRP and self-reported physical activity, independent of ponderal index⁽Reference Cook, Mendall and Whincup⁶⁶⁾. US children and young adults (aged 6 to 24 years) from the Columbia University BioMarkers Study showed an inverse correlation between cardiovascular fitness level and CRP, but only in boys, which remained after adjustment of confounders including BMI⁽Reference Isasi, Deckelbaum and Tracy⁶⁹⁾. Only one study has used accelerometry (an objective measure of total physical activity compared with leisure time physical activity or exercise) instead of questionnaires as well as cardiovascular fitness⁽Reference Ruiz, Ortega and Warnberg⁷⁴⁾. In this study of 9-year-old Swedish children, total physical activity was unrelated to CRP, fibrinogen, C3 or C4, but exercise was. Nevertheless, once body fat was entered in the regression models, no associations with cardiovascular fitness or physical activity and either of the inflammatory markers measured were observed⁽Reference Ruiz, Ortega and Warnberg⁷⁴⁾. Similarly, no associations were found between cardiorespiratory fitness or self-reported physical activity and CRP in 12-year-old healthy Welsh children⁽Reference Thomas, Baker and Graham⁷⁵⁾.

CRP, C3 and ceruloplasmin (but not C4) were negatively associated with muscle strength after controlling for sex, age, pubertal status, weight, height, socioeconomic status and cardiorespiratory fitness, but did not remain when adjusting body fat. Nevertheless, when stratifying according to overweight status, CRP (but not C3, C4 or ceruloplasmin) was associated with muscle strength in overweight adolescents (but not normal weights) after controlling for potential confounders, including body fat and fat-free mass⁽Reference Ruiz, Ortega and Warnberg⁷⁶⁾.