Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss

Abstract

Background and aims

We investigated the effect of different exercise modalities on high sensitivity-C reactive protein (hs-CRP) and other inflammatory markers in patients with type 2 diabetes and the metabolic syndrome.

Methods and results

Eighty-two patients were randomized into 4 groups: sedentary control (A); receiving counseling to perform low-intensity physical activity (B); performing prescribed and supervised high-intensity aerobic (C) or aerobic + resistance (D) exercise (with the same caloric expenditure) for 12 months. Evaluation of leisure-time physical activity and assessment of physical fitness, cardiovascular risk factors and inflammatory biomarkers was performed at baseline and every 3 months. Volume of physical activity increased and HbA_1c decreased in Groups B–D. VO_2max, HOMA-IR index, HDL-cholesterol, waist circumference and albuminuria improved in Groups C and D, whereas strength and flexibility improved only in Group D. Levels of hs-CRP decreased in all three exercising groups, but the reduction was significant only in Groups C and D, and particularly in Group D. Changes in VO_2max and the exercise modalities were strong predictors of hs-CRP reduction, independent of body weight. Leptin, resistin and interleukin-6 decreased, whereas adiponectin increased in Groups C and D. Interleukin-1β, tumor necrosis factor-α and interferon-γ decreased, whereas anti-inflammatory interleukin-4 and 10 increased only in Group D.

Conclusion

Physical exercise in type 2 diabetic patients with the metabolic syndrome is associated with a significant reduction of hs-CRP and other inflammatory and insulin resistance biomarkers, independent of weight loss. Long-term high-intensity (preferably mixed) training, in addition to daytime physical activity, is required to obtain a significant anti-inflammatory effect.

Introduction

Cardiovascular disease (CVD) represents the main cause of morbidity and mortality in patients with type 2 diabetes. The 2–4-fold increase in CVD risk in diabetic vs. nondiabetic subjects [1] has been attributed primarily to traditional CVD risk factors, including chronic hyperglycemia as well as central obesity, dyslipidemia and hypertension and clustering with insulin resistance in the setting of the metabolic syndrome (MS) [2], the prevalence of which is >80% in type 2 diabetic patients.

Chronic low-grade inflammation has recently emerged as the common denominator linking type 2 diabetes, MS, insulin resistance, endothelial dysfunction and CVD [3]. In particular, a growing body of evidence has indicated a fundamental role for inflammation in mediating all stages of atherosclerosis [4] and several pro-inflammatory mediators have been associated with CVD, independent of traditional CVD risk factors.

In particular, the acute phase reactant C-reactive protein (CRP) was shown to be an independent predictor of CVD [5], [6] and of the outcome of acute coronary syndromes [7]. The most recent American Heart Association (AHA) consensus statement recommended the use of high sensitivity (hs)-CRP to further stratify patients at intermediate (10–20%) 10-year risk according to the Framingham score [8]. Recently, CRP, known to be produced primarily by the liver in response to inflammatory cytokines such as IL-6, was also shown to be generated in adipose tissue [9] and atherosclerotic plaques [10] and to actively participate in the pathogenesis of atherosclerosis by promoting endothelial cell activation, macrophage recruitment, and foam cell generation within the arterial wall [11]. Other pro-inflammatory cytokines have also been implicated in CVD, including interleukin (IL)-6 [5] and tumor necrosis factor (TNF)-α [6].

In the general population, several studies have shown that levels of physical activity and cardiorespiratory fitness are inversely correlated to CRP [12] and that regular exercise significantly reduces circulating levels of CRP and other inflammatory mediators [13], [14]. From a review of cross-sectional and longitudinal studies, chronic training produces an anti-inflammatory effect [15], though a number of studies, including a meta-analysis [16], have shown that exercise programs do not significantly influence inflammatory markers. Moreover, it is uncertain whether exercise has a direct effect on CRP levels independent of weight loss, which has consistently been shown to reduce CRP levels [17].

A previous large trial in subjects with impaired glucose tolerance (IGT) demonstrated that physical activity is effective in reducing CRP [18], whereas few studies have prospectively examined the effect of exercise on elevated levels of inflammatory biomarkers in diabetic subjects and found contrasting results in terms of efficacy and dependence on weight loss [19], [20]. Moreover, the type, dose and intensity of physical activity needed to obtain a significant anti-inflammatory effect in this high-risk population are largely unknown.

This study was aimed at investigating the effect of different exercise modalities on circulating levels of several inflammatory markers, including high sensitivity (hs)-CRP considered as the primary endpoint, in type 2 diabetic patients with the MS and no history of CVD.