Original studyEffects of Tai Chi Chuan on Insulin and Cytokine Levels in a Randomized Controlled Pilot Study on Breast Cancer Survivors
Introduction
After the diagnosis of breast cancer, many women gain weight. Several studies have shown that the mean weight gain during the first year after diagnosis is 2.5 to 6.2 kg (range, 1.0->11 kg).1, 2, 3, 4 The lowest gains are observed in those receiving local radiation therapy or adjuvant hormonal therapies (eg, tamoxifen) alone. Highest gains appear in patients receiving adjuvant chemotherapy alone or combined with hormonal therapies. In all cases, weight gain is persistent and still increasing 5 years after treatment.1, 2, 3, 4 These levels of weight gain are greater than the weight gain experienced during normal aging and primarily represent an increase in fat mass and a loss of lean mass (fat-free mass), often referred to as sarcopenic obesity.5 Although advances in oncology have dramatically increased survival for women with early-stage breast cancer, weight gain after diagnosis appears to negatively affect quality of life and recurrence rate.6 Additionally, weight gain after diagnosis is associated with increases in all-cause mortality, breast cancer–specific mortality, and cardiovascular-related mortality; each 5-kg increase in weight after diagnosis increases mortality by 10% to 12%.7
Insulin and cytokine pathways may be key mediators of weight gain, recurrence, and survival for breast cancer survivors. Elevated fasting levels of insulin are associated with a 2-fold increased risk of breast cancer recurrence and a 3-fold decrease in survival.8 Indeed insulin-related pathways involving insulin and insulin-like growth factors (IGFs) are associated with increased cell growth and proliferation,9 providing an explanation for the link between elevated insulin levels and tumor growth. Multiple proinflammatory signaling pathways involving cytokines have been implicated in cancer development, progression, and recurrence. These cytokines can alter proliferation, lead to malignant transformation, and promote metastasis.10
Exercise interventions for breast cancer survivors have positive effects on survival,11, 12, 13 quality of life,14 and weight,15 and preliminary evidence suggests that exercise may also reduce the risk of cancer recurrence. Accumulating evidence suggests that exercise may elicit these beneficial effects by minimizing levels of circulating insulin and inflammatory molecules, thus providing positive effects on weight, recurrence, and survival. Regular exercise (both aerobic and strength training) can lower circulating insulin levels, reduce insulin resistance, and reduce weight gain.16, 17 Several recent randomized, controlled trials using moderately intense exercise interventions have investigated the effects of exercise on possible insulin-related predictors of recurrence and prognosis in breast cancer survivors.15, 18, 19, 20, 21, 22 For example, Irwin et al found statistically significant decreases in fasting insulin, IGF-1, and IGF binding protein (IGFBP)-3 in postmenopausal women who followed a moderately intense walking-based intervention of 5 days/week for 6 months when compared with nonexercisers.21 The 12-month intervention study by McTiernan et al in postmenopausal breast cancer survivors showed that both exercising and stretching produced small reductions in IGF-1 and IGFBP-3; however, there were no significant differences in mean IGF-1 and IGFBP3 levels between the group that exercised and the group that stretched.20 Reductions in insulin are also associated with reductions in hip and waist circumference as shown in a mixed aerobic and strength training study by Ligibel et al, suggesting that decreased insulin levels may be associated with reductions in abdominal adiposity, which is strongly predictive of cardiovascular risk and risk of diabetes in overweight survivors.15
Numerous studies in healthy individuals have revealed that exercise can reduce chronic inflammation by inducing anti-inflammatory effects.23 On a molecular level, during exercise IL-6 is rapidly produced by contracting skeletal muscle fibers24 and acts as a myokine with anti-inflammatory effects to inhibit proinflammatory cytokine expression.25 Exercise can also reduce adiposity by IL-6–mediated lipolysis and by diminishing levels of circulating and adipose-derived cytokines (eg, tumor necrosis factor [TNF]-α, IL-1β) in adults.26, 27, 28
These studies indicate that conventional exercise programs may represent a beneficial intervention for reducing fat mass, improving lean mass, and altering insulin, insulin-related molecules, and inflammation to reduce recurrence risk in breast cancer survivors. However, whether integrative medicine approaches with a physical activity component, such as tai chi chuan (TCC), may have the same beneficial effects on cancer patients and survivors remains unknown.
TCC is a traditional Chinese martial art that combines slow, fluid, weight-bearing physical movements with deep, controlled breathing exercises and relaxation techniques. Many cancer patients and survivors are trying integrative medicine approaches, such as TCC, as a way of reducing side effects of treatment such as weight gain.29, 30 TCC, which may result in an energy expenditure equivalent to that of brisk walking, improves aerobic capacity, flexibility, strength, mood, and quality of life in breast cancer survivors.31, 32, 33 Whether TCC, which has both a meditative and a physical activity component, can produce similar physiologic effects as traditional exercise programs in breast cancer patients and survivors is unknown. In a previous randomized, controlled trial conducted by our research group, breast cancer survivors used a 15-move Yang-style TCC as a form of integrative medicine to control side effects from cancer treatments. We found that TCC significantly improved functional capacity, self-esteem, bone health, and quality of life32, 33, 34, 35 and led to reduced fat mass when compared with the nonexercising group, although the difference in fat mass was not statistically significant.34
Little is known about the mechanisms linking exercise and weight gain in breast cancer survivors. Moreover we do not know whether TCC, an integrative medicine intervention with a meditative and a physical activity component, elicits physiologic responses in breast cancer survivors similar to those of traditional exercise programs that have already investigated. Because hormone (eg, insulin) and exercise-mediated anti-inflammatory mechanisms (eg, IL-6) are thought to be the most plausible explanation for the protective effects of exercise on weight gain and recurrence, we investigated the physiologic effects of TCC on insulin and cytokine levels. Additionally, interventions with meditative components are thought to have anti-inflammatory effects.36 Specifically the current post hoc pilot study was designed to identify molecules that may be altered by TCC and to identify novel correlative relationships between insulin and insulin-related molecules, cytokines, and fat and fat-free mass. Based on the effects of traditional exercise in breast cancer survivors and the anti-inflammatory properties of exercise, we developed a model to explain plausible effects of physical activity interventions, such as TCC, on insulin, insulin-related proteins, and cytokines in breast cancer survivors (Figure 1). We hypothesized that TCC, like more traditional exercise interventions, would reduce insulin levels. We also hypothesized that TCC would alter cytokine levels that may be linked with the reduction in fat mass and increase in fat-free mass induced by TCC.
Section snippets
Participants
The detailed methods of the original study assessing the effects of TCC on health-related quality of life, self-esteem, and functional capacity in breast cancer survivors have been previously described by Mustian et al.32, 33, 34 Approval from our institutional review board was obtained before acquiring written consent and enrolling participants. Potential participants were required to meet the following criteria for inclusion in this study: (1) female sex, (2) primary diagnosis of breast
Demographics and Medical Information
Demographic and clinical information (ie, participant's age, weight, stage of disease, surgery type, and treatment regimens) were obtained from the patient or her medical record at the time of entry into the trial. In addition, body mass index (BMI, kg/m2) was calculated for each participant.
Measurements of Insulin, Insulin-Related Molecules and Cytokines
Fasting-state blood samples were collected at both pre- and postintervention time points (N = 19). The blood samples were allowed to clot for ≥ 30 minutes and then were centrifuged and the serum was
Results
Thirty-one breast cancer survivors agreed to participate; 21 participants successfully completed the trial. Reasons for withdrawal were previously reported in our original study and included not liking their treatment group, work, family, and too many side effects after treatment. Additionally, those in the TCC group had a 72% exercise attendance rate and those in the PST group had a 67% attendance rate. Compliance at each attended session was 100% in both groups.32, 34 Nineteen participants
Discussion
The goal of this study was to identify differential changes in biologic marker profiles for insulin and cytokines in subjects who were randomized to an integrative medicine TCC intervention compared with a PST control and to identify novel correlative relationships between insulin and insulin-related molecules, cytokines, and fat and fat-free mass. Of the insulin and insulin-related proteins and cytokines assessed for group differences at postintervention (Table 2), only insulin showed a change
Conclusion
The results of this completed pilot study provide preliminary data suggesting that the integrative medicine intervention TCC can lower insulin levels in breast cancer survivors compared with a nonactive control population. We also found significant correlations between body composition and cytokines. Although these significant findings are encouraging, given the small sample size these analyses should be repeated in a larger study with higher power to be confirmatory.
These results are very
Disclosures
The authors have nothing to disclose.
Acknowledgments
We would like to thank all study participants. Funding support was provided by NCI K07CA120025 (KMM), Sally Schindel Cone Foundation (KMM), UNCG Center for Women's Health and Wellness Seed Grant (PGD), UNCG Center for the Study of Social Issues (JAK), and NCI R25CA10618 (GRM).
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