Immediate and long-term effects of addition of exercise to a 16-week very low calorie diet on low-grade inflammation in obese, insulin-dependent type 2 diabetic patients
Highlights
► Low-grade inflammation in T2DM patients is higher than in healthy control subjects. ► Using a 16-week VLCD + exercise reverses low-grade inflammation in T2DM patients even after 18 weeks of follow-up. ► Beneficial effects of weight loss through caloric restriction on inflammation become apparent in the eucaloric state. ► Severe caloric restriction increases cytokine production by adipose tissue macrophages directly after the diet.
Introduction
Insulin resistant states such as obesity and type 2 diabetes mellitus (T2DM) are associated with chronic low-grade inflammation, as indicated by higher circulating levels of C-reactive protein (CRP), interleukin 6 (IL6) and tumor necrosis factor alpha (TNFα) Dandona and Aljada, 2002. These pro-inflammatory proteins and cytokines can intervene in intracellular signaling pathways involved in glucose uptake and insulin secretion (Hotamisligil, 1999, Zeyda and Stulnig, 2009). However, the temporal and causal relationship between insulin resistance and elevated markers of inflammation is as of yet unclear.
Both obesity and T2DM are independent risk factors for the development of premature atherosclerosis and ischemic heart disease (Dandona and Aljada, 2002, Zimmet et al., 2001). Patients with T2DM have a 2–4 times increased cardiovascular disease (CVD) risk compared to healthy controls (Stamler et al., 1993). This increased cardiovascular risk appears to be associated not only with traditional cardiovascular risk factors such as smoking, gender, hypertension and dyslipidemia but also with the abovementioned markers of inflammation (Plutzky, 2001, Willerson and Ridker, 2004).
Caloric restriction (CR), weight loss and exercise improve glucoregulation in patients with T2DM and ameliorate the classic CVD risk factors hypertension and dyslipidemia (Roberts and Barnard, 2005). CR and weight loss induce a decline in CRP levels, both in obese, non-diabetic subjects as well as in obese diabetic subjects (Selvin et al., 2007). In addition, weight loss and lifestyle interventions decrease plasma IL6 and TNFα levels in obese non-diabetic subjects (Herder et al., 2009, You et al., 2004, Ziccardi et al., 2002, Wegge et al., 2004). The effect of exercise on these two markers of inflammation is controversial (Oberbach et al., 2006, Zoppini et al., 2006). Moreover, the effects of a very low calorie diet (VLCD) on IL6, TNFα and CRP has only been studied after a 3-week intervention (Bastard et al., 2000) in obese patients with T2DM and no long-term follow-up data are available. Therefore, the aim of this study was to assess the effects of a 4-month VLCD (Modifast, 450 kcal/day) on classic cardiovascular risk factors and low-grade inflammation in obese, insulin-dependent T2DM patients. We also assessed whether adding exercise to the VLCD had additional beneficial effects on these outcomes. Patients were re-examined at 6 and 18 months after the start of the 4-month intervention, to evaluate the durability of the effects. In addition, the levels of these inflammatory markers were compared with those obtained in lean and obese healthy controls.
Section snippets
Patients
Twenty-seven (14 males, 13 females) obese, insulin-dependent T2DM patients (disease duration 9 ± 0.8 years, mean ± standard error of the mean (SEM)) were enrolled in the study between June 2006 and June 2007. Clinical characteristics are summarized in Table 1. Exclusion criteria were smoking, known history of CVD and/or other chronic or endocrine disease, weight change within three months prior to the study and silent myocardial ischemia (as measured by an incremental cyclo-ergometer cardiac stress
Compliance
The attendance rate of the VLCD + exercise group to the in-hospital (mainly aerobic) exercise sessions was 97%. The average amount of training at home on the cyclo-ergometer (mainly resistance training) was 5.25 times/week with a length on average of 35.7 min/training. For compliance with the diet, the amount of modifast sachets provided to the patients were 100% correct, according to the questionnaires 100% of the modifast sachets were used by the patients.
Effect on bodyweight and glucoregulation
The VLCD + exercise and VLCD-only groups
Discussion
This study shows that a 4-month VLCD or a 4-month VLCD + exercise have equal effects on improving glucoregulation and dyslipidemia while there was a slightly greater reduction in bodyweight in the VLCD + exercise group. Remarkably, the substantial reduction in bodyweight and improvement in glucoregulation did not lead to an immediate lowering of markers of low-grade inflammation with the exception of a decrease in hsCRP in the VLCD + exercise group. Surprisingly, at 6 months all measured cytokines and
Conclusion
A 4-month VLCD with or without exercise does not directly decrease pro-inflammatory plasma cytokine levels despite a large decrease in body weight and waist circumference and an improvement in dyslipidemia and glucoregulation. The beneficial effects on chronic inflammation became apparent only when patients were on a eucaloric regular diet and were sustained up till 18 months after the start of the diet despite bodyweight regain and deterioration of glucoregulation. Our findings are compatible
Funding
This study was funded by an unrestricted grant of Roba Metals BV, IJsselstein, The Netherlands. In addition, Nutrition&Santé, Antwerp, Belgium, freely supplied the Modifast.
Conflict of Interest
The authors declare that there is no conflict of interest.
Acknowledgements
We are greatly indebted to E.J.M. Ladan-Eygenraam, Leiden University Medical Center, Leiden, The Netherlands, for technical assistance during the study.
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