Regular exercise offers protection against all-cause mortality, primarily by protection against cardiovascular disease and Type 2 diabetes mellitus. The latter disorders have been associated with chronic low-grade systemic inflammation reflected by a two- to threefold elevated level of several cytokines. Adipose tissue contributes to the production of TNF-alpha, which is reflected by elevated levels of soluble TNF-alpha receptors, IL-6, IL-1 receptor antagonist, and C-reactive protein. We suggest that TNF-alpha rather than IL-6 is the driver behind insulin resistance and dyslipidemia and that IL-6 is a marker of the metabolic syndrome, rather than a cause. During exercise, IL-6 is produced by muscle fibers via a TNF-independent pathway. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra and IL-10 and inhibits the production of the proinflammatory cytokine TNF-alpha. In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. We suggest that regular exercise induces suppression of TNF-alpha and thereby offers protection against TNF-alpha-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine that is produced and released by contracting skeletal muscle fibers, exerting its effects in other organs of the body. Here we suggest that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases.

Aims/hypothesis Decreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer's disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore explored whether BDNF plays a role in human glucose metabolism. Subjects and methods We included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic and a hyperinsulinaemic-euglycaemic clamp.Results Plasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism and diabetes or obesity. In Study 2 an output of BDNF from the human brain was detected at basal conditions. This output was inhibited when blood glucose levels were elevated. In contrast, when plasma insulin was increased while maintaining normal blood glucose, the cerebral output of BDNF was not inhibited, indicating that high levels of glucose, but not insulin, inhibit the output of BDNF from the human brain. Conclusions/interpretation Low levels of BDNF accompany impaired glucose metabolism. Decreased BDNF may be a pathogenetic factor involved not only in dementia and depression, but also in type 2 diabetes, potentially explaining the clustering of these conditions in epidemiological studies.

Our results indicate that IL-15 may be a regulator of trunk fat mass.

Smoking causes multiple organ dysfunction. The effect of smoking on skeletal muscle protein metabolism is unknown. We hypothesized that the rate of skeletal muscle protein synthesis is depressed in smokers compared with non-smokers. We studied eight smokers (Ն20 cigarettes/day for Ն20 years) and eight non-smokers matched for sex (4 men and 4 women per group), age (65 Ϯ 3 and 63 Ϯ 3 yr, respectively; means Ϯ SEM) and body mass index (25.9 Ϯ 0.9 and 25.1 Ϯ 1.2 kg/m 2 , respectively). Each subject underwent an intravenous infusion of stable isotope-labeled leucine in conjunction with blood and muscle tissue sampling to measure the mixed muscle protein fractional synthesis rate (FSR) and whole body leucine rate of appearance (Ra) in plasma (an index of whole body proteolysis), the expression of genes involved in the regulation of muscle mass (myostatin, a muscle growth inhibitor, and MAFBx and MuRF-1, which encode E3 ubiquitin ligases in the proteasome proteolytic pathway) and that for the inflammatory cytokine TNF-␣ in muscle, and the concentration of inflammatory markers in plasma (C-reactive protein, TNF-␣, interleukin-6) which are associated with muscle wasting in other conditions. There were no differences between nonsmokers and smokers in plasma leucine concentration, leucine rate of appearance, and plasma concentrations of inflammatory markers, or TNF-␣ mRNA in muscle, but muscle protein FSR was much less (0.037 Ϯ 0.005 vs. 0.059 Ϯ 0.005%/h, respectively, P ϭ 0.004), and myostatin and MAFBx (but not MuRF-1) expression were much greater (by ϳ33 and 45%, respectivley, P Ͻ 0.05) in the muscle of smokers than of nonsmokers. We conclude that smoking impairs the muscle protein synthesis process and increases the expression of genes associated with impaired muscle maintenance; smoking therefore likely increases the risk of sarcopenia. muscle growth; stable-isotope-labeled tracers; sarcopenia; protein turnover ALTHOUGH THE NUMBER OF SMOKERS has declined steadily over the past 50 years, ϳ20% of US adults still smoke regularly (3, 6). One-third of these are "heavy smokers," consuming 20 or more cigarettes daily (6). The prevalence of habitual tobacco consumption is even greater in Great Britain (6) and throughout Europe (17), as well as in the developing world (17).Tobacco use poses a major public health problem because smoking is a major risk factor for cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer (43, 57) and is associated with increased risk for other debilitating conditions, such as cataract, pneumonia, and cancers of the cervix, kidney, pancreas, and stomach (1). There is also some evidence that smoking may impair physical function (33) and probably increases the risk for sarcopenia (i.e., age-related muscle wasting) (2, 45). This suggests that smoking has direct adverse effects on muscle protein metabolism, which may lead to loss of independence and disability with advanced age. Nevertheless, the effect of smoking on muscle protein metabolism is not known.A number of conditions i...

Aims/hypothesis Clear evidence exists that TNF-α inhibits insulin signalling and thereby glucose uptake in myocytes and adipocytes. However, conflicting results exist with regard to the role of TNF-α in type 2 diabetes. Methods We obtained blood and biopsy samples from skeletal muscle and subcutaneous adipose tissue in patients with type 2 diabetes (n=96) and healthy controls matched for age, sex and BMI (n=103). Results Patients with type 2 diabetes had higher plasma levels of fasting insulin (p<0.0001) and glucose (p<0.0001) compared with controls, but there was no difference between groups with regard to fat mass. Plasma levels of TNF-α (p=0.0009) and soluble TNF receptor 2 (sTNFR2; p = 0.002) were elevated in diabetic patients. Insulin sensitivity was correlated with quartiles of plasma TNF-α after adjustment for age, sex, obesity, WHR, neutrophils,

BackgroundThe two inflammatory molecules, S100A8 and S100A9, form a heterodimer, calprotectin. Plasma calprotectin levels are elevated in various inflammatory disorders. We hypothesized that plasma calprotectin levels would be increased in subjects with low-grade systemic inflammation i.e. either obese subjects or subjects with type 2 diabetes.Methodology/Principal FindingsPlasma calprotectin and skeletal muscle S100A8 mRNA levels were measured in a cohort consisting of 199 subjects divided into four groups depending on presence or absence of type 2 diabetes (T2D), and presence or absence of obesity. There was a significant interaction between obesity and T2D (p = 0.012). Plasma calprotectin was increased in obese relative to non-obese controls (p<0.0001), whereas it did not differ between obese and non-obese patients with T2D (p = 0.62). S100A8 mRNA levels in skeletal muscle were not influenced by obesity or T2D. Multivariate regression analysis (adjusting for age, sex, smoking and HOMA2-IR) showed plasma calprotectin to be strongly associated with BMI, even when further adjusted for fitness, CRP, TNF-α or neutrophil number.Conclusions/SignificancePlasma calprotectin is a marker of obesity in individuals without type 2 diabetes.

Our results suggest that the excess of RBP relative to retinol, assessed as the RBP-to-retinol ratio, is more indicative of T2DM than RBP itself. Hence, the previously reported insulin resistance in mice induced by overexpression or injection of RBP could be because of higher levels of RBP relative to retinol rather than higher total levels of RBP. Moreover, TNF-alpha may have a role in RBP-mediated adipose to muscle crosstalk.

The aim of this study was to test the hypothesis that systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) is accompanied by enhanced interleukin 18 (IL-18) expression in skeletal muscle, which may precede muscle weight loss. Twenty patients with moderate to severe COPD [12 women, 66 +/- 9.4 years of age and forced expiratory volume in 1 second (FEV(1)) of 32% +/- 12 % of predicted value] and 20 healthy age-, gender-, and body mass index (BMI)-matched controls (10 nonsymptomatic smokers and 10 nonsmokers) were included in the study. Plasma levels of IL-18 were elevated in COPD patients (n = 20) versus healthy controls (n = 20) (221.2 pg/ml [196.0-294.2 pg/pl] vs. 164.8 pg/ml [144.4-193.3 pg/pl], p = 0.05) [corrected] and IL-18 was expressed in skeletal muscle, with IL-18 mRNA levels being elevated in biopsies from COPD patients (n = 19) versus healthy controls (n = 18) (4.3 [2.6-5.9] vs. 2.4 [1.6-3.1], p = 0.05) [corrected]. Immunohistochemical evaluation revealed a strong expression of IL-18 in Type II muscle fibers from COPD patients. Plasma levels and skeletal muscle mRNA levels of tumor necrosis factor alpha (TNF-alpha) and IL-6 did not differ between the groups. Elevated skeletal muscle expression of IL-18 was found in COPD patients with normal body weight, indicating that IL-18 potentially may be involved in the pathogenesis of COPD-associated muscle wasting.