Roux-en-Y gastric bypass (RYGB) has become a prominent therapeutic option for long-term treatment of morbid obesity and type 2 diabetes mellitus (T2D). Cross talk and pathogenetic consequences of RYGB-induced profound effects on metabolism and gut microbiome are poorly understood. The aim of the present study therefore was to characterize intra-individual changes of gut microbial composition before and 3 months after RYGB by metagenomic sequencing in morbidly obese patients (body mass index (BMI)440 kg m À 2 ) with T2D. Subsequently, metagenomic data were correlated with clinical indices. Based on gene relative abundance profile, 1061 species, 729 genera, 44 phyla and 5127 KO (KEGG Orthology) were identified. Despite high diversity, bacteria could mostly be assigned to seven bacterial divisions. The overall metagenomic RYGB-induced shift was characterized by a reduction of Firmicutes and Bacteroidetes and an increase of Proteobacteria. Twenty-two microbial species and 11 genera were significantly altered by RYGB. Using principal component analysis, highly correlated species were assembled into two common components. Component 1 consisted of species that were mainly associated with BMI and C-reactive protein. This component was characterized by increased numbers of Proteobacterium Enterobacter cancerogenus and decreased Firmicutes Faecalibacterium prausnitzii and Coprococcus comes. Functional analysis of carbohydrate metabolism by KO revealed significant effects in 13 KOs assigned to phosphotransferase system. Spearmen's Rank correlation indicated an association of 10 species with plasma total-or low-density lipoprotein cholesterol, and 5 species with triglycerides. F. prausnitzii was directly correlated to fasting blood glucose. This is the first clinical demonstration of a profound and specific intra-individual modification of gut microbial composition by full metagenomic sequencing. A clear correlation exists of microbiome composition and gene function with an improvement in metabolic and inflammatory parameters. This will allow to develop new diagnostic and therapeutic strategies based on metagenomic sequencing of the human gut microbiome.

The obstructive sleep apnea syndrome is typically associated with conditions known to increase insulin resistance as hypertension, obesity, and diabetes. We investigated whether obstructive sleep apnea itself is an independent risk factor for increased insulin resistance and whether continuous positive airway pressure (CPAP) treatment improves insulin sensitivity. Forty patients (apnea-hypopnea index > 20) were treated with CPAP. Before, 2 days after, and after 3 months of effective CPAP treatment, hyperinsulinemic euglycemic clamp studies were performed. Insulin sensitivity significantly increased after 2 days (5.75 +/- 4.20 baseline versus 6.79 +/- 4.91 micromol/kg.min; p = 0.003) and remained stable after 3 months of treatment. The improvement in insulin sensitivity after 2 days was much greater in patients with a body mass index less than 30 kg/m2 than in more obese patients. The improved insulin sensitivity after 2 nights of treatment may reflect a decreasing sympathetic activity, indicating that sleep apnea is an independent risk factor for increased insulin resistance. The effect of CPAP on insulin sensitivity is smaller in obese patients than in nonobese patients, suggesting that in obese individuals insulin sensitivity is mainly determined by obesity and, to a smaller extent, by sleep apnea.

Chemerin is a chemoattractant adipokine that regulates adipogenesis and may induce insulin resistance. Chemerin serum concentrations are elevated in obese, insulin-resistant, and inflammatory states in vivo. Here we investigate the role of omental (OM) and subcutaneous (SC) adipose tissue chemerin and CMKLR1 messenger RNA (mRNA) expression in human obesity. In addition, we test the hypothesis that changes in chemerin serum concentrations are primarily associated with reduced body fat mass in the context of 3 weight loss intervention studies. Chemerin serum concentration was measured in 740 individuals in a cross-sectional (n = 629) study including a subgroup (n = 161) for which OM and SC chemerin mRNA expression has been analyzed as well as in 3 interventions including 12 weeks of exercise (n = 60), 6 months of calorie-restricted diet (n = 19) studies, and 12 months after bariatric surgery (n = 32). Chemerin mRNA is significantly higher expressed in adipose tissue of patients with type 2 diabetes mellitus and correlates with circulating chemerin, body mass index (BMI), percentage body fat, C-reactive protein, homeostasis model assessment of insulin resistance, and glucose infusion rate in euglycemic-hyperinsulinemic clamps. CMKLR1 mRNA expression was not significantly different between the 2 fat depots. Obesity surgery-induced weight loss causes a significant reduction on both OM and SC chemerin expression. All interventions led to significantly reduced chemerin serum concentrations. Decreased chemerin serum concentrations significantly correlate with improved glucose infusion rate and reduced C-reactive protein levels independently of changes in BMI. Insulin resistance and inflammation are BMI-independent predictors of elevated chemerin serum concentrations. Reduced chemerin expression and serum concentration may contribute to improved insulin sensitivity and subclinical inflammation beyond significant weight loss.

In autoimmune polyglandular syndromes (APS), several organ-specific autoimmune diseases are clustered. Although APS type I is caused by loss of central tolerance, the etiology of APS type II (APS-II) is currently unknown. However, in several murine models, depletion of CD4+ CD25+ regulatory T cells (Tregs) causes a syndrome resembling human APS-II with multiple endocrinopathies. Therefore, we hypothesized that loss of active suppression in the periphery could be a hallmark of this syndrome. Tregs from peripheral blood of APS-II, control patients with single autoimmune endocrinopathies, and normal healthy donors showed no differences in quantity (except for patients with isolated autoimmune diseases), in functionally important surface markers, or in apoptosis induced by growth factor withdrawal. Strikingly, APS-II Tregs were defective in their suppressive capacity. The defect was persistent and not due to responder cell resistance. These data provide novel insights into the pathogenesis of APS-II and possibly human autoimmunity in general.

Serum leptin and ghrelin levels were investigated in patients with obstructive sleep apnoea (OSA) syndrome before and during continuous positive airways pressure (CPAP) treatment and compared with body mass index (BMI)-matched controls without OSA.Male patients (n=30) with OSA (apnoea/hypopnoea index=58 ¡ 16, BMI=32.6 ¡ 5.3 kg?m -2 ) underwent CPAP treatment. Fasting leptin and ghrelin were measured at baseline and 2 days, and in the case of leptin 2 months after initiation of treatment.Baseline plasma ghrelin levels were significantly higher in OSA patients than in controls. After 2 days of CPAP treatment, plasma ghrelin decreased in almost all OSA patients (n=9) to levels that were only slightly higher than those of controls (n=9). Leptin levels did not change significantly from baseline after 2 days of CPAP treatment, but were higher than in the control group. After 8 weeks, leptin levels decreased significantly, although the BMI of the patients showed no change. The decrease in leptin levels was more pronounced in patients with a BMI v30 kg?m -2 . These data indicate that the elevated leptin and ghrelin levels are not determined by obesity alone, since they rapidly decreased during continuous positive airways pressure therapy. Eur Respir J 2003; 22: 251-257 Obstructive sleep apnoea (OSA) is a common disorder affecting 2-4% of the adult population [1]. OSA is strongly associated with obesity. In a recent study involving 773 patients with OSA, only 6.5% had a normal body mass index (BMI), while 75.2% were obese (BMIo30 kg?m -2 ) [2]. Patients with OSA appear to be more likely to put on weight than equally obese subjects without OSA [3]. The mechanisms underlying this phenomenon remain obscure. Recently, a number of authors have speculated that changes in serum leptin levels or leptin-receptor insensitivity may be involved in the pathogenesis of progressive obesity in patients with OSA [4]. Leptin has been found to reduce appetite and simultaneously to increase respiratory drive in an animal model [5,6]. In humans, the situation may be expected to be more complicated. In recent studies, fasting leptin levels in patients with OSA decreased after initiation of continuous positive airways pressure (CPAP) treatment [7,8]. However, those leptin measurements were performed on awake individuals in the morning, when the respiratory situation was normalised, so that any linkage between leptin levels and respiratory effects is difficult in this setting. Furthermore, leptin levels are influenced by a multitude of factors, such as sex, body weight [9,10], the presence of hypertension, or specific medications impacting on leptin levels. Diurnal and ultradian variations in serum leptin levels are further factors complicating profound insights concerning significant respiratory effects [11][12][13].However, the finding that a hormone like leptin is able to cover a variety of biological functions, beyond its well-investigated role for the regulation of body weight and energy expenditure, also prompted the present aut...