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Introduction Obesity and atrial fibrillation (AF) pose a significant burden on healthcare systems worldwide. Reduction of body weight has been documented to reduce the risk of AF. Little is known about the effect of different weight-reducing interventions including bariatric surgery in obese individuals on the risk of arrhythmia recurrence following catheter ablation (CA) for AF, and about the pathophysiological mechanisms linking these two conditions. Methods The Effect of complex weigHt-reducing interventiOns on rhythm control in oBese subjects wITh Atrial Fibrillation (HOBIT-AF) is a single-blinded, parallel-group randomised controlled trial with 18-month follow-up to assess the effect of complex weight-reducing interventions supported by the use of smart technologies and bariatric surgery on the arrhythmia burden in obese individuals following CA for AF. One hundred and sixty individuals (age 18–70 years, body mass index ≥ 30 kg/m2) will be randomised in a 1:1 fashion to undergo a structured weight reduction programme and sleeve gastrectomy (when indicated and preferred by the patient) aiming to achieve greater than 10% weight reduction from baseline (intervention group) or standard post-ablation medical care (control group). Two-week continuous ECG monitoring will be used 3 and 18 months after CA to assess the arrhythmia burden. Other investigations will include transthoracic echocardiography with quantification of epicardial adipose tissue, and markers of low-grade inflammation and circulating adipokines. Planned Outcomes The main objective is to assess the effect of complex weight-reducing interventions on the arrhythmia burden and quality of life. Subgroup analyses to identify patient subgroups preferentially benefiting from weight loss related to a decrease in arrhythmia burden will be performed. Exploratory objectives will include investigation of potential mechanisms linking weight reduction with amelioration of arrhythmia burden such as changes in markers of low-grade inflammation, circulating adipokines, cytokines, monocytes or reduction of epicardial adipose tissue volume. Trial Registration NCT04560387

Context Gestational diabetes mellitus (GDM) is accompanied by subclinical inflammation; however, little is known about local inflammation in adipose tissue and placenta. Objective To analyze systemic and local subclinical inflammation and adipose tissue lymphocyte content and phenotype in pregnant women with and without GDM. Design Observational study. Settings Academic hospital. Patients Twenty-one pregnant women with GDM (GDM group), 16 pregnant women without GDM (non-GDM group) and 15 nonpregnant control women (N group). Interventions Serum samples taken at 28 to 32 (visit 1 [V1]) and 36 to 38 (V2) gestational weeks and 6 to 12 months after delivery (V3) in the GDM and non-GDM group and before elective gynecological surgery in the N group. Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained during cesarean delivery or surgery. Main Outcome Measures Serum levels and adipose tissue expression of proinflammatory cytokines, adipose tissue lymphocyte content and phenotype (for a subset of GDM and non-GDM subjects). Results Accented proinflammatory state in GDM was documented by increased circulating tumor necrosis factor-α (TNF-α) levels. In both groups of pregnant females total lymphocytes were higher in VAT compared to SAT. In GDM subjects B cells and NKT cells were higher in SAT compared to VAT and T helper cells were increased relative to SAT of non-GDM group, while no intercompartmental adipose tissue differences were seen in non-GDM women. Conclusions Pregnant females had higher total lymphocyte count in VAT relative to SAT regardless of GDM. In addition to increased systemic subclinical inflammation, GDM was associated with significant differences in lymphocyte composition between subcutaneous and visceral adipose tissue depots.

Immune cells are an inseparable component of adipose tissue intimately involved in most of its functions. Physiologically, they regulate adipose tissue homeostasis, while in case of adipose tissue stress, immune cells are able to change their phenotype, enhance their count and subsequently contribute to the development and maintenance of local adipose tissue inflammation. Immune cells are an important source of inflammatory cytokines and other pro-inflammatory products that further influence not only surrounding tissues but via systemic circulation also the whole organism being thus one of the main factors responsible for the transition from simple obesity to associated metabolic and cardiovascular complications. The purpose of this review is to summarize current knowledge on different adipose tissue immune cell subsets and their role in the development of obesity, type 2 diabetes mellitus and cardiovascular diseases.

(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects. Nuclear magnetic resonance (NMR)-based metabolomics, quantitative PCR of relevant genes involved in lipid and glucose metabolism, or senescence, glucose and palmitic acid oxidation in isolated tissues and cell lines of adipocytes and hepatocytes were used. (3) Results: empagliflozin inhibited weight gain and decreased adipose tissue weight, fasting blood glucose, and triglycerides and increased HDL-cholesterol. It also improved insulin sensitivity in white fat. NMR spectroscopy identified higher plasma concentrations of ketone bodies, ketogenic amino acid leucine and decreased levels of pyruvate and alanine. In the liver, adipose tissue and kidney, empagliflozin up-regulated expression of genes involved in gluconeogenesis and down-regulated expression of genes involved in lipogenesis along with reduction of markers of inflammation, oxidative stress and cell senescence. (4) Conclusion: multiple positive effects of empagliflozin, including reduced cell senescence and oxidative stress, could contribute to its long-term cardio- and nephroprotective actions.

The insulin-like growth factor (IGF) is involved in the regulation of growth and metabolism. The aim of this study was to determine selected parameters of IGF system at systemic and local levels [subcutaneous (SAT) and visceral adipose tissue (VAT)] to assess its possible role in gestational diabetes mellitus (GDM). 37 pregnant women (21 with GDM and 16 without GDM) and 15 age-matched non-pregnant females were included in the study. Blood samples were taken in 28-32 and 36-38 weeks of gestation and 6-12 months after delivery. SAT and VAT samples were obtained during delivery or surgery. Compared with non-pregnant women, serum IGF-1 and IGFBP-3 were increased in both groups of pregnant women. IGF-2 was elevated only in GDM women from 36 weeks of gestation culminating 6 months after delivery (p=0.003). Serum IGFBP-3 was increased and IGFBP-4 decreased in GDM women vs. pregnant women without GDM during the whole study (IGFBP-3: p˂0.001 for GDM vs. non-GDM; IGFBP-4: p=0.004 for GDM vs. non-GDM). Pregnant women with GDM had decreased mRNA expression of IGF-1, IGF-1R and IGF-2R and IGFBP-4 in VAT and IGF-1R in SAT compared to pregnant women without GDM. Changes in local activity of IGF are associated with the development of GDM.

The aim of our study was to assess the presence and degree of intestinal leakage in subjects suffering from short bowel syndrome (SBS) and its modification by parenteral nutrition. To this end we assessed circulating levels of selected makers of intestinal permeability including zonulin, fatty acid binding protein 2 (FABP-2), citrulline and glucagon-like peptide 2 (GLP-2). We also measured lipopolysaccharide binding protein (LBP) as a marker of circulating levels of lipopolysaccharide acting through the CD14 molecule. Eleven SBS and 10 age- and BMI-matched control subjects were included into the study. The effect of parenteral nutrition was assessed after 14 days, 6 and 12 months from its initiation, respectively. At baseline, SBS patients had increased gut permeability as measured by zonulin (47.24±2.14 vs. 39.48±1.20 ng/ml, p=0.006) and LBP (30.32±13.25 vs. 9.77±0.71 µg/ml, p

Context Neudesin has recently been identified as a novel regulator of energy expenditure in experimental animals; however, its role in humans remains unexplored. Objective The aim of this study was to assess the effects of obesity and type 2 diabetes mellitus (T2DM) along with selected weight reducing interventions on serum neudesin levels and adipose tissue mRNA expression. Patients and methods Fifteen obese subjects with T2DM undergoing endoscopic duodenal-jejunal bypass liner (DJBL) implantation, 17 obese subjects (11 with T2DM, 6 without T2DM) scheduled for gastric plication (GP), 15 subjects with functional hypoglycemia subjected to 72-hour acute fasting (AF), and 12 healthy controls were included in the study. Results Baseline neudesin levels were comparable between all groups. DJBL increased neudesin at 6 and 10 months after the procedure (1.77±0.86 vs 2.28±1.27 vs 2.13±1.02 ng/mL, P=0.001 for baseline vs 6 vs 10 months) along with reduction in body weight and improvement of HbA1c without any effect on neudesin mRNA expression in subcutaneous adipose tissue. Conversely, GP did not affect neudesin levels despite marked reduction in body weight and improvement of HbA1c. In contrast, AF decreased neudesin levels during the entire period (1.74±0.54 vs 1.46±0.48 ng/mL, P=0.001 for baseline vs 72 hours) with no impact of subsequent re-alimentation on neudesin concentrations. Conclusion Neudesin levels are differentially regulated during AF and chronic weight reduction induced by DJBL or GP. Further studies are needed to assess its possible significance in energy homeostasis regulation in humans.

Cellular senescence is a novel mechanism suggested to contribute to the development of type 2 diabetes mellitus (T2DM) and cardiovascular diseases. Here, we analyzed the expression of senescent markers in myocardium and adjacent adipose tissue of subjects with and without coronary artery disease (CAD) and T2DM undergoing elective cardiac surgery. Eleven subjects with CAD and T2DM (DM group), 13 subjects with CAD without T2DM (CAD group) and 8 subjects without both CAD and T2DM (C - control) group undergoing elective cardiac surgery (CABG and/or valvular surgery) were included into the study. Samples of subcutaneous (SAT) and epicardial (EAT) adipose tissue and myocardium form right atrial wall were taken along with standard biochemical and anthropometric parameters at the beginning and end of surgery. mRNA expression of senescent markers p21 and p16 was assessed using qRT PCR. All 3 groups did not differ with respect to age (65.2 ± 6.9 vs. 61.7 ± 9.8 vs. 57.9 ± 12.3 years for DM vs. CAD vs. C, n.s.) or BMI (30.8 ± 3.9 vs. 28.5 ± 3.9 vs. 30.2 ± 3.4 kg/m2, n.s.), while DM group showed higher levels of fasting glucose (8.4 ± 1.6 vs. 5.9 ± 1.1 vs. 5.9 ± 0.9 mmol/, p=0.005) and HbA1C (52.5 ± 8.9 vs. 38.9 ± 4.2 vs. 31.5 ± 8.9 mmol/mol, p Disclosure M. Mraz: None. M. Haluzik: Advisory Panel; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk, Consultant; Self; Sanofi. J. Trnovska: None. B. Kasperova: None. I. Dvorakova: None. Z. Lacinova: None. D. Hlavacek: None. J. Mahrik: None. P. Ivak: None. I. Netuka: None. Funding Ministry of Health of the Czech Republic (RVO-VFN64165, NV19-0200118); IKEM (IN00023001)

Obesity and associated metabolic complications are established risk factors for the development and progression of chronic kidney disease; however, BMI (body mass index)>35 kg/m2 is a contraindication for kidney transplantation. The aim of our study was to reduce excess body weight via laparoscopic sleeve gastrectomy (LSG) in obese patients with end-stage renal disease (ESRD) in order for them to become eligible for the transplantation program. Subjects with ESRD undergoing hemodialysis or peritoneal dialysis and BMI>35kg/m2 without serious comorbidities were included into the study. Anthropometric and biochemical parameters were measured before and 1, 3 and 6 months after LSG. In the thus far enrolled 7 subjects (6 females, aged 47.6 ± 9.6 years) LSG resulted in improved body weight (118.0 ± 17.6 vs. 107.5 ± 14.5 vs. 105.5 ± 14.4 vs. 99.5 ± 10.7 kg for baseline vs. 1 vs. 3 vs. 6 months, p To conclude, our pilot data suggest LSG to be an efficient and safe method to achieve the necessary weight reduction enabling renal transplantation in subjects with renal failure and higher degrees of obesity. Disclosure V. Hrádková: None. M. Kasalicky: None. S. Rajnochova-Bloudickova: None. I. Lankova: None. H. Kratochvilova: None. M. Mraz: None. K. Dvorakova: None. S. Slaba: None. J. Mendl: None. O. Viklicky: None. J. Fronek: None. M. Haluzik: Advisory Panel; Self; Lilly Diabetes, Sanofi. Consultant; Self; Ethicon US, LLC. Speaker’s Bureau; Self; AstraZeneca, Mundipharma International, Novartis AG, Novo Nordisk A/S. Funding Institute for Clinical and Experimental Medicine (00023001)

Diabetes and ageing are mutually linked and senescent cells might be involved in the development of obesity and type 2 diabetes mellitus (T2DM). Recent studies have shown that senolytic agents may improve diabetes-related pathologies. To this end we have tested our novel anti-cancer agent with senolytic properties, mitochondrially targeted tamoxifen (MitoTam), in a mouse model of T2DM. Obesity and diabetic metabolic profile were induced by high fat diet (HFD) feeding in 20 C57BL/6J male mice for 6 months with another group fed a standard diet (SD) serving as controls. Subsequently, both groups were divided into 2 subgroups (n=10 each) treated either with MitoTam (2µg/1g of body weight dissolved in 4% ethanol in corn oil) or the excipient given i.p. twice a week for a period of 4 weeks. In HFD animals, MitoTam decreased body weight already after 2 weeks of treatment, with most pronounced reduction of visceral adipose tissue (VAT, P In conclusion, our results suggest that MitoTam significantly improves HFD-induced obesity and diabetes in mice and that this effect might be in part mediated by alleviated senescence in adipose tissue. Disclosure J. Trnovska: None. E. Davidova: None. P. Svoboda: None. H. Kratochvilova: None. M. Mraz: None. S. Hubackova: None. J. Neuzil: None. M. Haluzik: Advisory Panel; Self; Lilly Diabetes, Sanofi. Consultant; Self; Ethicon US, LLC. Speaker’s Bureau; Self; AstraZeneca, Mundipharma International, Novartis AG, Novo Nordisk A/S. Funding Institute for Clinical and Experimental Medicine (00023001); Czech Science Foundation (GA 18-02550S)

Cardiovascular diseases (CVD) are the most common cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). C1q TNF-related protein 3 (CTRP3) is a novel adipokine that reduces inflammation and acts cardioprotectively. The aim of our study was to analyze serum levels and gene expression of CTRP3 in subcutaneous and epicardial adipose tissue in patients with CVD and T2DM undergoing elective cardiac surgery. 38 patients with coronary artery disease (CAD) without T2DM (CAD group), 21 subjects with CAD and T2DM (T2DM group) and 18 patients with a valvular defect without CAD or T2DM (nonCAD group) were included into the study. Peripheral blood, subcutaneous (SAT) and epicardial adipose tissue (EAT) were examined at the start and end of elective cardiac surgery. mRNA expression was determined using qRT-PCR. 21 healthy subjects served as controls for serum CTRP3 (C group). Baseline anthropometric and biochemical parameters were comparable in all groups except of higher fasting blood glucose (6.0±1.2 vs. 5.5±0.2 vs. 6.0±0.9 vs. 8.5±0.4 mmol/l for CAD vs. nonCAD vs. C vs. T2DM, p To conclude, decreased serum levels of CTRP3 in patients with CVD together with reduced mRNA expression in EAT in T2DM subjects with CAD indicate a possible role of CTRP3 in the pathogenesis of cardiovascular complications of type 2 diabetes mellitus. Disclosure H. Kratochvilova: None. B. Kasperova: None. Z. Lacinova: None. I. Lankova: None. J. Trnovska: None. I. Netuka: None. P. Ivak: None. J. Mahrík: None. D. Hlavácek: None. M. Mraz: None. M. Haluzik: Advisory Panel; Self; Lilly Diabetes, Sanofi. Consultant; Self; Ethicon US, LLC. Speaker’s Bureau; Self; AstraZeneca, Mundipharma International, Novartis AG, Novo Nordisk A/S. Funding Institute for Clinical and Experimental Medicine (00023001); RVOVFN64165; Ministry of Health of the Czech Republic (NV19-02-00118)

Metformin is considered the first-line treatment in all subjects with type 2 diabetes mellitus (T2DM) not having a contraindication for its use. Patient compliance with metformin is not optimal; however, objective compliance data are scarce. The aim of our study was to analyse the adherence to metformin treatment by determining its plasma levels and to identify its determinants in a broad spectrum of T2DM patients. In total, 309 patients with T2DM from a single tertiary diabetes centre (mean age 66.5 ± 9.0 years, HbA1C 57.2 ± 13.1 mmol/mol, BMI 30.8 ± 4.9 kg/m2) using standard or XR (sustained release) form of metformin were included in the study. Blood sampling for metformin together with a short questionnaire were performed during a regular outpatient visit. Hydrophilic interaction chromatography and high-resolution mass spectrometry (Q Exactive Plus instrumentation) were used to quantify metformin levels. Values ​​below 100 ng/ml were deemed sub-therapeutic. Out of 309 patients, sub-therapeutic values were measured in 4.2% and zero levels in 1.9% of subjects. The use of XR form did not increase compliance (16.7 vs. 15.4 vs. 13.8% of subjects for zero vs. sub-therapeutic vs. therapeutic range, n.s.), while all subjects using combination preparation with another antidiabetic agent (11.0%) were in therapeutic range. Zero levels of metformin were associated with a trend to increased HbA1C, higher number of other antidiabetic drugs and more frequent insulin use, whereas age, BMI and diabetes duration had no effect on metformin compliance. Adherence to metformin also increased with education status while not being affected by smoking or alcohol use. In conclusion, in a tertiary diabetes centre the compliance with metformin treatment was greater than 93% and increased with the use of combination preparations, lower number of antidiabetic drugs and higher education status. The XR form was not associated with increased adherence rate. Disclosure I. Lankova: None. I. Miskova: None. S. Frankova: None. D. Kobrova: None. T. Cajka: None. J. Hricko: None. M. Paucova: None. V. Hrádková: None. Z. Vlasakova: None. T. Pelikanova: None. M. Mraz: None. M. Haluzik: Advisory Panel; Self; Lilly Diabetes, Sanofi. Consultant; Self; Ethicon US, LLC. Speaker’s Bureau; Self; AstraZeneca, Mundipharma International, Novartis AG, Novo Nordisk A/S. Funding Institute for Clinical and Experimental Medicine (00023001); RVOVFN64165

[EN] Background The endoscopically implanted duodenal-jejunal bypass liner (DJBL) is an attractive alternative to bariatric surgery for obese diabetic patients. This article aims to study dynamical aspects of the glycaemic profile that may influence DJBL effects. Methods Thirty patients underwent DJBL implantation and were followed for 10 months. Continuous glucose monitoring (CGM) was performed before implantation and at month 10. Dynamical variables from CGM were measured: coefficient of variation of glycaemia, mean amplitude of glycaemic excursions (MAGE), detrended fluctuation analysis (DFA), % of time with glycaemia under 6.1 mmol/L (TU6.1), area over 7.8 mmol/L (AO7.8) and time in range. We analysed the correlation between changes in both anthropometric (body mass index, BMI and waist circumference) and metabolic (fasting blood glucose, FBG and HbA1c) variables and dynamical CGM-derived metrics and searched for variables in the basal CGM that could predict successful outcomes. Results There was a poor correlation between anthropometric and metabolic outcomes. There was a strong correlation between anthropometric changes and changes in glycaemic tonic control ( increment BMI- increment TU6.1: rho = - 0.67, P < .01) and between metabolic outcomes and glycaemic phasic control ( increment FBG- increment AO7.8: r = .60, P < .01). Basal AO7.8 was a powerful predictor of successful metabolic outcome (0.85 in patients with AO7.8 above the median vs 0.31 in patients with AO7.8 below the median: Chi-squared = 5.67, P = .02). Conclusions In our population, anthropometric outcomes of DJBL correlate with improvement in tonic control of glycaemia, while metabolic outcomes correlate preferentially with improvement in phasic control. Assessment of basal phasic control may help in candidate profiling for DJBL implantation., Research Center for Informatics, Grant/Award Number: CZ.02.1.01/0.0/0.0/16_019/0000765; Biomedical data acquisition, processing and visualization, Grant/Award Number: SGS19/171/OHK3/3T/13; MH CZ - DRO ("IKEM, IN 00023001"); RVO VFN64165

Epicardial adipose tissue is not only a specific adipose tissue depot but also an active endocrine organ producing numerous substances with an important role in the development of obesity-related heart diseases. It is located between myocardium and visceral pericardium and consists predominantly of adipocytes, immunocompetent cells, ganglia and interconnecting nerve branches. Several studies documented a positive correlation between pericardial and epicardial fat and left ventricular hypertrophy and septal thickening, leading to diastolic dysfunction, electrocardiographic abnormalities and facilitating cardiac failure. The cellular cross-talks between epicardial fat and myocardium may include both the vasocrine and the paracrine mechanisms. Adipokines secreted from epicardial adipose tissue, vascular and stromal cells diffuse into interstitial fluid crossing the adventitia, media and intima and modulate cardiac function and cardiomyocyte phenotype and survival. In this article, we review the significance of epicardial adipose tissue and its association with cardiovascular diseases, cellular interactions between epicardial fat and myocardium, secretions of adipokines and inflammatory mediators and a potential of epicardial fat as a therapeutic target for the prevention of obesity-related heart diseases.

Increasing worldwide prevalence of type 2 diabetes mellitus and its accompanying pathologies such as obesity, arterial hypertension and dyslipidemia represents one of the most important challenges of current medicine. Despite intensive efforts, high percentage of patients with type 2 diabetes does not achieve treatment goals and struggle with increasing body weight and poor glucose control. While novel classes of antidiabetic medications such as incretin-based therapies and gliflozins have some favorable characteristics compared to older antidiabetics, the only therapeutic option shown to substantially modify the progression of diabetes or to achieve its remission is bariatric surgery. Its efficacy in the treatment of diabetes is well established, but the exact underlying modes of action are still only partially described. They include restriction of food amount, enhanced passage of chymus into distal part of small intestine with subsequent modification of gastrointestinal hormones and bile acids secretion, neural mechanisms, changes in gut microbiota and many other possible mechanisms underscoring the importance of the gut in the regulation of glucose metabolism. In addition to bariatric surgery, less-invasive endoscopic methods based on the principles of bariatric surgery were introduced and showed promising results. This review highlights the role of the intestine in the regulation of glucose homeostasis focusing on the mechanisms of action of bariatric and especially endoscopic methods of the treatment of diabetes. A better understanding of these mechanisms may lead to less invasive endoscopic treatments of diabetes and obesity that may complement and widen current therapeutic options.

Type 2 diabetes represents one of the most significant global health threats of the 21st century owing to its constantly increasing prevalence and long-term debilitating complications (1). In addition to accelerated macrovascular disease in poorly controlled diabetes that is responsible for increased cardiovascular morbidity and mortality, microvascular complications, such as diabetic nephropathy, neuropathy, and retinopathy, cause a significant burden and may markedly impair not only life expectancy but also quality of life of patients with diabetes (2). Diabetic retinopathy is the most common cause of blindness in developed countries and one of the most feared diabetes complications (3). Significant progress has been made in our understanding of the etiopathogenesis of type 2 diabetes with numerous novel contributing mechanisms identified in the past couple of years (4). Both experimental and clinical studies have demonstrated that gut represents a vital organ with respect to regulation of glucose metabolism and modulation of the risk of type 2 diabetes development (5). Multiple facets of the gut–glucose metabolism interconnection have been uncovered in particular by studying the changes induced by weight loss associated with bariatric surgery or endoscopic methods mimicking bariatric surgery. The possible mechanisms of gut-driven improvements in glucose metabolism after surgical or endoscopic interventions include restriction of food amount, enhanced passage of chymus into distal parts of small …

Context Impaired glucose homeostasis is a common finding in pheochromocytoma (PHEO), especially with adrenergic phenotype. The possible contribution of incretin dysfunction to dysglycemia in PHEO patients has not been studied. Objective To compare changes in pancreatic endocrine function and gut hormones’ production during a liquid meal test before and 1 year after adrenalectomy. Methods In a prospective study, we included 18 patients with PHEO (13 females) with adrenergic biochemical phenotype. A liquid meal test with predefined isocaloric enteral nutrition was performed to evaluate dynamic changes in pancreatic hormones and incretins. Results During the meal test, insulin levels were significantly lower before adrenalectomy only in the early phase of insulin secretion, but changes in area under the curve (AUC) did not reach statistical significance (AUC = 0.07). Plasma glucagon (AUC Conclusions Our study shows suppression of pancreatic α and β cell function and impaired GLP-1 secretion during a dynamic meal test in patients with PHEO, which is improved after its surgical treatment. These data demonstrate a novel and potentially significant interconnection between excessive catecholamine production and the secretion of glucoregulatory hormones.

Duodenal-jejunal by-pass liner (DJBL) is an endoscopically implantable device designed to non-invasively mimic the effects of surgical gastric by-pass. However, the exact mechanisms responsible for improved glucose control associated with DJBL are still unclear. The aim of our study was to assess the effect of DJBL on insulin sensitivity and secretion in subjects with type 2 diabetes mellitus (T2DM) and obesity. Twenty-one obese subjects with T2DM (15 males, age 52.3 ± 11.2 years) underwent the implantation of the EndoBarrier DJBL (GI Dynamics, U.S.). Anthropometric, biochemical and hormonal parameters were measured before and 10 months after the implantation of DJBL. Insulin sensitivity was assessed using euglycemic-hyperinsulinemic clamp. Standard parameters including glucose disposal rate (M) and metabolic clearance rate of glucose (MCG) were calculated based on clamp results. Over 10 months the implantation of DJBL decreased body weight (body mass index 41.6 ± 6.1 vs. 37.5 ± 4.2 kg/m2, p Disclosure M. Kudlackova: None. M. Mraz: None. M. Haluzik: None. T. Pelikanova: None. M. Benes: None. D. Lapesova: None. D. Kobrova: None. Z. Vlasakova: None. O. Brizova: None. Z. Lacinova: None. Funding Institute for Clinical and Experimental Medicine (IN00023001)

The duodenum has recently emerged as a key regulator in glucose metabolism via modulation of a complex network of neural and hormonal signals in response to ingested food. DiaGone™ is an endoscopic device which utilizes precisely controlled laser technology to target the duodenal submucosal neural plexi with the aim of improving glucose control by modulating the gastrointestinal neurohumoral axis. Nine subjects (5 males) with obesity (BMI 34.0 ± 4.6 kg/m2) and type 2 diabetes mellitus (T2DM) insufficiently controlled on metformin were included in this first-in-human trial in order to assess the efficacy and safety of DiaGone™. Subjects were instructed to continue with regular diet 24h after the procedure and metformin dose was not changed during the study period. Biochemical and anthropometric parameters were assessed at baseline and 3 and 6 months after the procedure and continuous glucose monitoring (CGM) and a standard liquid meal test were performed at baseline and 3 months after the procedure. DiaGone™ significantly decreased HbA1C from 78.3 ± 13.3 mmol/mol at baseline to 64.9 ± 6.4 mmol/mol and 64.8 ± 7.1 mmol/mol at 3 and 6 months, respectively (p In conclusion, these pilot results suggest that endoscopic duodenal submucosal laser ablation using the DiaGone™ device is associated with improvements in both baseline and postprandial glycemia as well as HbA1C with no significant changes in insulin levels or body weight while having a favorable safety and tolerability profile. Disclosure M. Mraz: None. I. Marcovitch: Employee; Self; Digma Medical. I. Lankova: None. H. Kratochvilova: None. A. Cinkajzlova: None. M. Benes: None. J. Korner: Board Member; Self; Digma Medical. Stock/Shareholder; Self; Digma Medical. Z. Vlasakova: None. J. Spicak: None. T. Pelikanova: None. M. Haluzik: None. Funding MH CZ - DRO; Institute for Clinical and Experimental Medicine (IN00023001); RVO (VFN64165)

[EN] Diabetes is a disease of great and rising prevalence, with the obesity epidemic being a significant contributing risk factor. Duodenal¿jejunal bypass liner (DJBL) is a reversible implant that mimics the effects of more aggressive surgical procedures, such as gastric bypass, to induce weight loss. We hypothesized that DJBL also influences the glucose dynamics in type II diabetes, based on the induced changes already demonstrated in other physiological characteristics and parameters. In order to assess the validity of this assumption, we conducted a quantitative analysis based on several nonlinear algorithms (Lempel¿Ziv Complexity, Sample Entropy, Permutation Entropy, and modified Permutation Entropy), well suited to the characterization of biomedical time series. We applied them to glucose records drawn from two extreme cases available of DJBL implantation: before and after 10 months. The results confirmed the hypothesis and an accuracy of 86.4% was achieved with modified Permutation Entropy. Other metrics also yielded significant classification accuracy results, all above 70%, provided a suitable parameter configuration was chosen. With the Leave¿One¿Out method, the results were very similar, between 72% and 82% classification accuracy. There was also a decrease in entropy of glycaemia records during the time interval studied. These findings provide a solid foundation to assess how glucose metabolism may be influenced by DJBL implantation and opens a new line of research in this field., The Czech clinical partners were supported by DRO IKEM 000023001 and RVO VFN 64165. The Czech technical partners were supported by Research Centre for Informatics grant numbers CZ.02.1.01/0.0/16 - 019/0000765 and SGS16/231/OHK3/3T/13-Support of interactive approaches to biomedical data acquisition and processing. No funding was received to support this research work by the Spanish and British partners

Immunocompetent cells including lymphocytes play a key role in the development of adipose tissue inflammation and obesity-related cardiovascular complications. The aim of the study was to explore the relationship between epicardial adipose tissue lymphocytes and coronary artery disease (CAD). To this end, we studied the content and phenotype of lymphocytes in peripheral blood, subcutaneous adipose tissue (SAT), and epicardial adipose tissue (EAT) in subjects with and without CAD undergoing elective cardiac surgery. Eleven subjects without CAD (non-CAD group) and 22 age-, BMI-, and HbA1C-matched individuals with CAD were included into the study. Blood, SAT, and EAT samples were obtained at the beginning of surgery. Lymphocyte populations were quantified as % of CD45+ cells using flow cytometry. Subjects with CAD had a higher total lymphocyte amount in EAT compared with SAT (32.24±7.45 vs. 11.22±1.34%, p=0.025) with a similar trend observed in non-CAD subjects (29.68±7.61 vs. 10.13±2.01%, p=0.067). T (CD3+) cells were increased (75.33±2.18 vs. 65.24±4.49%, p=0.032) and CD3- cells decreased (21.17±2.26 vs. 31.64±4.40%, p=0.028) in EAT of CAD relative to the non-CAD group. In both groups, EAT showed an elevated percentage of B cells (5.22±2.43 vs. 0.96±0.21%, p=0.039 for CAD and 12.49±5.83 vs. 1.16±0.19%, p=0.016 for non-CAD) and reduced natural killer (NK) cells (5.96±1.32 vs. 13.22±2.10%, p=0.012 for CAD and 5.32±1.97 vs. 13.81±2.72%, p=0.022 for non-CAD) relative to SAT. In conclusion, epicardial adipose tissue in subjects with CAD shows an increased amount of T lymphocytes relative to non-CAD individuals as well as a higher number of total and B lymphocytes and reduced NK cells as compared with corresponding SAT. These changes could contribute to the development of local inflammation and coronary atherosclerosis.

Dendritic cells (DCs) are professional antigen-presenting cells contributing to regulation of lymphocyte immune response. DCs are divided into two subtypes: CD11c-positive conventional or myeloid (cDCs) and CD123-positive plasmacytoid (pDCs) DCs. The aim of the study was to assess DCs (HLA-DR+ lineage-) and their subtypes by flow cytometry in peripheral blood and subcutaneous (SAT) and epicardial (EAT) adipose tissue in subjects with (T2DM, n=12) and without (non-T2DM, n=17) type 2 diabetes mellitus undergoing elective cardiac surgery. Subjects with T2DM had higher fasting glycemia (8.6±0.7 vs. 5.8±0.2 mmol/l, p<0.001) and glycated hemoglobin (52.0±3.4 vs. 36.9±1.0 mmol/mol, p<0.001) and tended to have more pronounced inflammation (hsCRP: 9.8±3.1 vs. 5.1±1.9 mg/ml, p=0.177) compared with subjects without T2DM. T2DM was associated with reduced total DCs in SAT (1.57±0.65 vs. 4.45±1.56% for T2DM vs. non-T2DM, p=0.041) with a similar, albeit insignificant, trend in EAT (0.996±0.33 vs. 2.46±0.78% for T2DM vs. non-T2DM, p=0.171). When analyzing DC subsets, no difference in cDCs was seen between any of the studied groups or adipose tissue pools. In contrast, pDCs were increased in both SAT (13.5±2.0 vs. 4.6±1.9% of DC cells, p=0.005) and EAT (29.1±8.7 vs. 8.4±2.4% of DC, p=0.045) of T2DM relative to non-T2DM subjects as well as in EAT of the T2DM group compared with corresponding SAT (29.1±8.7 vs. 13.5±2.0% of DC, p=0.020). Neither obesity nor coronary artery disease (CAD) significantly influenced the number of total, cDC, or pDC in SAT or EAT according to multiple regression analysis. In summary, T2DM decreased the amount of total dendritic cells in subcutaneous adipose tissue and increased plasmacytoid dendritic cells in subcutaneous and even more in epicardial adipose tissue. These findings suggest a potential role of pDCs in the development of T2DM-associated adipose tissue low-grade inflammation.

The aim of our study was to analyze mitochondrial and endoplasmic reticulum (ER) gene expression profiles in subcutaneous (SAT) and epicardial (EAT) adipose tissue, skeletal muscle, and myocardium in patients with and without CAD undergoing elective cardiac surgery. Thirty-eight patients, 27 with (CAD group) and 11 without CAD (noCAD group), undergoing coronary artery bypass grafting and/or valvular surgery were included in the study. EAT, SAT, intercostal skeletal muscle, and right atrium tissue and blood samples were collected at the start and end of surgery, mRNA expression of selected mitochondrial and ER stress genes was assessed using qRT-PCR. The presence of CAD was associated with decreased mRNA expression of most of the investigated mitochondrial respiratory chain genes in EAT, while no such changes were seen in SAT or other tissues. In contrast, the expression of ER stress genes did not differ between the CAD and noCAD groups in almost any tissue. Cardiac surgery further augmented mitochondrial dysfunction in EAT. In our study, CAD was associated with decreased expression of mitochondrial, but not endoplasmic reticulum stress genes in EAT. These changes may contribute to the acceleration of coronary atherosclerosis.

Aim: Human exposure to organic pollutants (some of them also called endocrine disruptors) can be associated with adverse metabolic health outcomes including type 2 diabetes. The aim of this study was to compare the urine levels of bisphenol A and phthalate metabolites in subgroups of patients with metabolic syndrome composed of patients with and without three important components of metabolic syndrome (hypertension, dyslipidemia and diabetes). Methods: We have investigated 24 hours urine samples of 168 patients with metabolic syndrome from the Metabolic Outpatient Department of General University Hospital in Prague. Using standard metabolic syndrome criteria, we classified patients as dyslipidemic (n=87), hypertensive (n=96), and type 2 diabetic (n=58). Bisphenol A and 15 metabolites of phthalates were evaluated in relation to creatinine excretion. Samples were analysed with enzymatic cleavage of glucuronide using ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry in one laboratory with external quality control. Results: Four metabolites, mono-n-butyl phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, and mono-(2-ethyl-5-carboxypentyl) phthalate showed significantly higher levels in diabetic compared to non-diabetic patients (p

Angiopoietin-like protein 6 (ANGPTL6) is a circulating protein with a potential role in energy homeostasis. The aim of the study was to explore the changes in ANGPTL6 levels in patients with obesity (Body mass index, BMI40 kg/mThe study included 23 non-diabetic obese patients, 40 obese patients with T2DM (27 underwent VLCD and 13 underwent bariatric surgery), 22 patients with AN, and 37 healthy control subjects.ANGPTL6 levels of AN patients were increased relative to the control group (68.6 ± 9.9 ng/ml) and decreased from 110.2 ± 13.3 to 73.6 ± 7.1 ng/ml (p = 0.004) after partial realimentation. Baseline ANGPTL6 levels in patients with obesity and T2DM did not differ from the control group. VLCD decreased ANGPTL6 levels only in obese patients with T2DM. Bariatric surgery induced a transient elevation of ANGPTL6 levels with a subsequent decrease to baseline levels. ANGPTL6 mRNA expression transiently increased after bariatric surgery and returned to baseline levels after 12 months.Collectively, our data suggest that serum ANGPTL6 levels and ANGPTL6 mRNA expression in SAT are affected by metabolic disorders and their treatment but do not appear to directly reflect nutritional status.

Background The gut microbiome and metabolome may significantly influence clinical outcomes in patients with short bowel syndrome (SBS). The study aimed to describe specific metagenomic/metabolomics profiles of different SBS types and to identify possible therapeutic targets. Methods Fecal microbiome (FM), volatile organic compounds (VOCs), and bile acid (BA) spectrum were analyzed in parenteral nutrition (PN)-dependent SBS I, SBS II, and PN-independent (non-PN) SBS patients. Results FM in SBS I, SBS II, and non-PN SBS shared characteristic features (depletion of beneficial anaerobes, high abundance of Lactobacilaceae and Enterobacteriaceae). SBS I patients were characterized by the abundance of oxygen-tolerant microrganisms and depletion of strict anaerobes. Non-PN SBS subjects showed markers of partial FM normalization. FM dysbiosis was translated into VOC and BA profiles characteristic for each SBS cohort. A typical signature of all SBS patients comprised high saturated aldehydes and medium-chain fatty acids and reduced short-chain fatty acid (SCFA) content. Particularly, SBS I and II exhibited low protein metabolism intermediate (indole, p-cresol) content despite the hypothetical presence of relevant metabolism pathways. Distinctive non-PN SBS marker was high phenol content. SBS patients' BA fecal spectrum was enriched by chenodeoxycholic and deoxycholic acids and depleted of lithocholic acid. Conclusions Environmental conditions in SBS gut significantly affect FM composition and metabolic activity. The common feature of diverse SBS subjects is the altered VOC/BA profile and the lack of important products of microbial metabolism. Strategies oriented on the microbiome/metabolome reconstitution and targeted delivery of key compounds may represent a promising therapeutic strategy in SBS patients.

Neudesin has recently been identified as a negative regulator of energy expenditure in experimental animals; however, its role in humans remains unexplored. The aim of our study was to assess the effects of obesity and type 2 diabetes mellitus along with selected interventions including acute fasting and endoscopic duodenal-jejunal by-pass liner implantation (DJBL) on its serum levels and adipose tissue mRNA expression. Fifteen obese T2DM subjects undergoing DJBL implantation, 15 subjects with functional hypoglycemia subjected to 72-hour fasting (Fast) and 12 healthy controls (C) were included in the study. Samples were taken at baseline and 6 and 10 months after DJBL and after 78 hours of fasting and 2 hours after realimentation, respectively. Serum neudesin was measured using ELISA kit (Neudesin Human ELISA, Biovendor, CR). qRT PCR was used to detect mRNA expression of neudesin in white adipose tissue (WAT). Baseline serum neudesin levels were comparable between all groups (1.77 ± 0.86 vs. 1.74 ± 0.54 vs. 1.88 ± 0.70 ng/ml, n.s. for DJBL vs. Fast vs. C). Along with reduction in body weight (BMI 42.8 ± 6.53 vs. 36.6 ± 4.91 kg/m2, p=0.038) and improvement of HbA1c (73.5 ± 17.2 vs. 50.0 ± 12.6 mmol/mol, p=0.001) DJBL increased serum neudesin at 6 and 10 months after procedure (1.77 ± 0.86 vs. 2.28 ± 1.27 vs. 2.13 ± 1.02 ng/ml, p=0.001 for baseline vs. 6 vs. 10 months), while having no effect on neudesin mRNA expression in WAT. In contrast, acute fasting decreased serum neudesin during the whole period (1.74 ± 0.54 vs. 1.46 ± 0.48 ng/ml, p=0.001 for baseline vs. 72 hours) with no impact of subsequent realimentation (1.37 ± 0.44 ng/ml, n.s. 2 h postprandially).To conclude, serum neudesin levels are regulated differently during acute fasting and chronic weight reduction induced by DJBL. Further studies are needed to assess its potential in the treatment of obesity and T2DM. Disclosure H. Kratochvilova: None. Z. Lacinová: None. J. Klouckova: None. P. Kaválková: None. A. Cinkajzlova: None. P. Trachta: None. J. Krizova: None. M. Benes: None. Z. Vlasakova: None. T. Pelikanova: None. M. Mraz: None. M. Haluzik: None.

Obesity and type 2 diabetes mellitus are accompanied by low-grade inflammation and changed immune cell composition in adipose tissue. However, little is known about subclinical inflammation in gestational diabetes mellitus (GDM). The aim of our study was to analyse lymphocyte populations in subcutaneous (SAT) and visceral adipose tissue (VAT) together with systemic levels and mRNA expression of selected inflammatory markers in these depots and placenta. Thirty-seven pregnant females - 21 with GDM (GDM group) and 16 without GDM (P group) - were included into the study. Blood samples were taken in 28th-32th and 36th-38th gestational week and 6-12 months after delivery and SAT, VAT and placental samples were obtained during delivery. Lymphocytes were assessed as percent of CD45+ cells measured by flow cytometry. In both groups CD45+ lymphocytes were higher in VAT compared to SAT (19.2 ± 2.2 vs. 6.5 ± 0.7%, p Disclosure A. Cinkajzlova: None. K. Anderlová: None. P. Simjak: None. Z. Lacinová: None. J. Klouckova: None. H. Kratochvilova: None. H. Krejci: None. M. Mraz: None. M. Haluzik: None. M. Krsek: None.

The insulin-like growth factor (IGF) axis is involved in the regulation of growth and metabolism; however, little is known about its role in the development of gestational diabetes mellitus (GDM). The aim of our study was to determine serum IGF-1, IGF-2 and selected IGF binding protein (IGFBP) levels and their mRNA expression in subcutaneous (SAT) and visceral adipose tissue (VAT) and placenta in the context of pregnancy and GDM. Thirty-seven pregnant females - 21 with GDM (GDM group) and 16 without GDM (P group) - and 15 age-matched non-pregnant control females (NP group) were included into the study. Blood samples were taken in 28th-32th and 36th-38th gestational week and 6-12 months after delivery (GDM and P group) or before diagnostic laparoscopy (NP group). SAT, VAT and placental samples were obtained during delivery or surgery, respectively. Compared with NP group serum IGF-1, IGFBP-1 and 3 were increased in both GDM and P subjects reaching maximum levels in 38th-39th gestational week. IGF-2 was elevated only in GDM group culminating 6 months after delivery (745.1±24.7 vs. 909.2±62.8 vs. 998.7±92.7 ng/ml, p=0.017 for GDM and 726.9±28.4 vs. 791.2±44.2 vs. 748.9±58.4 ng/ml, p=0.341 for P group, respectively). IGFBP-3 was higher and IGFBP-4 was decreased in GDM vs. P group during the whole study (IGFBP3: 631.0±22.9 vs. 536.9±15.4 ng/ml, p=0.003 for GDM vs. P group; IGFBP4: 14.79±2.71 vs. 22.78±2.94 ng/ml, p In conclusion, females with GDM had increased serum IGF-2, IGFBP-3 and reduced IGFBP-4 levels and elevated placental mRNA expression of several components of IGF axis compared with pregnant women without GDM. These changes might play a role in the development of GDM. Disclosure K. Anderlová: None. P. Simjak: None. A. Cinkajzlova: None. J. Klouckova: None. H. Kratochvilova: None. Z. Lacinová: None. P. Kaválková: None. H. Krejci: None. M. Mraz: None. M. Haluzik: None. M. Krsek: None.

Lymphocytes play a role in the development of adipose tissue inflammation. Epicardial adipose tissue was shown to be a potential source of inflammatory mediators contributing to coronary atherosclerosis. The aim of the study was to assess lymphocyte content in peripheral blood, subcutaneous (SAT) and epicardial adipose tissue (EAT) in subjects with coronary artery disease (CAD) along with the effects of elective cardiac surgery. Twelve subjects without CAD (non-CAD group) and 24 age-, BMI- and HbA1C-matched subjects with CAD were included into the study. Blood, SAT and EAT samples were obtained before and at the end of elective cardiac surgery. Lymphocyte populations were quantified as percent of CD45+ cells using flow cytometry. Subjects with CAD had higher total lymphocyte (CD45+) amount in EAT compared to SAT (32.24±7.45 vs. 11.22±1.34%, p=0.025) with a similar trend observed in non-CAD subjects (29.68±7.61 vs. 10.13±2.01%, p=0.067). CD3+ cells were increased and CD3- cells decreased in EAT of CAD relative to non-CAD group with no difference between EAT and SAT. In both groups EAT showed reduced percentage of NK cells (CD15/56+CD3-) and elevated B cells (CD19+) relative to SAT (NK cells: 5.96±1.32 vs. 13.22±2.10%, p=0.012 for CAD and 5.32±1.97 vs. 13.81±2.72%, p=0.022 for non-CAD; B cells: 5.22±2.43 vs. 0.96±0.21%, p=0.039 for CAD and 12.49±5.83 vs. 1.16±0.19%, p=0.016 for non-CAD). CD8+ and NKT (CD16/56+CD3+) cells in EAT correlated positively with fasting glucose and HbA1C, while showing no association in SAT. Cardiac surgery decreased total lymphocytes in peripheral blood, SAT and EAT of both groups, while having only minor effects on lymphocyte subpopulations. To conclude, epicardial adipose tissue in subjects with CAD shows increased amount of total and CD3+ lymphocytes as compared with SAT or non-CAD subjects. These changes could contribute to the development of local inflammation and coronary atherosclerosis. Disclosure M. Mraz: None. A. Cinkajzlova: None. Z. Lacinov : None. J. Klouckova: None. H. Kratochvilova: None. M. Lips: None. P. Kopecky: None. M. Porizka: None. J. Lindner: None. M. Haluzik: None.

Gestational diabetes mellitus is defined as diabetes diagnosed in the second or third trimester of pregnancy in patients with no history of diabetes prior to gestation. It is the most common complication of pregnancy. The underlying pathophysiology shares some common features with type 2 diabetes mellitus (T2DM) combining relatively insufficient insulin secretion with increased peripheral insulin resistance. While a certain degree of insulin resistance is the physiological characteristics of the second half of pregnancy, it is significantly more pronounced in patients with gestational diabetes. Adipose tissue dysfunction and subclinical inflammation in obesity are well-described causes of increased insulin resistance in non-pregnant subjects and are often observed in individuals with T2DM. Emerging evidence of altered adipokine expression and local inflammation in adipose tissue in patients with gestational diabetes suggests an important involvement of adipose tissue in its etiopathogenesis. This review aims to summarize current knowledge of adipose tissue dysfunction and its role in the development of gestational diabetes. We specifically focus on the significance of alterations of adipokines and immunocompetent cells number and phenotype in fat. Detailed understanding of the role of adipose tissue in gestational diabetes may provide new insights into its pathophysiology and open new possibilities of its prevention and treatment.

Background Angiopoietin-like proteins (ANGPTLs) 3 and 4 are circulating factors that participate in the regulation of lipid and glucose metabolism. Subjects and methods We measured serum ANGPTL3 and 4 levels in 23 patients with obesity, 40 patients with obesity and type 2 diabetes mellitus (T2DM), 22 patients with anorexia nervosa (AN), 15 subjects undergoing 72-h fasting, and 12 patients with short bowel syndrome (SBS), and their changes after very-low-calorie diet (VLCD), bariatric surgery, partial realimentation, acute fasting, and parenteral nutrition in order to assess their possible role in metabolic regulations. Results Serum ANGPTL4 levels were higher in obese subjects without/with T2DM (94.50 ± 9.51 and 134.19 ± 7.69 vs. 50.34 ± 4.22 ng/ml, p p = 0.002), while serum ANGPTL3 levels demonstrated inverse tendency. Nutritional status had no effect on ANGPTL3 and 4 mRNA expression in adipose tissue. Fasting decreased ANGPTL3 and increased ANGPTL4 levels, while VLCD reduced only ANGPTL3. Bariatric surgery and realimentation of AN or SBS patients had no effect on either ANGPTL. Multiple regression analysis identified BMI as an independent predictor of ANGPTL3; and BMI and HbA1c as independent predictors of ANGPTL4, respectively. Conclusions Taken together, our data suggest that serum ANGPTL3 and 4 levels are influenced by nutritional status and fasting and could be involved in the metabolic disturbances present in obesity and AN.

Mitochondrial dysfunction is a potentially important player in the development of insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the changes of mRNA expression of genes encoding main enzymatic complexes of mitochondrial respiratory chain in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) of 11 subjects with simple obesity (OB), 16 obese patients with T2DM and 17 healthy lean subjects (C) before and after very low-calorie diet (VLCD) using quantitative real time PCR. At baseline in SCAT, both T2DM and OB group had decreased mRNA expression of all investigated mitochondrial genes with the exception of 2 complex I (NDUFA 12) and complex IV (COX 4/1) enzymes in OB subjects. In contrast, in PM only the expression of complex I enzymes NDUFA 12 and MT-ND5 was reduced in both T2DM and OB subjects along with decreased expression of citrate synthase (CS) in T2DM group. Additionally, T2DM subjects showed reduced activity of pyruvate dehydrogenase and complex IV in peripheral blood elements. VLCD further decreased mRNA expression of CS and complex I (NT-ND5) and II (SDHA) enzymes in SCAT and complex IV (COX4/1) and ATP synthase in PM of T2DM group, while increasing the activity of complex IV in their peripheral blood elements. We conclude that impaired mitochondrial biogenesis and decreased activity of respiratory chain enzymatic complexes was present in SCAT and PM of obese and diabetic patients. VLCD improved metabolic parameters and ameliorated mitochondrial oxidative function in peripheral blood elements of T2DM subjects but had only minor and inconsistent effect on mitochondrial gene mRNA expression in SCAT and PM.

Omentin is a novel adipokine with insulin-sensitizing effects expressed predominantly in visceral fat. We investigated serum omentin levels and its mRNA expression in subcutaneous adipose tissue (SCAT) of 11 women with type 2 diabetes mellitus (T2DM), 37 obese non-diabetic women (OB) and 26 healthy lean women (C) before and after various weight loss interventions: 2-week very-low-calorie diet (VLCD), 3-month regular exercise and laparoscopic sleeve gastrectomy (LSG). At baseline, both T2DM and OB groups had decreased serum omentin concentrations compared with C group while omentin mRNA expression in SCAT did not significantly differ among the groups. Neither VLCD nor exercise significantly affected serum omentin concentrations and its mRNA expression in SCAT of OB or T2DM group. LSG significantly increased serum omentin levels in OB group. In contrast, omentin mRNA expression in SCAT was significantly reduced after LSG. Baseline fasting serum omentin levels in a combined group of the studied subjects (C, OB, T2DM) negatively correlated with BMI, CRP, insulin, LDL-cholesterol, triglycerides and leptin and were positively related to HDL-cholesterol. Reduced circulating omentin levels could play a role in the etiopathogenesis of obesity and T2DM. The increase in circulating omentin levels and the decrease in omentin mRNA expression in SCAT of obese women after LSG might contribute to surgery-induced metabolic improvements and sustained reduction of body weight.

Appropriate differentiation capacity of adipose tissue significantly affects its ability to store lipids and to protect nonadipose tissues against lipid spillover and development of insulin resistance. Preadipocyte factor-1 (Pref-1) is an important negative regulator of preadipocyte differentiation. The aim of our study was to explore the changes in circulating Pref-1 concentrations in female subjects with obesity (OB) (n=19), females with obesity and type 2 diabetes mellitus (T2DM) (n=22), and sex- and age-matched healthy control subjects (C) (n=22), and to study its modulation by very low calorie diet (VLCD), acute hyperinsulinemia during isoglycemic-hyperinsulinemic clamp, and 3 months' treatment with PPAR-α agonist fenofibrate. At baseline, serum Pref-1 concentrations were significantly higher in patients with T2DM compared to control group, while only nonsignificant trend towards higher levels was observed in OB group. 3 weeks of VLCD decreased Pref-1 levels in both OB and T2DM group, whereas 3 months of fenofibrate treatment had no significant effect. Hyperinsulinemia during the clamp significantly suppressed Pref-1 levels in both C and T2DM subjects and this suppression was unaffected by fenofibrate treatment. In a combined population of all groups, circulating Pref-1 levels correlated positively with insulin, leptin and glucose levels and HOMA (homeostasis model assessment) index. We conclude that elevated Pref-1 concentrations in T2DM subjects may contribute to impaired adipose tissue differentiation capacity associated with insulin resistance in obese patients with T2DM. The decrease of Pref-1 levels after VLCD may be involved in the improvement of metabolic status and the amelioration of insulin resistance in T2DM patients.

Objective Fibroblast growth factor (FGF)-19 and FGF-21 are novel metabolic regulators that improve insulin resistance and obesity in rodents. The aim of the study was to assess the effects of laparoscopic sleeve gastrectomy (LSG) on serum concentrations of FGF-19 and FGF-21 along with circulating bile acids and other relevant hormonal and biochemical parameters. Design and Methods Seventeen females with obesity undergoing LSG and 15 lean healthy females were included into the study. Anthropometric and biochemical parameters, serum concentrations of FGF-19 and -21, insulin, adiponectin, leptin, C-reactive protein, resistin, amylin (total), ghrelin (active), glucagon-like peptide 1 (GLP-1, active), glucose-dependent insulinotropic peptide (GIP, total), peptide YY (PYY, total), pancreatic polypeptide (PP), and bile acids, and mRNA expression of selected adipokines and inflammatory markers in bioptic samples of subcutaneous fat were assessed at baseline and 6, 12, and 24 months after LSG. Results LSG markedly decreased body weight, BMI, waist circumference, and insulin levels and improved systemic inflammation and lipid levels. FGF-19 concentrations increased and FGF-21 concentrations decreased after LSG along with increased adiponectin and decreased leptin, amylin, and ghrelin levels. GLP-1, GIP, PP, and circulating bile acids were not affected by LSG. PYY decreased significantly 24 months after surgery only. mRNA expression analysis in subcutaneous fat showed markedly reduced proinflammatory state. Conclusions Our results indicate that increased FGF-19 and decreased ghrelin concentrations could have partially contributed to the improvement of systemic inflammation and some metabolic parameters after LSG, while changes of FGF-21 are rather secondary because of weight loss.

We explored serum concentrations and mRNA expression of insulin-like-growth factor-1 (IGF-1) axis components in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) of 18 healthy females, 11 obese non-diabetic females (OB) and 13 obese women with type 2 diabetes (T2DM) examined at baseline and after very-low-calorie diet (VLCD). T2DM women had decreased expression of IGF-1, IGF-1 receptor (IGF-1R), IGFBP-2 (IGF binding protein-2) and IGFBP-3 in SCAT and increased expression of IGF-1R in PM compared to control group. IGF-1R and IGFBP-3 mRNA expression in SCAT of OB was comparable to control group. In T2DM women VLCD increased serum levels and SCAT expression of IGFBP-2 and PM expression of IGFBP-3. We conclude that decreased IGF-1, IGF-1R and IGFBP-3 expression in SCAT and increased IGF-1R expression in PM of T2DM subjects might contribute to changes of fat differentiation capacity and to regulation of subclinical inflammation by PM, respectively. Increased SCAT and circulating IGFBP-2 and IGFBP-3 in PM might participate in metabolic improvements after VLCD.

ObjectiveMacrophage inhibitory cytokine-1 (MIC-1) is a novel regulator of energy homeostasis. We explored whether alterations in MIC-1 levels contribute to metabolic disturbances in patients with obesity and/or obesity and type 2 diabetes mellitus (T2DM).DesignWe measured serum MIC-1 levels and its mRNA expression in subcutaneous and visceral adipose tissue of 17 obese nondiabetic women, 14 obese women with T2DM and 23 healthy lean women. We also explored the relationship of MIC-1 with anthropometric and biochemical parameters and studied the influence of 2-week very low calorie diet (VLCD) on serum MIC-1 levels.MethodsSerum MIC-1 levels were measured by ELISA and its mRNA expression was determined by RT-PCR.ResultsBoth obese and T2DM group had significantly elevated serum MIC-1 levels relative to controls. T2DM group had significantly higher serum MIC-1 levels relative to obese group. Serum MIC-1 positively correlated with body weight, body fat, and serum levels of triglycerides, glucose, HbAlc, and C-reactive protein and it was inversely related to serum high-density lipoprotein cholesterol. Fat mRNA MIC-1 expression did not significantly differ between lean and obese women but it was significantly higher in subcutaneous than in visceral fat in both groups. VLCD significantly increased serum MIC-1 levels in obese but not T2DM group.ConclusionElevated MIC-1 levels in patients with obesity are further increased by the presence of T2DM. We suggest that in contrast to patients with cancer cachexia, increased MIC-1 levels in obese patients and diabetic patients do not induce weight loss.

Incretin-based therapies either increase endogenous levels of glucagon-like peptide-1 by prolonging its half-life (DPP-4 inhibitors) or directly stimulate its receptor (glucagon-like peptide-1 analogues; GLP-1 RA). They are currently widely used for the treatment of patients with type 2 diabetes mellitus owing to good antidiabetic efficacy, low risk of hypoglycemia, and relatively few other side effects. They also offer potential additional benefits such as weight neutrality or weight loss, positive effects on blood pressure and lipid levels, and potential cardio- and neuroprotectivity. Some experimental and clinical studies have raised concerns with respect to potential cardiovascular and pancreatic side effects of these therapies such as increased risk of heart failure with DPP-4 inhibitors as well as acute pancreatitis and pancreatic cancer with both classes. The available data are at present not robust enough to enable firm conclusions regarding these potential associations. Nevertheless, some recent data suggest a possibility of slightly increased risk of acute pancreatitis with GLP-1 RAs while they do not indicate increased risk of pancreatic cancer. Ongoing cardiovascular outcome trials will shed more light on the possible cardioprotective effects of incretin-based therapies as well as on the possible interconnection of DPP-4 inhibitors and heart failure.

Adipose tissue (AT) lies at the crossroad of nutrition, metabolism, and immunity; AT inflammation was proposed as a central mechanism connecting obesity with its metabolic and vascular complications. Resident immune cells constitute the second largest AT cellular component after adipocytes and as such play important roles in the maintenance of AT homeostasis. Obesity-induced changes in their number and activity result in the activation of local and later systemic inflammatory response, marking the transition from simple adiposity to diseases such as type 2 diabetes mellitus, arterial hypertension, and ischemic heart disease. This review has focused on the various subsets of immune cells in AT and their role in the development of AT inflammation and obesity-induced insulin resistance.

During the last 2 decades, the treatment of hyperglycemia in critically ill patients has become one of the most discussed topics in the intensive medicine field. The initial data suggesting significant benefit of normalization of blood glucose levels in critically ill patients using intensive intravenous insulin therapy have been challenged or even neglected by some later studies. At the moment, the need for glucose control in critically ill patients is generally accepted yet the target glucose values are still the subject of ongoing debates. In this review, we summarize the current data on the benefits and risks of tight glucose control in critically ill patients focusing on the novel technological approaches including continuous glucose monitoring and its combination with computer-based algorithms that might help to overcome some of the hurdles of tight glucose control. Since increased risk of hypoglycemia appears to be the major obstacle of tight glucose control, we try to put forward novel approaches that may help to achieve optimal glucose control with low risk of hypoglycemia. If such approaches can be implemented in real-world practice the entire concept of tight glucose control may need to be revisited.

Changes in endocrine function of adipose tissue during surgery, such as excessive production of proinflammatory cytokines, can significantly alter metabolic response to surgery and worsen its outcomes and prognosis of patients. Therapeutic hypothermia has been used to prevent damage connected with perioperative ischemia and hypoperfusion. The aim of our study was to explore the influence of deep hypothermia on systemic and local inflammation, adipose tissue hypoxia and adipocytokine production. We compared serum concentrations of proinflammatory markers (CRP, IL-6, IL-8, sIL-2R, sTNFRI, PCT) and mRNA expression of selected genes involved in inflammatory reactions (IL-6, TNF-α, MCP-1, MIF) and adaptation to hypoxia and oxidative stress (HIF1-α, MT3, GLUT1, IRS1, GPX1, BCL-2) in subcutaneous and visceral adipose tissue and in isolated adipocytes of patients undergoing cardiosurgical operation with hypothermic period. Deep hypothermia significantly delayed the onset of surgery-related systemic inflammatory response. The relative gene expression of the studied genes was not altered during the hypothermic period, but was significantly changed in six out of ten studied genes (IL-6, MCP-1, TNF-α, HIF1-α, GLUT1, GPX1) at the end of surgery. Our results show that deep hypothermia suppresses the development of systemic inflammatory response, delays the onset of local adipose tissue inflammation and thus may protect against excessive expression of proinflammatory and hypoxia-related factors in patients undergoing elective cardiac surgery procedure.

Aim. In postcardiac surgery patients, we assessed the performance of a system for intensive intravenous insulin therapy using continuous glucose monitoring (CGM) and enhanced model predictive control (eMPC) algorithm.Methods. Glucose control in eMPC-CGM group (n=12) was compared with a control (C) group (n=12) treated by intravenous insulin infusion adjusted according to eMPC protocol with a variable sampling interval alone. In the eMPC-CGM group glucose measured with a REAL-Time CGM system (Guardian RT) served as input for the eMPC adjusting insulin infusion every 15 minutes. The accuracy of CGM was evaluated hourly using reference arterial glucose and Clarke error-grid analysis (C-EGA). Target glucose range was 4.4–6.1 mmol/L.Results. Of the 277 paired CGM-reference glycemic values, 270 (97.5%) were in clinically acceptable zones of C-EGA and only 7 (2.5%) were in unacceptable D zone. Glucose control in eMPC-CGM group was comparable to C group in all measured values (average glycemia, percentage of time above, within, and below target range,). No episode of hypoglycemia (Conclusion. Our data show that the combination of eMPC algorithm with CGM is reliable and accurate enough to test this approach in a larger study population.

Recent studies linked circulating pigment epithelium-derived factor (PEDF) to obesity-associated insulin resistance, but the main source of circulating PEDF is unknown. We aimed to investigate liver and adipose tissue PEDF gene expression in association with obesity and insulin resistance. Three (two cross-sectional and one longitudinal) independent cohorts have been studied, for adipose tissue (n=80 and n=30) and liver gene expression (n=32 and n=14). Effects of high glucose and cytokines on HepG2 cell line were also investigated. PEDF gene expression and circulating PEDF were analyzed using real-time PCR and ELISA, respectively. In a first cohort of subjects, PEDF relative gene expression was higher in subcutaneous (SC) than in omental (OM) adipose tissue (P

Summary Objective Fibroblast growth factor-21 (FGF21) is a novel endocrine and paracrine regulator of metabolic homeostasis. The aim of our study was to measure its serum concentrations in patients with obesity, obesity and type 2 diabetes mellitus (T2DM) and healthy subjects (C), and to assess the changes of its circulating levels and mRNA expression after dietary and pharmacological interventions. Design We measured biochemical parameters, serum FGF21, adiponectin, leptin and insulin levels by commercial ELISA and RIA kits, and mRNA expression in the liver, subcutaneous and visceral fat by RT PCR in 26 obese patients, 11 T2DM patients and 32 control subjects. The interventions were acute hyperinsulinaemia during isoglycaemic–hyperinsulinaemic clamp, very low calorie diet (VLCD) and 3 months treatment with PPAR-α agonist fenofibrate. Results Baseline serum FGF21 levels were significantly higher in both obese and T2DM patients relative to healthy controls. FGF21 levels in obesity did not significantly differ from T2DM group. Both 3 weeks of VLCD and 3 months of fenofibrate treatment significantly increased FGF21 levels. FGF21 mRNA expression in visceral fat was twofold higher in obesity relative to C group, while it did not differ in subcutaneous fat. VLCD significantly increased FGF21 mRNA expression in subcutaneous fat of obesity. 3-h hyperinsulinaemia during the clamp increased FGF21 levels in T2DM but not in C group. Conclusion An increase in FGF21 levels after VLCD and fenofibrate treatment may contribute to positive metabolic effect of these interventions and suggests the possibility of direct positive metabolic effects of FGF21 in humans.

Clusterin is a heterodimeric glycoprotein with wide range of functions. To further explore its possible regulatory role in energy homeostasis and in adipose tissue, we measured plasma clusterin and its mRNA expression in subcutaneous adipose tissue (SCAT) of 15 healthy lean women, 15 obese women (OB) and 15 obese women with type 2 diabetes mellitus (T2DM) who underwent a 2-week very low-calorie diet (VLCD), 10 obese women without T2DM who underwent laparoscopic sleeve gastrectomy (LSG) and 8 patients with T2DM, 8 patients with impaired glucose tolerance (IGT) and 8 normoglycemic patients who underwent hyperinsulinemic euglycemic clamp (HEC). VLCD decreased plasma clusterin in OB but not in T2DM patients while LSG and HEC had no effect. Clusterin mRNA expression in SCAT at baseline was increased in OB and T2DM patients compared with controls. Clusterin mRNA expression decreased 6 months after LSG and remained decreased 12 months after LSG. mRNA expression of clusterin was elevated at the end of HEC compared with baseline only in normoglycemic but not in IGT or T2DM patients. In summary, our data suggest a possible local regulatory role for clusterin in the adipose tissue rather than its systemic involvement in the regulation of energy homeostasis.

We explored the effect of chronically elevated circulating levels of growth hormone (GH)/insulin-like-growth-factor-1 (IGF-1) on mRNA expression of GH/IGF-1/insulin axis components and p85alpha subunit of phosphoinositide-3-kinase (p85alpha) in subcutaneous adipose tissue (SCAT) of patients with active acromegaly and compared these findings with healthy control subjects in order to find its possible relationships with insulin resistance and body composition changes. Acromegaly group had significantly decreased percentage of truncal and whole body fat and increased homeostasis model assessment-insulin resistance (HOMA-IR). In SCAT, patients with acromegaly had significantly increased IGF-1 and IGF-binding protein-3 (IGFBP-3) expression that both positively correlated with serum GH. P85alpha expression in SCAT did not differ from control group. IGF-1 and IGFBP-3 expression in SCAT were not independently associated with percentage of truncal and whole body fat or with HOMA-IR while IGFBP-3 expression in SCAT was an independent predictor of insulin receptor as well as of p85alpha expression in SCAT. Our data suggest that GH overproduction in acromegaly group increases IGF-1 and IGFBP-3 expression in SCAT while it does not affect SCAT p85alpha expression. Increased IGF-1 or IGFBP-3 in SCAT of acromegaly group do not appear to contribute to systemic differences in insulin sensitivity but may have local regulatory effects in SCAT of patients with acromegaly.