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(1) Background: C1q TNF-related protein 3 (CTRP3) is an adipokine with anti-inflammatory and cardioprotective properties. In our study, we explored changes in serum CTRP3 and its gene expression in epicardial (EAT) and subcutaneous (SAT) adipose tissue in patients with and without coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) undergoing elective cardiac surgery. (2) Methods: SAT, EAT, and blood samples were collected at the start and end of surgery from 34 patients: (i) 11 without CAD or T2DM, (ii) 14 with CAD and without T2DM, and (iii) 9 with both CAD and T2DM. mRNA levels of CTRP3 were assessed by quantitative reverse transcription PCR. Circulating levels of CTRP3 and other factors were measured using ELISA and Luminex Multiplex commercial kits. (3) Results: Baseline plasma levels of TNF-α and IL6 did not differ among the groups and increased at the end of surgery. Baseline circulating levels of CTRP3 did not differ among the groups and decreased after surgery. In contrast, baseline CTRP3 mRNA levels in EAT were significantly decreased in CAD/T2DM group, while no differences were found for TNF- α and IL6 gene expression. (4) Conclusions: Our data suggest that decreased EAT mRNA levels of CTRP3 could contribute to higher risk of atherosclerosis in patients with CAD and T2DM., Competing Interests: The authors declare no conflict of interest.

Background: Adiponectin, adipocyte fatty acid-binding protein (A-FABP), and fibroblast growth factor-19 (FGF-19) belong to proteins involved in glucose metabolism regulation. The aims of the study were to compare the plasma levels of these proteins in women with early diagnosed gestational diabetes mellitus (GDM) to those in healthy controls and to investigate their changes during pregnancy after early intervention. Methods: The study was undertaken as a case-control study. Early GDM diagnosis was based on repeated fasting plasma glucose ≥5.1 and <7.0 mmol/L during the first trimester of pregnancy and exclusion of overt diabetes. Age-matched controls comprised healthy pregnant and non-pregnant women. In addition to adipokines, clinical parameters and measures of glucose control were assessed. Results: Women with GDM (n = 23) had significantly lower adiponectin and higher A-FABP levels compared to healthy pregnant (n = 29) or non-pregnant (n = 25) controls, while no significant differences in FGF-19 between the groups were found. The therapeutic intervention shifted adiponectin and A-FABP levels in GDM women towards concentrations of healthy pregnant controls. Adipokines were associated with visceral adiposity and glucose control. Conclusion: Women with GDM showed altered adipokine production even in the first trimester of pregnancy. Early therapeutic intervention not only improved glucose control but also normalized impaired adipokine production.

Type 2 diabetes mellitus represents a major health problem with increasing prevalence worldwide. Limited efficacy of current therapies has prompted a search for novel therapeutic options. Here we show that treatment of pre-diabetic mice with mitochondrially targeted tamoxifen, a potential anti-cancer agent with senolytic activity, improves glucose tolerance and reduces body weight with most pronounced reduction of visceral adipose tissue due to reduced food intake, suppressed adipogenesis and elimination of senescent cells. Glucose-lowering effect of mitochondrially targeted tamoxifen is linked to improvement of type 2 diabetes mellitus-related hormones profile and is accompanied by reduced lipid accumulation in liver. Lower senescent cell burden in various tissues, as well as its inhibitory effect on pre-adipocyte differentiation, results in lower level of circulating inflammatory mediators that typically enhance metabolic dysfunction. Targeting senescence with mitochodrially targeted tamoxifen thus represents an approach to the treatment of type 2 diabetes mellitus and its related comorbidities, promising a complex impact on senescence-related pathologies in aging population of patients with type 2 diabetes mellitus with potential translation into the clinic., (© 2022. The Author(s).)

Recent studies suggest that treatment with SGLT-2 inhibitors can reduce hepatic lipid storage and ameliorate non-alcoholic fatty liver disease (NAFLD) development beyond their glycemic benefits. However, the exact mechanism involved is still unclear. We investigated the hepatic metabolic effect of empagliflozin (10 mg/kg/day for eight weeks) on the development of NAFLD and its complications using HHTg rats as a non-obese prediabetic rat model. Empagliflozin treatment reduced neutral triacylglycerols and lipotoxic diacylglycerols in the liver and was accompanied by significant changes in relative mRNA expression of lipogenic enzymes ( Scd-1 , Fas ) and transcription factors ( Srebp1 , Pparγ ). In addition, alterations in the gene expression of cytochrome P450 proteins, particularly Cyp2e1 and Cyp4a , together with increased Nrf2, contributed to the improvement of hepatic lipid metabolism after empagliflozin administration. Decreased circulating levels of fetuin-A improved lipid metabolism and attenuated insulin resistance in the liver and in peripheral tissues. Our results highlight the beneficial effect of empagliflozin on hepatic lipid metabolism and lipid accumulation independent of obesity, with the mechanisms understood to involve decreased lipogenesis, alterations in cytochrome P450 proteins, and decreased fetuin-A. These changes help to alleviate NAFLD symptoms in the early phase of the disease and before the onset of diabetes.

(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.

Diabetes represents the leading risk factor for the development of cardiovascular disease (CVD). Chronic hyperglycemia and/or acute post-prandial changes in blood glucose determine an increase in reactive oxygen species (ROS), which play a fundamental role in endothelial dysfunction and in the nuclear transport of pro-atherogenic transcription factors that activate the "inflammasome". In addition, the glycemic alteration favors the formation and stabilization of atherosclerotic plaque through the mechanism of non-enzymatic glycation of different molecules, with the establishment of the so-called "advanced glycosylation end products" (AGE). Laboratory information provided by the level of biomarkers could make a quantitative and qualitative contribution to the clinical process of screening, prediction, prevention, diagnosis, prognosis and monitoring of cardiovascular (CV) risk linked to diabetes. This review describes the importance of specific biomarkers, with particular focus on novel ones, for stratifying and management of diabetes CV risk., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background & Aims: Reward circuitry in the brain plays a key role in weight regulation. We tested the effects of a plant-based meal on these brain regions., Methods: A randomized crossover design was used to test the effects of two energy- and macronutrient-matched meals: a vegan (V-meal) and a conventional meat (M-meal) on brain activity, gastrointestinal hormones, and satiety in participants with type 2 diabetes (T2D; n = 20), overweight/obese participants (O; n = 20), and healthy controls (H; n = 20). Brain perfusion was measured, using arterial spin labeling functional brain imaging; satiety was assessed using a visual analogue scale; and plasma concentrations of gut hormones were determined at 0 and 180 min. Repeated-measures ANOVA was used for statistical analysis. Bonferroni correction for multiple comparisons was applied. The Hedge's g statistic was used to measure the effect size for means of paired difference between the times (180-0 min) and meal types (M-V meal) for each group., Results: Thalamus perfusion was the highest in patients with T2D and the lowest in overweight/obese individuals (p = 0.001). Thalamus perfusion decreased significantly after ingestion of the M-meal in men with T2D (p = 0.04) and overweight/obese men (p = 0.004), and it decreased significantly after ingestion of the V-meal in healthy controls (p < 0.001; Group x Meal x Time: F = 3.4; p = 0.035). The effect size was -0.41 (95% CI, -1.14 to 0.31; p = 0.26) for men with diabetes; -0.72 (95% CI, -1.48 to 0.01; p = 0.05) for overweight/obese men; and 0.82 (95% CI, 0.09 to 1.59; p = 0.03) for healthy men. Postprandial secretion of active GLP-1 increased after the V-meal compared with the M-meal by 42% (95% CI 25-62%; p = 0.003) in men with T2D and by 41% (95% CI 24-61%; p = 0.002) in healthy controls. Changes in thalamus perfusion after ingestion of both test meals correlated with changes in satiety (r = +0.68; p < 0.01), fasting plasma insulin (r = +0.40; p < 0.01), C-peptide (r = +0.48; p < 0.01) and amylin (r = +0.55; p < 0.01), and insulin secretion at 5 mmol/l (r = +0.77; p < 0.05)., Conclusions: The higher postprandial GLP-1 secretion after the V-meal in men with T2D, with concomitant greater satiety and changes in thalamus perfusion, suggest a potential use of plant-based meals in addressing the key pathophysiologic mechanisms of food intake regulation. Trial registration ClinicalTrials.gov number, NCT02474147., Competing Interests: Conflict of interest None declared., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Cachexia worsens long-term prognosis of patients with heart failure (HF). Effective treatment of cachexia is missing. We seek to characterize mechanisms of cachexia in adipose tissue, which could serve as novel targets for the treatment., Methods: The study was conducted in advanced HF patients (n = 52; 83% male patients) undergoing heart transplantation. Patients with ≥7.5% non-intentional body weight (BW) loss during the last 6 months were rated cachectic. Clinical characteristics and circulating markers were compared between cachectic (n = 17) and the remaining, BW-stable patients. In epicardial adipose tissue (EAT), expression of selected genes was evaluated, and a combined metabolomic/lipidomic analysis was performed to assess (i) the role of adipose tissue metabolism in the development of cachexia and (ii) potential impact of cachexia-associated changes on EAT-myocardium environment., Results: Cachectic vs. BW-stable patients had higher plasma levels of natriuretic peptide B (BNP; 2007 ± 1229 vs. 1411 ± 1272 pg/mL; P = 0.010) and lower EAT thickness (2.1 ± 0.8 vs. 2.9 ± 1.4 mm; P = 0.010), and they were treated with ~2.5-fold lower dose of both β-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACE/ARB-inhibitors). The overall pattern of EAT gene expression suggested simultaneous activation of lipolysis and lipogenesis in cachexia. Lower ratio between expression levels of natriuretic peptide receptors C and A was observed in cachectic vs. BW-stable patients (0.47 vs. 1.30), supporting activation of EAT lipolysis by natriuretic peptides. Fundamental differences in metabolome/lipidome between BW-stable and cachectic patients were found. Mitochondrial phospholipid cardiolipin (CL), specifically the least abundant CL 70:6 species (containing C16:1, C18:1, and C18:2 acyls), was the most discriminating analyte (partial least squares discriminant analysis; variable importance in projection score = 4). Its EAT levels were higher in cachectic as compared with BW-stable patients and correlated with the degree of BW loss during the last 6 months (r = -0.94; P = 0.036)., Conclusions: Our results suggest that (i) BNP signalling contributes to changes in EAT metabolism in cardiac cachexia and (ii) maintenance of stable BW and 'healthy' EAT-myocardium microenvironment depends on the ability to tolerate higher doses of both ACE/ARB inhibitors and β-adrenergic blockers. In line with preclinical studies, we show for the first time in humans the association of cachexia with increased adipose tissue levels of CL. Specifically, CL 70:6 could precipitate wasting of adipose tissue, and thus, it could represent a therapeutic target to ameliorate cachexia., (© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Objectives: It is suggested that delivery whether spontaneous or by elective cesarean section is associated with an inflammatory reaction which may be modified by the type of delivery. Inflammatory reactions are associated with endothelial activation. The aim of our study was to assess endothelial biomarkers in cord and neonatal blood following different modes of delivery., Study Design: The study group consisted of term healthy newborns after uncomplicated pregnancies and either spontaneous vaginal delivery (n = 39) or elective cesarean section (n = 20). Plasma soluble biomarkers were measured using multiplex magnetic bead immunoassay. The microvesicle count and number of surface antigen-specific microvesicles were determined by flow cytometry., Results: We found significantly increased concentrations of cord blood endothelial markers (sVEGFR1, Endothelin-1 and sVCAM1) and microvesicles (EPCR/CD201+, ICAM1/CD54+ and PECAM1/CD31+) in spontaneous vaginal delivery when compared to elective cesarean section. Irrespective of the delivery mode endothelial markers sVEGFR1, Endocan, Angiopoietin-2, VEGF, and sICAM1, were significantly increased in neonatal compared to cord blood., Conclusion: We found increased cord blood concentrations of endothelial markers and microvesicles following spontaneous vaginal delivery, which may reflect the natural activation of endothelial cells during labor. Following the delivery, most of the soluble markers increased, as a possible consequence of activation of neonatal innate immunity and postnatal cardiovascular transition., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Patients with type 2 diabetes (T2DM) generally experience a higher incidence of cancer. However, the association between T2DM and thyroid cancer is inconclusive., Methods: Case-control prospective study, 722 patients were screened for T2DM and prediabetes (PDM) and underwent thyroid ultrasound and biochemical tests. The patients were assigned to groups of PDM (n=55), T2DM (n=79) or a non-diabetes group (NDM) (n=588). Fine needle aspiration biopsy was carried out in 263 patients. Histological examinations were done for 109 patients after surgery, with findings of 52 benign (BS) and 57 malignant tumors (MS)., Results: 33 % of patients with T2DM and especially PDM were newly diagnosed by our screening: 6.5 % with T2DM and 72 % with PDM, respectively. The percentage of thyroid cancers did not significantly differ between the groups (χ2 test=0.461; p=0.794). Relevant positive thyroid predictors for T2DM (t-statistic=25.87; p<0.01) and PDM (21.69; p<0.01) contrary to NDM (-26.9; p<0.01) were thyroid volume (4.79; p<0.01), thyroid nodule volume (3.25; p<0.01) and multinodular thyroid gland (4.83; p<0.01), while negative relevant predictors included the occurrence of autoimmune thyroid disease (AITD) (-2.01; p<0.05)., Conclusion: In general, we did not observe an increased risk for thyroid cancer in the diabetic and prediabetic groups in comparison to controls, in spite of well-established increased risk for other malignancies. Structural and benign changes such as larger and multinodular thyroid glands, in comparison to autoimmune thyroid disease, are present more often in diabetics.

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 (∆BMI-∆TU6.1: rho = - 0.67, P < .01) and between metabolic outcomes and glycaemic phasic control (∆FBG-∆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., (© 2020 John Wiley & Sons Ltd.)

Background and Aims: Dicarbonyl stress plays an important role in the pathogenesis of microvascular complications that precede the formation of advanced glycation end products, and contributes to the development of renal dysfunction. In renal cells, toxic metabolites like methylglyoxal lead to mitochondrial dysfunction and protein structure modifications.In our study, we investigated the effect of methylglyoxal on metabolic, transcriptomic, metabolomic and proteomic profiles in the context of the development of kidney impairment in the model of metabolic syndrome., Materials and Methods: Dicarbonyl stress was induced by intragastric administration of methylglyoxal (0.5 mg/kg bw for 4 weeks) in a strain of hereditary hypertriglyceridaemic rats with insulin resistance and fatty liver., Results: Methylglyoxal administration aggravated glucose intolerance (AUC 0-120 p  < 0.05), and increased plasma glucose ( p  < 0.01) and insulin ( p  < 0.05). Compared to controls, methylglyoxal-treated rats exhibited microalbuminuria ( p  < 0.01). Targeted proteomic analysis revealed increases in urinary secretion of pro-inflammatory parameters (MCP-1, IL-6, IL-8), specific collagen IV fragments and extracellular matrix proteins. Urine metabolomic biomarkers in methylglyoxal-treated rats were mainly associated with impairment of membrane phospholipids (8-isoprostane, 4-hydroxynonenal).Decreased levels of glutathione ( p  < 0.01) together with diminished activity of glutathione-dependent antioxidant enzymes contributed to oxidative and dicarbonyl stress. Methylglyoxal administration elevated glyoxalase 1 expression ( p  < 0.05), involved in methylglyoxal degradation. Based on comparative transcriptomic analysis of the kidney cortex, 96 genes were identified as differentially expressed (FDR < 0.05). Network analysis revealed an over-representation of genes related to oxidative stress and pro-inflammatory signalling pathways as well as an inhibition of angiogenesis suggesting its contribution to renal fibrosis., Conclusion: Our results support the hypothesis that dicarbonyl stress plays a key role in renal microvascular complications. At the transcriptome level, methylglyoxal activated oxidative and pro-inflammatory pathways and inhibited angiogenesis. These effects were further supported by the results of urinary proteomic and metabolomic analyses., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Nicotinamide phosphoribosyltransferase (NAMPT) is located in both the nucleus and cytoplasm and has multiple biological functions including catalyzing the rate-limiting step in NAD synthesis. Moreover, up-regulated NAMPT expression has been observed in many cancers. However, the determinants and regulation of NAMPT's nuclear transport are not known. Here, we constructed a GFP-NAMPT fusion protein to study NAMPT's subcellular trafficking. We observed that in unsynchronized 3T3-L1 preadipocytes, 25% of cells had higher GFP-NAMPT fluorescence in the cytoplasm, and 62% had higher GFP-NAMPT fluorescence in the nucleus. In HepG2 hepatocytes, 6% of cells had higher GFP-NAMPT fluorescence in the cytoplasm, and 84% had higher GFP-NAMPT fluorescence in the nucleus. In both 3T3-L1 and HepG2 cells, GFP-NAMPT was excluded from the nucleus immediately after mitosis and migrated back into it as the cell cycle progressed. In HepG2 cells, endogenous, untagged NAMPT displayed similar changes with the cell cycle, and in nonmitotic cells, GFP-NAMPT accumulated in the nucleus. Similarly, genotoxic, oxidative, or dicarbonyl stress also caused nuclear NAMPT localization. These interventions also increased poly(ADP-ribosyl) polymerase and sirtuin activity, suggesting an increased cellular demand for NAD. We identified a nuclear localization signal in NAMPT and amino acid substitution in this sequence ( 424 RSKK to ASGA), which did not affect its enzymatic activity, blocked nuclear NAMPT transport, slowed cell growth, and increased histone H 3 acetylation. These results suggest that NAMPT is transported into the nucleus where it presumably increases NAD synthesis required for cell proliferation. We conclude that specific inhibition of NAMPT transport into the nucleus might be a potential avenue for managing cancer., (© 2019 Svoboda et al.)

Diminished postprandial secretion of incretins and insulin represents one of the key pathophysiological mechanisms behind type 2 diabetes (T2D). We tested the effects of two energy- and macronutrient-matched meals: A standard meat (M-meal) and a vegan (V-meal) on postprandial incretin and insulin secretion in participants with T2D. A randomized crossover design was used in 20 participants with T2D. Plasma concentrations of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), amylin, and gastric inhibitory peptide (GIP) were determined at 0, 30, 60, 120, and 180 min. Beta-cell function was assessed with a mathematical model, using C-peptide deconvolution. Repeated-measures ANOVA was used for statistical analysis. Postprandial plasma glucose responses were similar after both test meals ( p = 0.64). An increase in the stimulated secretion of insulin (by 30.5%; 95% CI 21.2 to 40.7%; p < 0.001), C-peptide (by 7.1%; 95% CI 4.1 to 9.9%; p < 0.001), and amylin (by 15.7%; 95% CI 11.8 to 19.7%; p < 0.001) was observed following consumption of the V-meal. An increase in stimulated secretion of GLP-1 (by 19.2%; 95% CI 12.4 to 26.7%; p < 0.001) and a decrease in GIP (by -9.4%; 95% CI -17.3 to -0.7%; p = 0.02) were observed after the V-meal. Several parameters of beta-cell function increased after the V-meal, particularly insulin secretion at a fixed glucose value 5 mmol/L, rate sensitivity, and the potentiation factor. Our results showed an increase in postprandial incretin and insulin secretion, after consumption of a V-meal, suggesting a therapeutic potential of plant-based meals for improving beta-cell function in T2D.

One of the most significant challenges of current medicine is the increasing prevalence of obesity worldwide that is accompanied by a wide range of chronic health complications and increased mortality. White adipose tissue actively contributes to metabolic regulation by production of a variety of hormones and cytokines, commonly referred to as adipokines. The spectrum and quantity of adipokines produced by the adipose tissue of obese patients is directly or indirectly involved in much obesity-related pathology (type 2 diabetes mellitus, cardiovascular disease, inflammatory response). One of the underlying mechanisms linking obesity, diabetes, and cardiovascular complications is subclinical inflammation, primarily arising in visceral adipose tissue. Adipocyte size, number and polarization of lymphocytes and infiltrated macrophages are closely related to metabolic and obesity-related diseases. The storage capacity of hypertrophic adipocytes in obese patients is limited. This results in chronic energy overload and leads to increased apoptosis of adipocytes that in turn stimulates the infiltration of visceral adipose tissue by immune cells, in particular macrophages. These cells produce many proinflammatory factors; while the overall production of anti-inflammatory cytokines and adipokines is decreased. The constant release of proinflammatory factors into the circulation then contributes to a subclinical systemic inflammation, which is directly linked to the metabolic and cardiovascular complications of obesity.

Gastrointestinal hormones are involved in regulation of glucose metabolism and satiety. We tested the acute effect of meal composition on these hormones in three population groups. A randomized crossover design was used to examine the effects of two energy- and macronutrient-matched meals: a processed-meat and cheese (M-meal) and a vegan meal with tofu (V-meal) on gastrointestinal hormones, and satiety in men with type 2 diabetes (T2D, n = 20), obese men (O, n = 20), and healthy men (H, n = 20). Plasma concentrations of glucagon-like peptide -1 (GLP-1), amylin, and peptide YY (PYY) were determined at 0, 30, 60, 120 and 180 min. Visual analogue scale was used to assess satiety. We used repeated-measures Analysis of variance (ANOVA) for statistical analysis. Postprandial secretion of GLP-1 increased after the V-meal in T2D (by 30.5%; 95%CI 21.2 to 40.7%; p < 0.001) and H (by 15.8%; 95%CI 8.6 to 23.5%; p = 0.01). Postprandial plasma concentrations of amylin increased in in all groups after the V-meal: by 15.7% in T2D (95%CI 11.8 to 19.6%; p < 0.001); by 11.5% in O (95%CI 7.8 to 15.3%; p = 0.03); and by 13.8% in H (95%CI 8.4 to 19.5%; p < 0.001). An increase in postprandial values of PYY after the V-meal was significant only in H (by 18.9%; 95%CI 7.5 to 31.3%; p = 0.03). Satiety was greater in all participants after the V-meal: by 9% in T2D (95%CI 4.4 to 13.6%; p = 0.004); by 18.7% in O (95%CI 12.8 to 24.6%; p < 0.001); and by 25% in H (95%CI 18.2 to 31.7%; p < 0.001). Our results indicate there is an increase in gut hormones and satiety, following consumption of a single plant-based meal with tofu when compared with an energy- and macronutrient-matched processed-meat meat and cheese meal, in healthy, obese and diabetic men.

This paper analyses the performance of SampEn and one of its derivatives, Fuzzy Entropy (FuzzyEn), in the context of artifacted blood glucose time series classification. This is a difficult and practically unexplored framework, where the availability of more sensitive and reliable measures could be of great clinical impact. Although the advent of new blood glucose monitoring technologies may reduce the incidence of the problems stated above, incorrect device or sensor manipulation, patient adherence, sensor detachment, time constraints, adoption barriers or affordability can still result in relatively short and artifacted records, as the ones analyzed in this paper or in other similar works. This study is aimed at characterizing the changes induced by such artifacts, enabling the arrangement of countermeasures in advance when possible. Despite the presence of these disturbances, results demonstrate that SampEn and FuzzyEn are sufficiently robust to achieve a significant classification performance, using records obtained from patients with duodenal-jejunal exclusion. The classification results, in terms of area under the ROC of up to 0.9, with several tests yielding AUC values also greater than 0.8, and in terms of a leave-one-out average classification accuracy of 80%, confirm the potential of these measures in this context despite the presence of artifacts, with SampEn having slightly better performance than FuzzyEn.

Introduction: The aim of this study was to determine the level of awareness of hypoglycemia, the level of fear for hypoglycemia, and the response to hypoglycemic events among insulin-treated diabetes patients from Central and Eastern Europe (CEE). The impact of hypoglycemia on the use of healthcare resources and patient productivity was also assessed., Methods: This was a multicenter, non-interventional, two-part, patient self-reported questionnaire study that comprised both a retrospective cross-sectional evaluation and a prospective observational evaluation. Study participants were insulin-treated adult patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) from CEE., Results: Most patients (85.4% T1DM and 83.6% T2DM) reported normal hypoglycemia awareness. The median hypoglycemia fear score was 5 out of 10 for T1DM and 4 out of 10 for T2DM patients. Patients increased glucose monitoring, consulted a doctor/nurse, and/or reduced the insulin dose in response to hypoglycemia. As a consequence of hypoglycemia, patients took leave from work/studies or arrived late and/or left early. Hospitalization was required for 31 (1.2%) patients with T1DM and 66 (2.1%) patients with T2DM., Conclusion: Hypoglycemia impacts patients' personal and social functioning, reduces productivity, and results in additional costs, both direct (related to increased use of healthcare resources) and indirect (related to absenteeism., Funding: Novo Nordisk.

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: To explore partial jejunal diversion (PJD) via a side-to-side jejuno-jejunostomy for improved glycemic control in type 2 diabetes mellitus (T2DM). PJD is an anatomy-sparing, technically simple surgery in comparison to the predominate metabolic procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Positive results in a rodent model prompted a human proof-of-concept study., Research Design and Methods: Pre-clinically, 71 rats were studied in a model of metabolic dysfunction induced by a high-fat diet; 33 animals undergoing one of two lengths of PJD were compared with 18 undergoing sham, 10 RYGB and 10 jejuno-ileal bypass. Clinically, 15 adult subjects with treated but inadequately controlled T2DM (hemoglobin A1c (HbA1c) of 8.0%-11.0%), body mass index of 27.0-40.0 kg/m 2 , and C peptide ≥3 ng/mL were studied. Follow-up was at 2 weeks, and 3, 6, 9, and 12 months post-PJD., Results: Pre-clinically, positive impacts with PJD on glucose homeostasis, cholesterol, and body composition versus sham control were demonstrated. Clinically, PJD was performed successfully without serious complications. Twelve months post-surgery, the mean (SD) reduction from baseline in HbA1c was 2.3% (1.3) (p<0.01)., Conclusions: PJD may provide an anatomy sparing, low-risk, intervention for poorly controlled T2DM without significant alteration of the patient's lifestyle. The proof-of-concept study is limited by a small sample size and advanced disease, with 80% of participants on insulin and a mean time since diagnosis of over 10 years. Further study is warranted., Trial Registration Number: NCT02283632; Pre-results., Competing Interests: Competing interests: MF, KD, APC, and MH have nothing to declare. RJS currently receives funding from Ethicon, Inc. EJF, RS, MLS, and JRW are employed by Ethicon, Inc.

Objective: As glucagon-like peptide-1 receptor agonists lower blood pressure (BP) in type 2 diabetes mellitus (T2DM), we examined BP control in relation to targets set by international bodies prior to randomization in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial., Methods: We analyzed baseline data from LEADER (NCT01179048), an ongoing phase 3B, randomized, double-blind, placebo-controlled cardiovascular outcomes trial examining the cardiovascular safety of the glucagon-like peptide-1 receptor agonist liraglutide in 9340 people with T2DM from 32 countries [age (all mean ± SD) 64 ± 7.2 years, BMI 32.5 ± 6.3 kg/m, duration of diabetes 12.7 ± 8.0 years], all of whom were at high risk for cardiovascular disease (CVD)., Results: A total of 81% (n = 7592) of participants had prior CVD and 90% (n = 8408) had a prior history of hypertension. Despite prescription of multiple antihypertensive agents at baseline, only 51% were treated to a target BP of less than 140/85 mmHg and only 26% to the recommended baseline BP target of less than 130/80 mmHg. In univariate analyses, those with prior CVD were prescribed more agents (P < 0.001) and had lower BP than those without (137 ± 18.8/78 ± 10.6 mmHg versus 140 ± 17.7/80 ± 9.9 mmHg; P < 0.001). In logistic regression analyses, residency in North America (64% treated to <140/85 mmHg; 38% treated to <130/80 mmHg) was the strongest predictor of BP control., Conclusion: These contemporary data confirm that BP remains insufficiently controlled in a large proportion of individuals with T2DM at high cardiovascular risk, particularly outside North America. Longitudinal data from the LEADER trial may provide further insights into BP control in relation to cardiovascular outcomes in this condition.

Background: Huntington's disease is induced by CAG expansion in a single gene coding the huntingtin protein. The mutated huntingtin (mtHtt) primarily causes degeneration of neurons in the brain, but it also affects peripheral tissues, including testes., Objective: We studied sperm and testes of transgenic boars expressing the N-terminal region of human mtHtt., Methods: In this study, measures of reproductive parameters and electron microscopy (EM) images of spermatozoa and testes of transgenic (TgHD) and wild-type (WT) boars of F1 (24-48 months old) and F2 (12-36 months old) generations were compared. In addition, immunofluorescence, immunohistochemistry, Western blot, hormonal analysis and whole-genome sequencing were done in order to elucidate the effects of mtHtt., Results: Evidence for fertility failure of both TgHD generations was observed at the age of 13 months. Reproductive parameters declined and progressively worsened with age. EM revealed numerous pathological features in sperm tails and in testicular epithelium from 24- and 36-month-old TgHD boars. Moreover, immunohistochemistry confirmed significantly lower proliferation activity of spermatogonia in transgenic testes. mtHtt was highly expressed in spermatozoa and testes of TgHD boars and localized in all cells of seminiferous tubules. Levels of fertility-related hormones did not differ in TgHD and WT siblings. Genome analysis confirmed that insertion of the lentiviral construct did not interrupt any coding sequence in the pig genome., Conclusions: The sperm and testicular degeneration of TgHD boars is caused by gain-of-function of the highly expressed mtHtt., (© 2016 S. Karger AG, Basel.)

Background: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of a metabolic syndrome. To date, liver biopsy has been the gold standard used to differentiate between simple steatosis and steatohepatitis/fibrosis. Our aim was to compare the relevance of serum non-invasive parameters and scoring systems in the staging of liver fibrosis and non-alcoholic steatohepatitis (NASH) in patients with NAFLD., Methods and Findings: A total of 112 consecutive patients diagnosed with NAFLD were included. A liver biopsy was performed on 56 patients. The Kleiner score was used for the staging and grading of the histology. Non-invasive parameters for fibrosis (hyaluronic acid; AST/ALT; fibrosis scoring indexes OELF, ELF, BARD score, APRI, NAFLD fibrosis score); and inflammation (M30 and M65 cytokeratin-18 fragments) were measured and calculated. The same analyses were performed in 56 patients diagnosed with NAFLD, who were not indicated for liver biopsy. Based on the liver histology, NASH was diagnosed in 38 patients; simple steatosis in 18 patients. A cut-off value of 750 U/L of serum M65 discriminated patients with and without NASH with a 80% sensitivity and 82% specificity (95% CI:57-95). Fibrosis stage F0-F2 was present in 39 patients; F3-F4 in 17 patients. Serum concentrations of hyaluronic acid were higher in patients with advanced fibrosis (p<0.01); a cut-off value of 25 µg/l discriminated patients with F3-F4 with a 90% sensitivity and 84% specificity from those with F0-F2 (95% CI:59-99). When applying the non-invasive criteria to those patients without a liver biopsy, NASH could only be diagnosed in 16%; however, advanced fibrosis could be diagnosed in 35% of them., Conclusions: In patients with NAFLD, non-invasive serum parameters with a high accuracy can differentiate those patients with NASH and/or advanced fibrosis from those with simple steatosis. A substantial portion of those patients not indicated for liver biopsy might have undiagnosed advanced fibrosis.

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., (© 2014 Society for Endocrinology.)

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., (© 2014 Diabetes Technology Society.)

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., (Copyright © 2014. Published by Elsevier Inc.)

Introduction: Laparoscopic sleeve gastrectomy (LSG) is a bariatric procedure with very good long-term weight-reducing and metabolic effects., Aim: Here we report 6 years' experience with LSG performed in morbidly obese patients by one surgical team focusing on the impact of the degree of sleeve restriction and safety of the procedure without over-sewing the staple line., Material and Methods: From 2006 to 2012, 207 morbid obese patients with average age of 43.4 years and average body mass index 44.9 kg/m(2) underwent LSG without over-sewing the staple line. The complete 5- and 3-year follow-up is recorded in 59 and 117 patients with prospective data collection at 3, 6, 9, 12, 18, 24, 36, 42 and 60 months after LSG. Group 1 patients operated in 2006-2008 had smaller sleeve restriction. Group 2 patients operated in 2009-2012 had major sleeve restriction. All procedures were performed without over-sewing of the staple line., Results: The average %EBMIL (excess body mass index loss) in group 1 patients with minor sleeve restriction reached 54.1% and average %EWL (excess weight loss) was 50.8% while in group 2 with major sleeve restriction the average %EBMIL reached 69.7% and average %EWL was 66.8%. Final weight reduction was significantly higher in group 2 patients compared to group 1 patients with smaller sleeve restriction. Out of 49 patients with preoperatively diagnosed T2DM (type 2 diabetes mellitus) was completely resolved in 70.8%. Pre-operatively diagnosed hypertension normalized in 64.2%, improved in 23.2%, and remained unchanged in 12.6% of patients., Conclusions: Carefully performed LSG without over-sewing the staple line is feasible and safe. A better weight-reducing effect was present in patients with major sleeve restriction.

Background & Aims: Wilson disease (WD) is an inherited disorder of copper disposition caused by an ATP7B transporter gene mutation, leading to copper accumulation in predisposed tissues. In addition to a genetic predisposition, other factors are likely to contribute to its clinical manifestation. The aim of the study was to assess whether oxidative stress affects the phenotypic manifestation of WD., Methods: In 56 patients with WD (29 men; 26 with the hepatic form, 22 with the neurologic form, and eight asymptomatic; mean age 38.5 ± 12 years), total serum antioxidant capacity (TAC) and inflammatory parameters (hs-CRP, IL-1β, IL-2, IL-6, IL-10, and TNF-α) were analyzed and related to the clinical manifestation, and mutations of the ATP7B gene. The control group for the TAC and inflammatory parameters consisted of 50 age- and gender-matched healthy individuals., Results: WD patients had a significantly lower TAC (p < 0.00001), lower IL-10 levels (p = 0.039), as well as both higher IL-1β (p = 0.019) and IL-6 (p = 0.005) levels compared to the control subjects. TNF-α, hs-CRP, and IL-2 did not differ from the controls. Patients with the neurological form of WD had a significantly lower TAC than those with the hepatic form (p < 0.001). In addition, the lower TAC was associated with the severity of the neurological symptoms (p = 0.02). No relationship between the inflammatory parameters and clinical symptoms was found., Conclusions: Data from our study suggest that the increased oxidative stress contributes significantly to the clinical manifestation of WD; as a lower TAC is associated with the neurological symptoms in WD patients.

The peroxisome proliferator activated receptor-α (PPARα) is a major transcriptional regulator of lipid metabolism in liver and represents the molecular target for hypolipidemic fibrate drugs. Effects of PPARα on lipid metabolism are partially mediated by circulating proteins such as FGF21 and ANGPTL4. The present study was undertaken to screen for and identify circulating proteins produced by human liver that are under the control of PPARα. Toward that aim, primary human hepatocytes were treated with the synthetic PPARα agonist Wy-14643 and whole genome expression data selected for secreted proteins. Expression of FGF21, ANGPTL4, and mannose-binding lectin (MBL), a soluble mediator of innate immunity and primary component of the lectin branch of the complement system, was markedly upregulated by Wy-14643 in primary human hepatocytes. Mice express two MBL isomers, Mbl1 and Mbl2. Mbl1 mRNA was weakly induced by Wy-14643 in primary mouse hepatocytes and remained unaltered by Wy-14643 in mouse liver. Mbl2 mRNA was unchanged by Wy-14643 in primary mouse hepatocytes and was strongly reduced by Wy-14643 in mouse liver. Remarkably, plasma Mbl1 levels were increased by chronic PPARα activation in lean and obese mice. Importantly, in two independent clinical trials, treatment with the PPARα agonist fenofibrate at 200 mg/day for 6 wk and 3 mo increased plasma MBL levels by 73 (P = 0.0016) and 86% (P = 0.017), respectively. It is concluded that hepatocyte gene expression and plasma levels of MBL are stimulated by PPARα and fenofibrate in humans, linking PPARα to regulation of innate immunity and complement activation in humans and suggesting a possible role of MBL in lipid metabolism.

Objectives: The influence of body fat reduction on adipocyte fatty acid-binding protein (A-FABP) in obese patients with type 1 diabetes mellitus (T1DM) was investigated to examine whether it relates to the etiopathogenesis of insulin resistance (IR) and obesity., Methods: We studied 14 obese patients with T1DM and IR (42.6±9.4 years, BMI 32.4±2.1 kg/m2) and 13 non-obese control patients with T1DM (36.9±13.9 years, BMI 22.6±2.1 kg/m2). Plasma FABP was measured by ELISA and plasma free fatty acids (FFA) were measured spectrophotometrically before weight reduction, immediately after 7 days of fasting and after 21 days on a low-calorie diet. The control group was studied only after overnight fasting. Body composition was examined using bioimpedance spectroscopy. The means ± SD, T-test, one-way ANOVA and Spearman's correlation were used for statistical evaluation., Results: All patients tolerated the period of fasting. Obese T1DM patients lost 6.1±1.1 kg. There was a significant decrease in body mass index and body fat measured 21 days after weight reduction (p<0.05). Plasma FABP and FFA concentrations in obese T1DM patients before weight reduction were significantly higher than in controls, further increased significantly after fasting (p<0.05) and were restored thereafter. Significant positive correlations between FABP and FFA and between FABP and BMI (p<0.05) were found., Conclusion: Increased plasma FABP indicates insulin resistance in obese patients with T1DM. Weight reduction in T1DM patients is associated with a desirable decrease of body fat and transiently increased FABP. This increase might be a temporary adaptation of metabolism to non-stress fasting.

Objectives: Weight gain has been reported in patients with Parkinson's disease (PD) treated with deep brain stimulation of the subthalamic nucleus (STN-DBS). To evaluate the influence of STN-DBS on weight changes, we studied food-related hormones., Design: Anthropometric parameters and food-related hormones (leptin, adiponectin, resistin, ghrelin, cortisol, insulin, and thyroid stimulating hormone) were measured in 27 patients with STN-DBS during a 12 month period following electrode implantation., Results: Besides marked motor improvements on STN-DBS, PD patients significantly gained weight. The mean weight gain at 12 months was 5.2±(SD)5.8 kg. A significant decrease in cortisol levels compared to baseline appeared at month 2 and persisted at 12 months (p<0.01, corrected), with no significant changes in other hormones tested., Conclusions: Changes in peripheral food-related hormones do not appear to cause weight gain in PD patients. Direct effects of STN-DBS on hypothalamic catabolic/anabolic peptide balance remain hypothetical and necessitate further elucidation.

Objective: The number of patients with end-stage renal disease (ESRD) is rising and these patients are at higher risk of cardiovascular disease. We studied the role of hormonal production of adipose tissue in the development of chronic inflammation in patients with ESRD before kidney transplantation., Methods: Fifteen women with ESRD and 17 healthy women (control) underwent single blood drawing and visceral and subcutaneous adipose tissue sampling during surgery (kidney transplantation in the ESRD group or cholecystectomy in the control group). Serum concentrations of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, leptin, adiponectin, resistin, monocyte chemoattractant protein-1 were measured. Messenger RNA expression of the same hormones, adiponectin receptors 1 and 2 and immunocompetent cell marker CD68 in subcutaneous and visceral samples were measured using real-time polymerase chain reaction. Adipose tissue was examined immunohistochemically for CD68-positive cells., Results: Serum concentrations of C-reactive protein, adiponectin, resistin, interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 were significantly higher in the ESRD versus control group. Subcutaneous and visceral mRNA expressions of tumor necrosis factor-alpha and CD68 were significantly increased in the ESRD versus control group. Adiponectin receptor-1 and monocyte chemoattractant protein-1 mRNA expressions were significantly higher in visceral but not in subcutaneous adipose tissue of the ESRD group. Messenger RNA expressions of resistin, leptin, adiponectin, interleukin-6, and adiponectin receptor-2 in both fat depots did not significantly differ between groups. Increased infiltration of subcutaneous and visceral adipose tissue with CD68-positive immunocompetent cells was found in the ESRD group by histologic examination., Conclusion: Subcutaneous and visceral adipose tissues in ESRD express higher amounts of proinflammatory cytokines and may play a role in the development of systemic inflammation.

We investigated the role of LMNA in adipose tissue by developing a novel mouse model of lipodystrophy. Transgenic mice were generated that express the LMNA mutation that causes familial partial lipodystrophy of the Dunnigan type (FPLD2). The phenotype observed in FPLD-transgenic mice resembles many of the features of human FPLD2, including lack of fat accumulation, insulin resistance, and enlarged, fatty liver. Similar to the human disease, FPLD-transgenic mice appear to develop normally, but after several weeks they are unable to accumulate fat to the same extent as their wild-type littermates. One poorly understood aspect of lipodystrophies is the mechanism of fat loss. To this end, we have examined the effects of the FPLD2 mutation on fat cell function. Contrary to the current literature, which suggests FPLD2 results in a loss of fat, we found that the key mechanism contributing to the lack of fat accumulation involves not a loss, but an apparent inability of the adipose tissue to renew itself. Specifically, preadipocytes are unable to differentiate into mature and fully functional adipocytes. These findings provide insights not only for the treatment of lipodystrophies, but also for the study of adipogenesis, obesity, and insulin resistance.

Objective: We performed a randomized trial to compare three insulin-titration protocols for tight glycemic control (TGC) in a surgical intensive care unit: an absolute glucose (Matias) protocol, a relative glucose change (Bath) protocol, and an enhanced model predictive control (eMPC) algorithm., Research Design and Methods: A total of 120 consecutive patients after cardiac surgery were randomly assigned to the three protocols with a target glycemia range from 4.4 to 6.1 mmol/l. Intravenous insulin was administered continuously or in combination with insulin boluses (Matias protocol). Blood glucose was measured in 1- to 4-h intervals as requested by the protocols., Results: The eMPC algorithm gave the best performance as assessed by time to target (8.8 +/- 2.2 vs. 10.9 +/- 1.0 vs. 12.3 +/- 1.9 h; eMPC vs. Matias vs. Bath, respectively; P < 0.05), average blood glucose after reaching the target (5.2 +/- 0.1 vs. 6.2 +/- 0.1 vs. 5.8 +/- 0.1 mmol/l; P < 0.01), time in target (62.8 +/- 4.4 vs. 48.4 +/- 3.28 vs. 55.5 +/- 3.2%; P < 0.05), time in hyperglycemia >8.3 mmol/l (1.3 +/- 1.2 vs. 12.8 +/- 2.2 vs. 6.5 +/- 2.0%; P < 0.05), and sampling interval (2.3 +/- 0.1 vs. 2.1 +/- 0.1 vs. 1.8 +/- 0.1 h; P < 0.05). However, time in hypoglycemia risk range (2.9-4.3 mmol/l) in the eMPC group was the longest (22.2 +/- 1.9 vs. 10.9 +/- 1.5 vs. 13.1 +/- 1.6; P < 0.05). No severe hypoglycemic episode (<2.3 mmol/l) occurred in the eMPC group compared with one in the Matias group and two in the Bath group., Conclusions: The eMPC algorithm provided the best TGC without increasing the risk of severe hypoglycemia while requiring the fewest glucose measurements. Overall, all protocols were safe and effective in the maintenance of TGC in cardiac surgery patients.

Objective: Food intake is activated by hypothalamic orexigenic neuropeptide Y (NPY), which is mainly under the dual control of leptin and ghrelin. Rat adjuvant arthritis (AA), similarly as human rheumatoid arthritis, is associated with cachexia caused by yet unknown mechanisms. The aim of our study was to evaluate NPY expression in hypothalamic arcuate nuclei (nARC) under the conditions of AA-induced changes in leptin, ghrelin and adiponectin. Since IL-1beta is involved in the central induction of anorexia, we studied its expression in the nARC as well., Methods: AA was induced to Lewis rats using complete Freund's adjuvant. On days 12, 15 and 18 after complete Freund's adjuvant injection, the levels of leptin, adiponectin, ghrelin and IL-1beta were determined by RIA or ELISA. The mRNA expressions for NPY, leptin receptor (OB-R), ghrelin receptor (Ghsr) and IL-1beta were determined by TaqMan RT-PCR from isolated nARC., Results: In AA rats, decreased appetite, body mass and epididymal fat stores positively correlated with reduced circulating and epididymal fat leptin and adiponectin. Ghrelin plasma levels were increased. In nARC, mRNA for OB-R, Ghsr and NPY were overexpressed in AA rats. AA rats showed overexpression of mRNA for IL-1beta in nARC while circulating, and spleen IL-1beta was unaltered., Conclusion: During AA, overexpression of orexigenic NPY mRNA in nARC along with enhanced plasma ghrelin and lowered leptin levels occur. Decreased food intake indicates a predominant effect of the anorexigenic pathway. Activated expression of IL-1beta in nARC suggests its role in keeping AA-induced anorexia in progress. The reduction in adiponectin may also contribute to AA-induced anorexia., (Copyright 2009 S. Karger AG, Basel.)

Minimally invasive techniques to access subcutaneous adipose tissue for glucose monitoring are successfully applied in type1 diabetic and critically ill patients. During critical illness, the addition of a lactate sensor might enhance prognosis and early intervention. Our objective was to evaluate SAT as a site for lactate measurement in critically ill patients. In 40 patients after major cardiac surgery, arterial blood and SAT microdialysis samples were taken in hourly intervals. Lactate concentrations from SAT were prospectively calibrated to arterial blood. Analysis was based on comparison of absolute lactate concentrations (arterial blood vs. SAT) and on a 6-hour lactate trend analysis, to test whether changes of arterial lactate can be described by SAT lactate. Correlation between lactate readings from arterial blood vs. SAT was highly significant (r2 = 0.71, P < .001). Nevertheless, 42% of SAT lactate readings and 35% of the SAT lactate trends were not comparable to arterial blood. When a 6-hour stabilization period after catheter insertion was introduced, 5.5% of SAT readings and 41.6% of the SAT lactate trends remained incomparable to arterial blood. In conclusion, replacement of arterial blood lactate measurements by readings from SAT is associated with a substantial shortcoming in clinical predictability in patients after major cardiac surgery.

The aim of our study was to evaluate the influence of surgical removal of pheochromocytoma on the endocrine function of adipose tissue and subclinical inflammation as measured by circulating C-reactive protein (CRP) levels. Eighteen patients with newly diagnosed pheochromocytoma were included into study. Anthropometric measures, biochemical parameters, serum CRP, leptin, adiponectin and resistin levels were measured at the time of diagnosis and six months after surgical removal of pheochromocytoma. Surgical removal of pheochromocytoma significantly increased body weight, decreased both systolic and diastolic blood pressure, fasting blood glucose and glycated hemoglobin levels. Serum CRP levels were decreased by 50 % six months after surgical removal of pheochromocytoma (0.49+/-0.12 vs. 0.23+/-0.05 mg/l, p<0.05) despite a significant increase in body weight. Serum leptin, adiponectin and resistin levels were not affected by the surgery. We conclude that increased body weight in patients after surgical removal of pheochromocytoma is accompanied by an attenuation of subclinical inflammation probably due to catecholamine normalization. We failed to demonstrate an involvement of the changes in circulating leptin, adiponectin or resistin levels in this process.

EU project OLDES (Older People's e-services at home) develops easy to use and low cost ICT platform in order to offer a better quality of life to elderly people directly in their homes through innovative systems of tele-accompany, tele-assistance and tele-medicine. The elderly are able to access the services and send relevant medical data from their home by being connected to the central server via a low cost PC which is based on Negroponte paradigm. The OLDES platform interface uses television screens controlled through a remote control customized for the elderly. The feasibility of OLDES project is evaluated by the pilot study concentrating on compensation of diabetic patients. Compensation of diabetes is achieved by monitoring glucose glycemia level, blood pressure and weight. Moreover, the patient feeds into OLDES system daily consumption of food using interactive food scales and obtains advice if necessary.

Objective: We have assessed in obese renal transplant recipients a course of selected proinflammatory factors liable to influence the long-term outcome of transplant patients and kidney grafts., Design and Patients: In a prospective cohort study, we examined a total of 68 obese renal transplant recipients (body mass index [BMI] >or= 30 kg/m(2)) for a period of 12 months (Group I). A control group consisted of 72 comparable non-obese renal transplant recipients (Group II)., Results: Significant differences were found in plasma 12 months after renal transplantation (Group I versus Group II) in asymmetric dimethylarginine (ADMA; 3.68 micromol/L +/- 0.42 micromol/L vs 2.10 micromol/L +/- 0.34 micromol/L; P < .01), adiponectin (ADPN; 15.1 microg/mL +/- 6.0 microg/mL vs 22.80 microg/mL +/- 7.2 microg/mL; P < .01), leptin (50.4 ng/L +/- 10.2 ng/L vs 22.0 ng/L +/- 8.4 ng/L; P < .01), solubile leptin receptor (ObRe; 23.6 U/mL +/- 7.4 U/mL vs 47.2 U/mL +/- 10.7 U/mL; P < .01), resistin (21.2 microg/mL +/- 10.2 microg/mL vs 15.0 microg/mL +/- 6.2 microg/mL; P < .025) and triglycerides (3.9 mmol/L +/- 1.6 mmol/L vs 2.8 mmol/L +/- 1.6 mmol/L; P < .01). There were significant correlations between ADMA and BMI (r = 0.525, P < .001), ADPN and BMI (r = -0.574, P < .001), and ADMA and ADPN in visceral fat (r = -0.510, P < .001). Correlation between ADMA and Cin was weak, but significant (r = -0.190, P < .05)., Conclusion: The results indicate that obesity after renal transplantation was associated with increased plasma ADMA and decreased ADPN in plasma and in fat tissue and may represent a risk factor for renal transplant recipients.

Background: In the past few years, laparoscopic sleeve gastrectomy (LSG) became a widely used bariatric method. Based on results of recent LSG studies, LSG is being increasingly used even as a single bariatric method. On contrary with some other reports, we do not reinforce the LSG staple line with over-sewing. Our pilot study presents treatment outcomes and results 18 months after LSG., Methods: Sixty-one consecutive morbidly obese (MO) patients (19 male and 42 female) who underwent LSG from January 2006 to May 2008 were included into the study. The mean age, height, and weight were 37.3 years (29-57), 168 cm (151-187), and 118 kg (97-181), respectively, while mean body mass index (BMI) was 41.8 (36.1-60.4). LSG started at 6 cm from pylorus and ended at the angle of Hiss. For gastric sleeve calibration 38F, intragastric tube was used. All 61 LSG were performed without over-sewing of the staple line. In the last 24 cases, the staple line was covered with Surgiceltrade mark strips, which were however placed without any fixation to the underlying gastric tissue., Results: Mean operating time was 105 min (80-170) and no conversion to open surgery. An 18-month follow-up was recorded in 39 MO patients. The mean weight loss was 31.3 (range, 21-67 kg) and mean % excess BMI loss reached 72% (range, 64-97%). Neither leak nor disruptions of the staple line and/or sleeve dilatation were recorded., Conclusion: LSG is an effective and safe bariatric procedure with low incidence of complications and mortality in our experience.

Aim: Comparison of manual and automatic (MagNA Pure) isolation methods of total RNA from adipose tissue with respect to its quality and recovery factor., Material: 120 human subcutaneous adipose tissue samples (about 100 mg/sample) were collected from patients during surgical operations. The tissue sample was stabilized in RNAlater (QIAGEN GmbH, Germany)., Methods: Total RNA was extracted by the following kits: Rneasy Protect Mini, Rneasy Lipid Tissue (QIAGEN GmbH, Germany) and MagNA Pure Compact RNA Isolation (Tissue) for MagNA Pure Compact Instrument (Roche Diagnostics GmbH, Germany)., Results: The average RNA yields with Rneasy Lipid Tissue kits were about two-fold higher in comparison with the Rneasy Protect Mini kit. When the MagNA Pure Compact System was used, RNA yields from the same sample were more uniform compared with manual systems. It was also more convenient and less time-consuming than the manual approach. No DNA contamination of total RNA samples was detected except for samples isolated by Rneasy Protect Mini Kit., Conclusion: Rneasy Lipid Tissue Kit and MagNA Pure Compact RNA Isolation Kit (Tissue) provide RNA samples of high quantity, purity and PCR amplificability. RNA samples are suitable for further processing using methods of molecular biology.

The A-ZIP/F-1 transgenic mouse is a model of lipoatrophic diabetes with severe insulin resistance, hyperglycemia and hyperlipidemia. Recently, a regulatory role of adipose tissue on adrenal gland function and blood pressure has been suggested. To further explore the importance of adipose tissue in the regulation of adrenal function and blood pressure, we studied this mouse model of lipodystrophy. A-ZIP/F-1 mice exhibit significantly elevated systolic and diastolic blood pressure values despite lack of white adipose tissue and its hormones. Furthermore, A-ZIP/F-1 lipoatrophic mice have a significant reduction of adrenal zona glomerulosa, while plasma aldosterone levels and aldosterone synthase mRNA expression remain unchanged. On the other hand, lipoatrophic mice present elevated corticosterone levels but no adrenocortical hyperplasia. Ultrastructural analysis of adrenal gland show significant alterations in adrenocortical cells, with conformational changes of mitochondrial internal membranes and high amounts of liposomes. In conclusion, lipodystrophy in A-ZIP/F-1 mice is associated with hypertension, possibly due to hypercorticosteronemia and/or others metabolic-vascular changes.

Background: In obese renal transplant recipients, we assessed the course of selected proinflammatory factors liable to influence long-term outcomes of transplant patients and kidney grafts., Methods: In a prospective cohort study, we examined a total of 140 renal transplant recipients for a period of 12 months. Based on body mass index (BMI), patients were divided into Group I (BMI > or = 30 kg/m2, 68 patients) and Group II (BMI < or = 30 kg/m2, 72 patients)., Results: Twelve months after renal transplantation, significant differences were found between Group I versus Group II in plasma levels of asymmetric dimethylarginine (ADMA) (3.65 [SD +/- 0.47 micromol/L] versus 2.01 [SD +/- 0.36 micromol/L], P < .01), adiponectin (ADPN) (15.4 [SD +/- 6.6 microg/mL] versus 22.3 [SD +/- 8.2 microg/mL], P < .01), leptin (51.3 [SD +/- 11.2 ng/L] versus 21.3 [SD +/- 9.2 ng/L], P < .01), soluble leptin receptor (24.6 [SD +/- 8.4 U/mL] versus 46.1 [SD +/- 11.4 U/mL], P < .01), resistin (20.8 [SD +/- 10.1 microg/mL] versus 14.6 [SD +/- 6.4 microg/mL], P < .025), and triglycerides (3.9 [SD +/- 1.6] versus mmol/L 2.8 [SD +/- 1.6 mmol/L], P < .01). There were significant correlations between ADMA and BMI (r = 0.520; P < .001), and ADPN and BMI (r = -0.570, P < .001). The correlation between ADMA and inulin clearance (Cin) was weak (r = -0.185, P < .05)., Conclusions: Obesity after renal transplantation is associated with increased ADMA and decreased ADPN in plasma, and this may represent a risk factor for renal transplant recipients.

Resistin is a member of adipokine family involved in the regulation of inflammatory reactions and insulin sensitivity. In presented study its possible role in the development of benign prostate hyperplasia and prostate cancer was evaluated. Blood samples and prostate specimens were collected from 26 patients with benign prostate hyperplasia (BPH) and from 42 patients with prostate cancer (PCa) stage pT2 (n=18) and pT3 (n=24). Selected metabolic and biochemical parameters and serum resistin levels were measured and anthropometric measurements were performed as well as tissue immunohistochemistry for resistin. Serum resistin levels did not differ significantly between benign hyperplasia and prostate cancer but in cancer patients there was a trend towards decrease with higher cancer stage. Moreover, serum resistin levels were significantly lower in patients with seminal vesicle invasion in comparison to those without invasion. While in BPH serum resistin levels correlated with insulin resistance, inflammatory status and cortisol, in PCa positive correlation with F/T PSA ratio and cortisol was observed. Tissue immunohistochemistry did not show any differences in staining pattern between benign and neoplastic prostate tissue. We conclude that serum resistin levels do not significantly differ between patients with benign prostate hyperplasia and prostate cancer, but there is a trend towards decrease in resistin serum levels in advanced cancer cases.

EU project OLDES (Older People's e-services at home) aims at developing a very low cost and easy to use entertainment and health care platform designed to ease the life of older people in their homes. The platform is based on a PC corresponding to Negroponte's paradigm of a 100 $ device. OLDES combines user entertainment services (through easy-to-access thematic interactive channels and special interest forums supported by animators) and health care facilities. The pilot case study of diabetes type II compensation under the OLDES framework is presented. Apart from measurement of continuous glucose, blood pressure and weight, the user feeds into OLDES system food daily consumption using interactive food scales via user friendly software interface designed by user-centered design paradigm and obtains advice if necessary.

Objective: To study the influence of chronic malnutrition in patients with anorexia nervosa on endocrine function of adipose tissue on both circulating and subcutaneous fat mRNA expression level., Patients and Design: A total of 12 patients with anorexia nervosa and 18 normal weight age-matched women underwent anthropometric examination, single blood drawing and subcutaneous adipose tissue biopsy., Measurements: Serum concentrations of high-sensitive CRP (hsCRP), leptin, soluble leptin receptor, adiponectin, resistin, interleukin-6 and insulin were measured by Luminex, enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) kits. Subcutaneous adipose tissue mRNA expression of the same adipokines, adiponectin receptors 1 and 2 and immunocompetent cells marker CD68 was measured by real-time polymerase chain reaction (PCR)., Results: Decreased body fat content of patients with anorexia nervosa was accompanied by reduced hsCRP, leptin and increased adiponectin and soluble leptin receptor. Resistin, interleukin-6 and insulin levels did not differ from those of the control group. Fat mRNA adiponectin, leptin, interleukin-6 and CD68 expression was reduced, resistin mRNA expression was increased and adiponectin receptor 1 and 2 expression were unchanged as compared to the control group., Conclusions: Local perturbations in resistin, adiponectin and interleukin-6 mRNA expression in subcutaneous adipose tissue are not reflected by its circulating levels. These changes could be involved in some local metabolic disturbances in subcutaneous adipose tissue of anorexia nervosa patients.

Context: Elevated blood glucose levels occur frequently in the critically ill. Tight glucose control by intensive insulin treatment markedly improves clinical outcome., Objective and Design: This is a randomized controlled trial comparing blood glucose control by a laptop-based model predictive control algorithm with a variable sampling rate [enhanced model predictive control (eMPC); version 1.04.03] against a routine glucose management protocol (RMP) during the peri- and postoperative periods., Setting: The study was performed at the Department of Cardiac Surgery, University Hospital., Patients: A total of 60 elective cardiac surgery patients were included in the study., Interventions: Elective cardiac surgery and treatment with continuous insulin infusion (eMPC) or continuous insulin infusion combined with iv insulin boluses (RMP) to maintain euglycemia (target range 4.4-6.1 mmol/liter) were performed. There were 30 patients randomized for eMPC and 30 for RMP treatment. Blood glucose was measured in 1- to 4-h intervals as requested by each algorithm during surgery and postoperatively over 24 h., Main Outcome Measures: Mean blood glucose, percentage of time in target range, and hypoglycemia events were used., Results: Mean blood glucose was 6.2 +/- 1.1 mmol/liter in the eMPC vs. 7.2 +/- 1.1 mmol/liter in the RMP group (P < 0.05); percentage of time in the target range was 60.4 +/- 22.8% for the eMPC vs. 27.5 +/- 16.2% for the RMP group (P < 0.05). No severe hypoglycemia (blood glucose < 2.9 mmol/liter) occurred during the study. Mean insulin infusion rate was 4.7 +/- 3.3 IU/h in the eMPC vs. 2.6 +/- 1.7 IU/h in the RMP group (P < 0.05). Mean sampling interval was 1.5 +/- 0.3 h in the eMPC vs. 2.1 +/- 0.2 h in the RMP group (P < 0.05)., Conclusions: Compared with RMP, the eMPC algorithm was more effective and comparably safe in maintaining euglycemia in cardiac surgery patients.

Anorexia nervosa (AN) is an eating disorder affecting mostly young people which could lead to serious complications and consequences. There are ethnical and gender differences in the incidence and prevalence of AN, but the influence of urbanization has not yet been proved. The relationship of genetic background to the risk of AN is still being investigated. In this review we summarize current knowledge about the relationship between AN and polymorphism of substances known to be regulating eating behaviour or metabolic pathways e.g. serotonin, ghrelin, catechol-O-methyl transferase, neuropeptide Y, brain-derived neurotrophic factor and adipokines.