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Aims Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). Methods DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 μg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. Results We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. Conclusions Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.

Type 2 diabetes mellitus (T2DM) is a prototypical complex disease with polygenic architecture playing an important role in determining susceptibility to develop the disease (and its complications) in subjects exposed to modifiable lifestyle factors. A current challenge is to quantify the degree of the individual's genetic risk using genetic risk scores (GRS) capturing the results of genome-wide association studies while incorporating possible ethnicity- or population-specific differences.This study included three groups of T2DM (T2DM-I, N = 1,032; T2DM-II, N = 353; and T2DM-III, N = 399) patients and 2,481 diabetes-free subjects. The status of the microvascular and macrovascular diabetes complications were known for the T2DM-I patients. Overall, 21 single nucleotide polymorphisms (SNPs) were analyzed, and selected subsets were used to determine the GRS (both weighted - wGRS and unweighted - uGRS) for T2DM risk predictions (6 SNPs) and for predicting the risks of complications (7 SNPs).The strongest T2DM markers (P 0.0001) were within the genes for TCF7L2 (transcription factor 7-like 2), FTO (fat mass and obesity associated protein) and ARAP1 (ankyrin repeat and PH domain 1). The T2DM-I subjects with uGRS values greater (Odds Ratio, 95 % Confidence Interval) than six had at least twice (2.00, 1.72-2.32) the risk of T2DM development (P 0.0001), and these results were confirmed in the independent groups (T2DM-II 1.82, 1.45-2.27; T2DM-III 2.63, 2.11-3.27). The wGRS (0.6) further improved (P 0.000001) the risk estimations for all three T2DM groups. The uGRS was also a significant predictor of neuropathy (P 0.0001), nephropathy (P 0.005) and leg ischemia (P 0.0005).If carefully selected and specified, GRS, both weighted and unweighted, could be significant predictors of T2DM development, as well as the diabetes complications development.

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.

Background: Increased oxidative/dicarbonyl stress and chronic inflammation are considered key pathological mediators in the progression of complications in type 2 diabetes (T2D) and obesity. Lifestyle and diet composition have a major impact. In this study, we tested the effects of a vegan (V) and a conventional meat containg (M) meal, matched for energy and macronutrients, on postprandial oxidative and dicarbonyl stress, inflammatory markers and appetite hormones. Methods: A randomised crossover design was used to evaluate T2D, obese and control participants (n=20 in each group), with serum concentrations of analytes determined at 0, 120 and 180 minutes. Repeated-measures ANOVA was used for statistical analysis.Results: Postprandial glucose, triglycerides and free fatty acid responses were similar after both meals. After the V-meal consumption, we observed decreased postprandial concentrations of oxidised glutathione (p˂0.001) and increased glutathione peroxidase activity (p=0.045) compared with the M-meal in T2D subjects. In obese participants, V-meal consumption increased postprandial concentrations of reduced glutathione (p=0.041) and decreased methylglyoxal concentrations (p=0.023). There were no differences in postprandial secretion of TNFa, MCP-1 or ghrelin, but we did observe higher postprandial secretion of leptin after the V-meal in T2D subjects (p=0.002) compared with the M-meal. Conclusions: The results show that a plant-based meal is efficient in ameliorating the postprandial oxidative and dicarbonyl stress compared to a conventional energy- and macronutrient-matched meal, indicating the therapeutic potential of plant-based nutrition in improving the progression of complications in T2D and obese patients.Registered under ClinicalTrials.gov Identifier No. NCT02474147.

OBJECTIVE To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup. RESEARCH DESIGN AND METHODS In a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12–24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7–193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 μg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months. RESULTS Primary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845–1.408]; P = 0.5009). However, GAD-alum–treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126–2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose–adjusted HbA1c ≤9; P = 0.0310). Minor transient injection site reactions were reported. CONCLUSION Intralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.

Excessive methylglyoxal (MG) production contributes to metabolic and vascular changes by increasing inflammatory processes, disturbing regulatory mechanisms and exacerbating tissue dysfunction. MG accumulation in adipocytes leads to structural and functional changes. We used transcriptome analysis to investigate the effect of MG on metabolic changes in the visceral adipose tissue of hereditary hypetriglyceridaemic rats, a non-obese model of metabolic syndrome. Compared to controls, 4-week intragastric MG administration impaired glucose tolerance (p &lt, 0.05) and increased glycaemia (p &lt, 0.01) and serum levels of MCP-1 and TNF&alpha, (p &lt, 0.05), but had no effect on serum adiponectin or leptin. Adipose tissue insulin sensitivity and lipolysis were impaired (p &lt, 0.05) in MG-treated rats. In addition, MG reduced the expression of transcription factor Nrf2 (p &lt, 0.01), which controls antioxidant and lipogenic genes. Increased expression of Mcp-1 and TNF&alpha, 0.05) together with activation of the SAPK/JNK signaling pathway can promote chronic inflammation in adipose tissue. Transcriptome network analysis revealed the over-representation of genes involved in insulin signaling (Irs1, Igf2, Ide), lipid metabolism (Nr1d1, Lpin1, Lrpap1) and angiogenesis (Dusp10, Tp53inp1).

Background and Aims: Metformin (MET) treatment in patients with type 2 diabetes (T2D) and chronic heart failure (HF) is associated with better cardiovascular outcomes. Possible mechanism of cardioprotective effect of metformin may be a reduction of dicarbonyl and oxidative stress. In particular, a reduction of methylglyoxal levels (MG). The aim of our study was to evaluate the effect of MET on cardiac structure, cardiac function and exercise capacity in patients with T2D and HF. Materials and Methods: A randomized, double-blind, placebo-controlled, crossover study in a total time of six months testing the effect of 3- month usage of MET (2 g/day) vs. placebo. A group of 44 treatment naive patients with T2D and HF were included. At the beginning and at the end of each intervention period various metabolic tests were done including echocardiography, spiroergometry, and parameters of dicarbonyl stress like MG, Glutathione (GSH), glutathione disulfide (GSSG), and the activity of Glyoxalase1 (GLO-1). Results: MET treatment led to a decrease in HbA1c levels (∆ MET vs. placebo: -3.39 ± 5.33mmol/mol, p = 0.00007), and fasting plasma glucose levels (∆MET vs. placebo: -0.381 ± 1.1mmol/l; p = 0.00145). MET had no effect on oxygen consumption at the maximum tolerated load during spiroergometry (VOmax) (∆MET vs. placebo: -0.142 ± 1.18ml/kg/min; p = 0.64). MET did not affect left ventricular ejection fraction (∆MET vs. placebo: -0.789 ± 6.32%; p = 0.53). The levels of MG didn’t change after MET (∆ MET vs. placebo: 0.0306 ± 0.13nmol/ml; p = 0.19). The activity of GLO-1 was not affected too (∆ MET vs. placebo: 0.0073 ± 0.017 mmol/min/mg Hb; p = 0.22). Conclusion: MET treatment is safe in patients with severe heart failure. Our results do not support the evidence that one of the cardioprotective pathways of metformin is through reducing dicarbonyl stress. Disclosure E. Hošková: None. J. Kopecky: None. J. Veleba: None. H. Malinska: None. K. Velebova: None. V. Melenovsky: None. T. Pelikanova: None. Funding Institute for Clinical and Experimental Medicine 00023001)

Aim: Metformin (MET) is a mainstay for treatment of type 2. diabetes (DM). Its use in patients with chronic heart failure (HF) patients is recent, associated with lower frequency of cardiovascular events and with better survival, but mechanisms of action are unclear. GLP-1 incretin is reported to have cardioprotective effects. Our aim was to assess the effects of MET on glucose metabolism, incretin secretion and cardiac function in patients with DM and HF. Methods: A randomized, double-blind, placebo-controlled, crossover study testing the effect of 3 - month usage of metformin vs. placebo. Treatment naive patients with DM and HF were randomized to metformin (2 g/day) or to placebo group. At the beginning and the end of each intervention period (baseline, after MET and after placebo) panel of various metabolic tests including meal test and cardiac function tests (echocardiography, cardiopulmonary exercise test) was done. Results: Metformin significantly reduced HbA1c. During meal test, metformin significantly reduced AUC of glucose, insulin and amylin; and increased GLP-1 and peptide YY. Details in Table. There was no change in cardiac function as assessed by echocardiography and spiroergometry. Conclusions: Metformin therapy in patients with HF improves diabetes compensation and has no significant effect on cardiac function. Improvement might be partly mediated by alteration of gut endocrine function. Disclosure J. Kopecky: None. E. Hošková: None. J. Veleba: None. V. Melenovsky: None. T. Pelikanova: None. Funding VZ 00023001 IKEM

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

Aim: We examined associations of eight SNPs in/near seven candidate genes with glycemic response to 6 month treatment with DPP4 inhibitors. Patients & methods: 206 patients with type 2 diabetes (116 men and 90 women) were treated with sitagliptin or vildagliptin (both 100 mg/day) in combination with metformin or metformin/sulphonylurea over 6 months, and the reduction in glycated hemoglobin (HbA1c) was measured. Results: Rs6923761 in GLP1R was significantly associated with a reduction in HbA1c (adjusted p = 0.006). Homozygotes for the minor A allele had smaller reduction in HbA1c by 0.4% (4 mmol/mol) than the G allele carriers (p = 0.016). Conclusion: The missense variant rs6923761 in the GLP1R gene was associated with a smaller glycemic response to 6 month gliptin therapy in diabetic patients of central European origin.

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.

Genome-wide association studies have resulted in the identification of the FTO gene as an important genetic determinant of diabetes mellitus. The aim of this study was to confirm the role of this gene in the development of DM in the Czech-Slavonic population and to analyse whether this gene is associated with common DM complications.Two groups of patients (814 with T1DM and 848 with T2DM) and a group of healthy controls (2339 individuals) - both of Czech origin - were genotyped for the FTO rs17817449 SNP. ANOVA and logistic regression were used for the statistical evaluations.The frequency of the GG genotype was significantly higher in T2DM (25.4% vs. 16.7%, P0.0005) but not in T1DM patients (19.3% vs. 16.7%, P=0.20) than in controls. The increased risk of development of diabetic nephropathy was observed both for T1DM patients (GG vs. TT homozygotes, P0.01) and T2DM patients (G carriers vs. TT homozygotes, P0.05). FTO genotype predicted the development of diabetic neuropathy (GG vs. TT comparison; P0.01) in the T2DM patients only. No association between FTO genotype and development of retinopathy was detected. All presented values are after adjustment for age, sex, BMI and duration of diabetes.We confirm the association between the FTO rs17817449 SNP and susceptibility to T2DM in the Czech-Slavonic population. The same variant is associated with a spectrum of chronic complications in both types of diabetes.

Introduction: Patients with type 2 diabetes (DM) are known to have decreased metabolic flexibility when switching between carbohydrate and lipid oxidation. Our aim was to assess the energy substrates utilization in patients with isolated heart failure (HF) and HF with DM. Methods: A cross-sectional comparative trial with 77 subjects in 4 age matched groups. 21 healthy subjects (HF-DM-), 14 patients with HF alone (HF+DM-), 21 patients with diabetes alone (HF-DM+) and 21 patients with DM or prediabetes and heart failure (HF+DM+). The subjects underwent indirect calorimetry before and during hyperinsulinemic isoglycemic clamp. Results: Metabolic clearance of glucose (MCG) was significantly lower (p ˂ 0.05) in the groups of patients with DM+ (HF-DM-: 6.08 ± 2.03; HF+DM-: 5.86 ± 2.37; HF-DM+: 4.29 ± 2.2; HF+DM+: 3.9 ± 1.76 ml/kg.min). Compared to healthy subjects all the other groups had significantly smaller increase in respiratory quotient during clamp (p ˂ 0.01 for HF-DM- vs. HF+DM- and HF-DM- vs. HF-DM+; p ˂ 0.05 for HF-DM- vs. HF+DM+). Differences between groups with isolated HF and isolated DM were not significant, see Table. Conclusions: Our results on a unique group of patients show similarly deteriorated metabolic flexibility of carbohydrate versus lipid oxidation in patients with type 2 diabetes and heart failure supporting the comparable deleterious effect of both diseases on utilization of energy substrates. Disclosure E. Hošková: None. J. Kopecky: None. J. Veleba: None. K. Velebova: None. V. Melenovsky: None. T. Pelikanova: None. Funding Czech Health Research Council (AZV16-27496A)

Objective: Gastrointestinal hormones play a key role in glucose metabolism and satiety. We examined the acute effect of meal composition on these hormones in three population groups. Research Design and Methods: A randomized crossover design was used to test the effects of two energy- and macronutrient-matched meals: a processed-meat (M-meal) and a vegan (V-meal) on gastrointestinal hormones, and satiety in participants with type 2 diabetes (T2D, n=20), obese participants (O, n=20), and healthy controls (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 minutes. Satiety was assessed using a visual analogue scale. Repeated-measures ANOVA was used for statistical analysis. Results: An increase in postprandial secretion of GLP-1 was observed after the V-meal in T2D (by 30.5%; 95% CI 21.2 to 40.7%; p Conclusions: Our results indicate there is an increase in gut hormones and satiety, following consumption of a single plant-based meal when compared with an energy- and macronutrient-matched standard meat meal. Disclosure J. Veleba: None. M. Klementova: None. L. Belinova: None. M. Haluzik: None. R. Pavlovicova: None. M. Hill: None. T. Pelikanova: None. H. Kahleova: None. Funding Ministry of Health of the Czech Republic (AZV15-27338A); Institute for Clinical and Experimental Medicine (MZCR00023001)

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)

Background and Aims: Treatment with metformin (MET) in diabetic patients with chronic heart failure (HF) is associated with better cardiovascular outcomes. The endothelial dysfunction, atherosclerosis and macrovascular diabetic complications are associated with excessive generation of reactive dicarbonyls like methylglyoxal (MG). MET has been proposed as a scavenger of methylglyoxal. The aim of the study was to evaluate the effects of MET on substrate metabolism and dicarbonyl stress in patients with DM and HF. Materials and Methods: A randomized, double-blind, placebo-controlled, crossover study in a total time of six months testing the effect of 3- month usage of MET (2 g/day) vs. placebo. A group of 40 treatment naive patients with type 2 DM and HF were included. At the beginning and at the end of each intervention period various metabolic tests were done including hyperinsulinemic-isoglycemic clamp, parameters of dicarbonyl stress like MG, Glutathione (GSH), glutathione disulfide (GSSG), and the activity of Glyoxalase1 (GLO-1). Results: MET significantly reduced HbA1c compared to placebo (p˂0.01). Insulin sensitivity, measured as a metabolic clearance rate of glucose (MCR) during the clamp, improved significantly with MET (p˂0.001) but also, although less significantly, with placebo (p˂0.05), difference between MET and placebo was not significant. Compared to placebo, GHS levels increased after the intervention (baseline vs. MET vs. PL: 866 ± 231 vs. 994 ± 342 vs. 878 ± 266µmol/l, p Conclusions: Our results on a unique group of patients with heart failure and diabetes support the evidence that one of the cardioprotective pathways of metformin is through reducing dicarbonyl stress. As there was no change in the GLO-1 activity, it might be due to binding and deactivation of reactive dicarbonyls by MET. Disclosure J. Kopecky: None. E. Hošková: None. J. Veleba: None. H. Malinska: None. K. Velebova: None. V. Melenovsky: None. T. Pelikanova: None. Funding Agentura pro zdravotnický výzkum Ceské Republiky (AZV16-27496A)

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)

Background: 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. Findings: Thalamus perfusion was the highest in patients with T2Dand 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

Duodenal–jejunal bypass liner (DJBL) is an endoscopically implantable device designed to noninvasively mimic the effects of gastrointestinal bypass operations by excluding the duodenum and proximal jejunum from the contact with ingested food. The aim of our study was to assess the influence of DJBL on anthropometric parameters, glucose regulation, metabolic and hormonal profile in obese patients with type 2 diabetes mellitus (T2DM) and to characterize both the magnitude and the possible mechanisms of its effect. Thirty obese patients with poorly controlled T2DM underwent the implantation of DJBL and were assessed before and 1, 6 and 10months after the implantation, and 3months after the removal of DJBL. The implantation decreased body weight, and improved lipid levels and glucose regulation along with reduced glycemic variability. Serum concentrations of fibroblast growth factor 19 (FGF19) and bile acids markedly increased together with a tendency to restoration of postprandial peak of GLP1. White blood cell count slightly increased and red blood cell count decreased throughout the DJBL implantation period along with decreased ferritin, iron and vitamin B12 concentrations. Blood count returned to baseline values 3months after DJBL removal. Decreased body weight and improved glucose control persisted with only slight deterioration 3months after DJBL removal while the effect on lipids was lost. We conclude that the implantation of DJBL induced a sustained reduction in body weight and improvement in regulation of lipid and glucose. The increase in FGF19 and bile acids levels could be at least partially responsible for these effects.

White adipose tissue (WAT) is a complex organ with both metabolic and endocrine functions. Dysregulation of all of these functions of WAT, together with low-grade inflammation of the tissue in obese individuals, contributes to the development of insulin resistance and type 2 diabetes. n-3 polyunsaturated fatty acids (PUFAs) of marine origin play an important role in the resolution of inflammation and exert beneficial metabolic effects. Using experiments in mice and overweight/obese patients with type 2 diabetes, we elucidated the structures of novel members of fatty acid esters of hydroxy fatty acids—lipokines derived from docosahexaenoic acid (DHA) and linoleic acid, which were present in serum and WAT after n-3 PUFA supplementation. These compounds contained DHA esterified to 9- and 13-hydroxyoctadecadienoic acid (HLA) or 14-hydroxydocosahexaenoic acid (HDHA), termed 9-DHAHLA, 13-DHAHLA, and 14-DHAHDHA, and were synthesized by adipocytes at concentrations comparable to those of protectins and resolvins derived from DHA in WAT. 13-DHAHLA exerted anti-inflammatory and proresolving properties while reducing macrophage activation by lipopolysaccharides and enhancing the phagocytosis of zymosan particles. Our results document the existence of novel lipid mediators, which are involved in the beneficial anti-inflammatory effects attributed to n-3 PUFAs, in both mice and humans.

Introduction: Metformin (MET) is a 1st choice drug used in patients with type 2 diabetes (DM). Treatment with MET in patient with DM and heart failure (HF) is associated with better cardiovascular outcomes, but mechanisms of MET-mediated effects are unexplained. Our aim was to evaluate the effects of MET on substrate metabolism, cardiac function and structure in patient with DM and HF. Methods: 40 patients with DM and stable chronic HF (age: 59 ± 9 years) were studied in a random sequence cross-over clinical study testing the effect of 3-month usage of MET vs. placebo. The subjects were randomized to MET (2 g/day) or to placebo group. After the three months of treatment the medication was changed and the treatment continued for next 3 months. At the beginning and the end of each intervention period (3 times in total) the panel of various metabolic and cardiovascular tests was done: echocardiography, spiroergometry and meal test with evaluation of several variables like incretins (GLP-1 and peptide YY) and parameters of oxidative stress (MCP-1, TNFα). Results: Compared to placebo, MET was accompanied with significantly higher increase of selected gut-related hormones. GLP-1 area-under-curve increased during the meal test (MET vs. PL: 8571.39±6899.57 vs. 5665.82±4580.57pmol.hour.l-1; p Conclusions: Our results suggest that metabolic effects of MET might be mediated by improvement of gut endocrine function. MET had neutral effect on cardiac function or structure. Disclosure E. Stolarikova: None. J. Kopecky: None. J. Veleba: None. K. Velebova: None. L. Belinova: None. V. Melenovsky: None. J. Kopecky: None. T. Pelikanova: None.

Objective: Gastrointestinal hormones play a key role in glucose metabolism and energy homeostasis. Methods: A randomized cross-over study was used to test the effects of two energy- (600 kcal) and macronutrient-matched plant-based and processed-meat meals (41% carbohydrates, 19% protein, and 40% lipids) on glucose metabolism, plasma concentrations of gastrointestinal hormones, and satiety in subjects with T2D (n=20), obese subjects (n=20) and healthy controls (n=20). Plasma concentrations of glucose, immunoreactive insulin, C-peptide, GLP-1, GIP, amylin and PYY, along with satiety, were determined at 0, 30, 60, 120 and 180 min. Repeated-measures ANOVA was used for statistical analysis. Results: An increase in stimulated secretion of immunoreactive insulin was observed in T2D and obese subjects (p=0.005, and p=0.045, respectively) after the plant-based meal. We observed an increase in stimulated secretion of C-peptide in all groups after the plant-based meal (p Conclusions: Our study suggests that plant-based meals may be effective in increasing stimulated secretion of GLP-1, insulin, amylin and PYY, as well as in promoting satiety. Disclosure M. Klementova: None. L. Belinova: None. M. Haluzik: None. R. Pavlovicova: None. M. Hill: None. T. Pelikanova: None. H. Kahleova: None.

To determine whether acutely-induced supraphysiological hyperinsulinemia influences brain metabolism in patients with type 1 diabetes (D) and healthy controls (C) as detected by MR Spectroscopy. Group D consisted of 4 patients with the average duration of diabetes for 7 years. They were matched according to age, sex and BMI to 4 healthy controls. 1H MR Spectroscopy was performed with a 1.5 Tesla. Spectra were obtained from parietooccipital white matter repeatedly during a 3-h hyperinsulinemic euglycemic clamp with 2 mU.kgˉ¹.minˉ¹. In group D, significantly lower basal concentrations of N-acetylaspartate (p=0.02), choline (p=0.03), creatine (p=0.002) and inositol (p=0.007) were detected compared to C. After the induction of hyperinsulinemia, concentrations of choline, creatine, GABA, inositol, lactate, NAA and composite signal glutamate + glutamine (Glx) stayed stable. The detection of glucose signal is less realiable at 1.5 Tesla but we registered the alteration in glucose concentration (p=0.003) in the whole group. Originally sightly elevated glucose concentration in D decreased on the contrary to the increase of originally lower glucose level in C. In conclusions, brain metabolism was altered in D. Short term supraphysiological euglycemic hyperinsulinemia induced changes in the concentration of brain glucose in both C and D.

Hana Rosolova *, Terezie Pelikanova , Zuzana Motovska c Charles University Prague – Medical Faculty in Pilsen, Czech Republic b Institute of Clinical and Experimental Medicine Prague, Czech Republic c Faculty Hospital Kralovske Vinohrady Prague, Czech Republic Authors of the original ESC guidelines document [1]: Lars Ryden, Peter J. Grant, on behalf of ESC Task Force on diabetes, pre-diabetes, and cardiovascular diseases.

Objective Our previous 6-month, randomized study demonstrated the beneficial effect of a vegetarian (V) compared to a conventional diet (C) with similar caloric restriction on cardiovascular risk factors for patients with type 2 diabetes (T2D), namely increased insulin sensitivity, reduced body weight, reduced volume of visceral and subcutaneous fat, decreased LDL-cholesterol and improved oxidative stress markers and chosen adipokines. We conducted post-trial monitoring to determine whether the improved outcomes persisted 1 year after the end of the study. Methods 62 subjects with T2D who completed the study were asked to come for a 1-year follow-up to measure weight, waist circumference, HbA1c and blood lipids. No attempts were made to maintain their previously assigned diets. Results 44 patients (71%) attended the post-trial monitoring. Hypoglycemic agents were increased by 14% in V and by 26% in C; insulin therapy was introduced in 5% in V and in 13% in C one year after the end of the intervention. Neither weight nor waist circumference changed significantly in either group. HbA1c increased (p ≤ 0.05) similarly in both groups (+0.49 ± 1.04% in V vs. +0.42 ± 0.8% in C). Blood lipids did not change in either group. Conclusion One year after the end of the intervention, the positive effects of a vegetarian diet on cardiovascular risk factors compared to a conventional diet were partially maintained.

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 &lt, 0.001), C-peptide (by 7.1%, 95% CI 4.1 to 9.9%, 0.001), and amylin (by 15.7%, 95% CI 11.8 to 19.7%, 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%, 0.001) and a decrease in GIP (by &minus, 9.4%, 95% CI &minus, 17.3 to &minus, 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.

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 &lt, 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%, 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%, 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%, and by 25% in H (95%CI 18.2 to 31.7%, 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.

Background The marine n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exert numerous beneficial effects on health, but their potency to improve treatment of type 2 diabetic (T2D) patients remains poorly characterized. We aimed to evaluate the effect of a combination intervention using EPA + DHA and the insulin-sensitizing drug pioglitazone in overweight/obese T2D patients already treated with metformin. Methods In a parallel-group, four-arm, randomized trial, 69 patients (66 % men) were assigned to 24-week-intervention using: (i) corn oil (5 g/day; Placebo), (ii) pioglitazone (15 mg/day; Pio), (iii) EPA + DHA concentrate (5 g/day, containing ~2.8 g EPA + DHA; Omega-3), or (iv) pioglitazone and EPA + DHA concentrate (Pio& Omega-3). Data from 60 patients were used for the final evaluation. At baseline and after intervention, various metabolic markers, adiponectin and cytokines were evaluated in serum using standard procedures, EPA + DHA content in serum phospholipids was evaluated using shotgun lipidomics and mass spectrometry, and hyperinsulinemic-euglycemic clamp and meal test were also performed. Indirect calorimetry was conducted after the intervention. Primary endpoints were changes from baseline in insulin sensitivity evaluated using hyperinsulinemic-euglycemic clamp and in serum triacylglycerol concentrations in fasting state. Secondary endpoints included changes in fasting glycemia and glycated hemoglobin (HbA1c), changes in postprandial glucose, free fatty acid and triacylglycerol concentrations, metabolic flexibility assessed by indirect calorimetry, and inflammatory markers. Results Omega-3 and Pio& Omega-3 increased EPA + DHA content in serum phospholipids. Pio and Pio& Omega-3 increased body weight and adiponectin levels. Both fasting glycemia and HbA1c were increased by Omega-3, but were unchanged by Pio& Omega-3. Insulin sensitivity was not affected by Omega-3, while it was improved by Pio& Omega-3. Fasting triacylglycerol concentrations and inflammatory markers were not significantly affected by any of the interventions. Lipid metabolism in the meal test and metabolic flexibility were additively improved by Pio& Omega-3. Conclusion Besides preventing a modest negative effect of n-3 fatty acids on glycemic control, the combination of pioglitazone and EPA + DHA can be used to improve lipid metabolism in T2D patients on stable metformin therapy. Trial registration EudraCT number 2009-011106-42. Electronic supplementary material The online version of this article (doi:10.1186/s12986-015-0047-9) contains supplementary material, which is available to authorized users.

Diabet. Med. 28, 549–559 (2011) Abstract Aims The aim of this study was to compare the effects of calorie-restricted vegetarian and conventional diabetic diets alone and in combination with exercise on insulin resistance, visceral fat and oxidative stress markers in subjects with Type 2 diabetes. Methods A 24-week, randomized, open, parallel design was used. Seventy-four patients with Type 2 diabetes were randomly assigned to either the experimental group (n = 37), which received a vegetarian diet, or the control group (n = 37), which received a conventional diabetic diet. Both diets were isocaloric, calorie restricted (-500 kcal/day). All meals during the study were provided. The second 12 weeks of the diet were combined with aerobic exercise. Participants were examined at baseline, 12 weeks and 24 weeks. Primary outcomes were: insulin sensitivity measured by hyperinsulinaemic isoglycaemic clamp; volume of visceral and subcutaneous fat measured by magnetic resonance imaging; and oxidative stress measured by thiobarbituric acid reactive substances. Analyses were by intention to treat. Results Forty-three per cent of participants in the experimental group and 5% of participants in the control group reduced diabetes medication (P

Background Appetite and gastrointestinal hormones (GIHs) participate in energy homeostasis, feeding behavior and regulation of body weight. We demonstrated previously the superior effect of a hypocaloric diet regimen with lower meal frequency (B2) on body weight, hepatic fat content, insulin sensitivity and feelings of hunger compared to the same diet divided into six smaller meals a day (A6). Studies with isoenergetic diet regimens indicate that lower meal frequency should also have an effect on fasting and postprandial responses of GIHs. The aim of this secondary analysis was to explore the effect of two hypocaloric diet regimens on fasting levels of appetite and GIHs and on their postprandial responses after a standard meal. It was hypothesized that lower meal frequency in a reduced-energy regimen leading to greater body weight reduction and reduced hunger would be associated with decreased plasma concentrations of GIHs: gastric inhibitory peptide (GIP), glucagon-like peptide-1(GLP-1), peptide YY(PYY), pancreatic polypeptide (PP) and leptin and increased plasma concentration of ghrelin. The postprandial response of satiety hormones (GLP-1, PYY and PP) and postprandial suppression of ghrelin will be improved. Methods In a randomized crossover study, 54 patients suffering from type 2 diabetes (T2D) underwent both regimens. The concentrations of GLP-1, GIP, PP, PYY, amylin, leptin and ghrelin were determined using multiplex immunoanalyses. Results Fasting leptin and GIP decreased in response to both regimens with no difference between the treatments (p = 0.37 and p = 0.83, respectively). Fasting ghrelin decreased in A6 and increased in B2 (with difference between regimens p = 0.023). Fasting PP increased in B2with no significant difference between regimens (p = 0.17). Neither GLP-1 nor PYY did change in either regimen. The decrease in body weight correlated negatively with changes in fasting ghrelin (r = -0.4, p

Background The intake of meat, particularly processed meat, is a dietary risk factor for diabetes. Meat intake impairs insulin sensitivity and leads to increased oxidative stress. However, its effect on postprandial gastrointestinal hormone (GIH) secretion is unclear. We aimed to investigate the acute effects of two standardized isocaloric meals: a processed hamburger meat meal rich in protein and saturated fat (M-meal) and a vegan meal rich in carbohydrates (V-meal). We hypothesized that the meat meal would lead to abnormal postprandial increases in plasma lipids and oxidative stress markers and impaired GIH responses. Methods In a randomized crossover study, 50 patients suffering from type 2 diabetes (T2D) and 50 healthy subjects underwent two 3-h meal tolerance tests. For statistical analyses, repeated-measures ANOVA was performed. Results The M-meal resulted in a higher postprandial increase in lipids in both groups (p

BACKGROUND AND AIMS: Fatty acids are important cellular constituents that may affect many metabolic processes relevant for the development of diabetes and its complications. We showed previously that vegetarian diet leads to greater increase in metabolic clearance rate of glucose (MCR) than conventional hypocaloric diet. The aim of this secondary analysis was to explore the role of changes in fatty acid composition of serum phospholipids in diet- and exercise-induced changes in MCR in subjects with type 2 diabetes (T2D). METHODS: Subjects with T2D (n=74) were randomly assigned into a vegetarian group (VG, n=37) following vegetarian diet or a control group (CG, n=37) following a conventional diet. Both diets were calorie restricted (−500 kcal day–1). Participants were examined at baseline, 12 weeks of diet intervention and 24 weeks (subsequent 12 weeks of diet were combined with aerobic exercise). The fatty acid composition of serum phospholipids was measured by gas liquid chromatography. MCR was measured by hyperinsulinemic isoglycemic clamp. Visceral fat (VF) was measured by magnetic resonance imaging. RESULTS: Linoleic acid (LA; 18:2n6) increased in VG (P=0.04), whereas it decreased in CG (P=0.04) in response to dietary interventions. It did not change significantly after the addition of exercise in either group (group × time Pr=+0.22; P=0.04) and negatively with changes in VF (r=−0.43; P=0.01). After adjustment for changes in body mass index, the association between 18:2n6 and MCR was no longer significant. The addition of exercise resulted in greater changes of phospholipid fatty acids composition in VG than in CG. CONCLUSION: We demonstrated that the insulin-sensitizing effect of a vegetarian diet might be related to the increased proportion of LA in serum phospholipids.

In the article cited listed above, the grant number from the Czech Science Foundation was listed incorrectly and …

The goal of the study was to examine whether resting or post-exercise metabolic substrate levels are associated with differential exercise performance and long-term outcome in control subjects or heart failure (HF) patients with or without type 2 diabetes mellitus (DM). Methods and results Twenty five healthy controls matched with 97 patients with stable advanced HF were prospectively enrolled. Exercise capacity, age, gender, and HF aetiology were balanced between HFDM- and HFDM+ groups. Subjects underwent maximal bicycle spiroergometry with blood sampling to measure metabolites and neurohormones before and imme- diately after the exercise. HFDM+ patients had increased free fatty acids, glucose, and b-hydroxybutyrate compared with controls. HFDM+ patients had higher baseline copeptin (24+ 16 vs. 17+ 13 pmol/L, P , 0.05) but otherwise showed similar neurohumoral activation and exercise response to HFDM- patients. Peak oxygen consumption (VO2) was unrelated to post-exercise free fatty acids, glucose, lactate, or glycerol, but strongly correlated with post-exercise pyruvate (in all: r ¼ 0.62, P , 0.001). During the next 17+ 10 months, 36% of HF patients experienced an adverse event (death, urgent transplantation, or assist device insertion). From metabolic factors, only post-exercise glucose (hazard ratio (HR) 1.28, P ¼ 0.04), total body fat (HR 0.58, P , 0.001), and the presence of DM (HR 1.98, P ¼ 0.04) were predictive of the outcome. Conclusions With the exception of pyruvate, acute changes of metabolic substrates are not related to cardiac performance in HF, regardless of diabetic status. Inhibition of body fat depletion, attenuation of stress-related hyperglycaemia, or increas- ing dynamics of plasma pyruvate may represent therapeutic targets in advanced HF.

Diabetic nephropathy (DN), the most serious complication of Type 1 diabetes (DM1), has a strong genetic component. Cyclooxygenase-2 (COX-2), an inducible enzyme by a number of stimuli, has been implicated in pathophysiology of cardiovascular and renal disease, including DN. The allele -765C, of the -765G>C polymorphism (rs20417) in the COX-2 promoter has lower promoter activity compared with the -765G allele and protective effects in cardiovascular disease. This polymorphism was not investigated in patients with DM1 and nephropathy. The study was conducted in 779 Caucasian patients with DM1 and compared to a representative sample of healthy Czech population. The patients demonstrated lower frequencies of the CC genotype (P=0.005). From the DM1 cohort, 153 patients met the criteria for low risk of the development of DN (LRDN, duration of DM1>10 years, normoalbuminuria, normotension) and 139 patients had manifest DN. There were no differences in -765G>C polymorphisms between LRDN and DN patients. Moreover, the C/G allele frequencies did not also differ between the groups. In conclusion, patients with DM1 display lower freqencies of the protective CC genotype as compared to healthy subjects. However, the study did not reveal associations of -765G>C polymorphism with the risk of DN.

ObjectiveTelmisartan improves glucose and lipid metabolism in rodents. This study evaluated the effect of telmisartan on insulin sensitivity, substrate utilization, selected plasma adipokines and their expressions in subcutaneous adipose tissue (SAT) in metabolic syndrome.Design and methodsTwelve patients with impaired fasting glucose completed the double-blind, randomized, crossover trial. Patients received telmisartan (160 mg/day) or placebo for 3 weeks and vice versa with a 2-week washout period. At the end of each period, a hyperinsulinemic euglycemic clamp (HEC) combined with indirect calorimetry was performed. During HEC (0, 30, and 120 min), plasma levels of adipokines were measured and a needle biopsy (0 and 30 min) of SAT was performed.ResultsFasting plasma glucose was lower after telmisartan compared with placebo (PPPPConclusionsDespite the decrease in fasting plasma glucose, telmisartan does not improve insulin sensitivity and substrate utilization. Telmisartan increases plasma leptin as well as insulin-stimulated plasma adiponectin, leptin and resistin, and decreases plasma TNFα during HEC. Changes in plasma adipokines cannot be explained by their expressions in SAT. The changes in plasma adipokines might be involved in the metabolic effects of telmisartan in metabolic syndrome.

Our aim was to assess the reaction of TNFα, resistin, leptin and adiponectin to lipid infusion. Eight healthy subjects underwent a 24-hour lasting infusion of lipid emulsion. Plasma concentrations and expressions of selected cytokines in subcutaneous fat were measured. TNFα plasma concentration did not change during the first 4 hours of hypertriglyceridemia, but a significant increase after 24 hours was detected (p

Insulin action and insulin specific binding to erythrocytes were examined in ten recipients of a pancreatic segment and renal graft (Group 1), in nine non-diabetic kidney recipients (Group 2) and in ten age- and weight-matched healthy control subjects (Group 3). All transplant recipients were normoglycaemic without need of insulin, received the same immunosuppression and had good renal graft function at 11-18 months post-transplantation, when the investigation was performed. Using the insulin clamp technique, insulin action was expressed as the metabolic clearance rate of glucose at insulin infusion rates of 1.0 (MCRsubmax) and 10.0 (MCRmax) mU.kg-1.min-1. In comparison with the healthy control subjects, fasting free insulin and C-peptide levels were significantly higher in Groups 1 and 2, but no differences between Groups 1 and 2 were found (p greater than 0.05). Mean values +/- SEM of MCRsubmax in Groups 1, 2 and 3 were 6.30 +/- 0.55, 6.09 +/- 0.69 and 10.52 +/- 1.10 ml.kg-1.min-1 respectively, and of MCRmax 12.65 +/- 0.78, 13.14 +/- 0.92 and 19.28 +/- 1.42 ml.kg-1.min-1 respectively. Insulin action was significantly decreased in Groups 1 and 2 at the low as well as the high insulin infusion rates but there was no difference between the two groups of recipients (p greater than 0.05). No differences in binding data (specific binding, number of binding sites per cell) were found. It is concluded that insulin resistance is common to all immunosuppressed organ recipient and is not related to the pancreas graft. The decrease maximal response to insulin and normal insulin binding to erythrocytes tend to suggest a post-receptor defect in insulin action.

Objective: The potential insulin-sensitizing function of angiotensin II type 1 receptor blockade (ARB) with regard to selected adipokines is not fully explained so far. Our study aimed to explore the influence of acute hyperinsulinaemia and acutely induced ARB on resistin and adiponectin concentrations and expressions in healthy subjects. Design and methods: Plasma adipokines were measured: 1) at 0, 30 and 240 min of hyperinsulinaemic (1 mU/kg per min) euglycaemic (5 mmol/l) clamp (HEC), and 2) during HEC after acute ARB (losartan 200 mg; AT-HEC) using the same protocol, in eight healthy subjects. Needle biopsy of abdominal s.c. fat was performed at 0, 30 and 240 min of both clamps to assess the adipokines’ expressions. Results: Comparing the glucose disposals of HEC and AT-HEC, no difference in insulin sensitivity was found. Plasma resistin increased equally during HEC and AT-HEC (P < 0.05). The expression of resistin in s.c. fat increased during HEC (P < 0.05), while no significant changes in expression were observed during AT-HEC. Plasma levels of adiponectin did not change during both clamps. Adiponectin expression increased during HEC (P < 0.05), while it did not change during AT-HEC. Conclusions: In healthy subjects, acute hyperinsulinaemia is associated with an increase in plasma resistin independently of ARB, while plasma adiponectin is not influenced by insulin or ARB. The expressions of both resistin and adiponectin in s.c. adipose tissue are stimulated by acute hyperinsulinaemia, whereas losartan attenuates their insulin-stimulated expressions. This suggests a potential effect of losartanon adipokines’ expression.