Sodium-glucose cotransporter 2 inhibitors induce anti-inflammatory and anti-ferroptotic shift in epicardial adipose tissue of subjects with severe heart failure.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure. METHODS: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. RESULTS: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects. CONCLUSIONS: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.

The role of basal insulins in the treatment of people with type 2 diabetes and chronic kidney disease: A narrative review.

The majority of cases of chronic kidney disease (CKD) worldwide are driven by the presence of type 2 diabetes (T2D), resulting in an increase in CKD rates over the past few decades. The existence of CKD alongside diabetes is associated with increased burden of cardiovascular disease and increased risk of death. Optimal glycaemic control is essential to prevent progression of CKD, but achieving glycaemic targets in people with CKD and diabetes can be challenging because of increased risk of hypoglycaemia and limitations on glucose-lowering therapeutic options. This review considers the challenges in management of T2D in people with impaired kidney function and assesses evidence for use of basal insulin analogues in people with CKD.

Glucose control during pregnancy in patients with type 1 diabetes correlates with fetal hemodynamics: a prospective longitudinal study.

BACKGROUND: Maternal diabetes adversely affects fetal cardiovascular system development. Previous studies have reported that the fetuses of mothers with diabetes exhibit both structural and functional changes; nevertheless, prior studies have not examined the association between glucose control and fetal cardiac morphology and performance. Thus, the objective was to determine the association between fetal cardiac morphology and function and maternal glucose control in type 1 diabetes and to compare the differences in measured cardiac parameters between the fetuses of mothers with diabetes and healthy controls. METHODS: In this prospective, longitudinal case-control study - including 62 pregnant women with type 1 diabetes mellitus and 30 healthy pregnant women - fetal cardiac assessment using B-mode, M-mode, and spectral pulsed-wave Doppler was performed in the second and third trimesters. In women with T1DM, glycated hemoglobin and data obtained from glucose sensors - including the percentage of time in, below, and above the range (TIR, TBR, and TAR, respectively), and coefficient of variation (CV) - were analyzed across three time periods: the last menstrual period to 13 (V1), 14-22 (V2), and 23-32 weeks (V3) of gestation. Fetal cardiac indices were compared between groups, and the correlation between glucose control and fetal cardiac indices was assessed. RESULTS: At 28-32 weeks, the fetuses of women with T1DM exhibited increased left ventricular end-diastolic length, relative interventricular septum thickness, right ventricular cardiac output, and pulmonary valve peak systolic velocity compared with healthy controls. At 18-22 weeks, pulmonary and aortic valve diameters, left and right ventricular stroke volumes, and left cardiac output inversely correlated with the CV and glycated hemoglobin levels at V1 and V2. Furthermore, at 28-32 weeks, pulmonary and aortic valve diameters, left ventricular stroke volume, cardiac output, and right/left atrioventricular valve ratio inversely correlated with the TBR at V1, V2, and V3. Moreover, diastolic functional parameters correlated with the TAR and glycated hemoglobin levels, particularly after the first trimester. CONCLUSION: In women with T1DM, maternal hyperglycemia during pregnancy correlates with fetal diastolic function, whereas glucose variability and hypoglycemia inversely correlate with fetal left ventricular systolic function in the second and third trimesters.

iGlarLixi (insulin glargine 100 U/ml plus lixisenatide) is effective and well tolerated in people with uncontrolled type 2 diabetes regardless of age: A REALI pooled analysis of prospective real-world data.

AIM: To evaluate the effectiveness and safety in routine clinical practice of insulin glargine/lixisenatide (iGlarLixi) in people with type 2 diabetes (T2D) according to age. METHODS: Patient-level data were pooled from 1316 adults with T2D inadequately controlled on oral antidiabetic drugs with or without basal insulin who initiated iGlarLixi for 24 weeks. Participants were classified into age subgroups of younger than 65 years (N = 806) and 65 years or older (N = 510). RESULTS: Compared with participants aged younger than 65 years, those aged 65 years or older had a numerically lower mean body mass index (31.6 vs. 32.6 kg/m2 ), a longer median diabetes duration (11.0 vs. 8.0 years), were more likely to receive prior basal insulin (48.4% vs. 43.5%) and had a lower mean HbA1c (8.93% [74.10 mmol/mol] vs. 9.22% [77.28 mmol/mol]). Similar and clinically relevant reductions in HbA1c and fasting plasma glucose from baseline to week 24 of iGlarLixi therapy were observed regardless of age. At 24 weeks, least-squares adjusted mean (95% confidence interval [CI]) change in HbA1c from baseline was -1.55% (-1.65% to -1.44%) in those aged 65 years or older and -1.42% (-1.50% to -1.33%) in those aged younger than 65 years (95% CI: -0.26% to 0.00%; P = .058 between subgroups). Low incidences of gastrointestinal adverse events and hypoglycaemic episodes were reported in both age subgroups. iGlarLixi decreased mean body weight from baseline to week 24 in both subgroups (-1.6 kg in those aged ≥ 65 years and -2.0 kg in those aged < 65 years). CONCLUSIONS: iGlarLixi is effective and well tolerated in both younger and older people with uncontrolled T2D.

Early-Onset Neonatal Sepsis: Inflammatory Biomarkers and MicroRNA as Potential Diagnostic Tools in Preterm Newborns.

Mortality and morbidity of newborns with sepsis can be improved by early and accurate diagnosis and targeted therapy. To evaluate the early molecular events associated with inflammation and infection, we evaluated markers of endothelial activation and injury and circulating plasma miRNAs in preterm newborns with sepsis. The study group consisted of newborns with gestational age ≤ 32 weeks, with culture-positive early-onset neonatal sepsis (sepsis group, N = 8), and as a control group, we enrolled newborns without sepsis (control group, N = 12). Soluble markers of inflammation were measured using Luminex-based multiplex assay. Platelet-free plasma RNA was used to construct the library for miRNA sequencing analysis. Normalized counts were calculated and used to measure differential expression of individual detected miRNAs. We found a significant increase of interleukin 18 (IL-18) in the cord blood of the sepsis group (mean ± SEM, 104.7 ± 30.4 pg/ml vs 52.7 ± 5.6 pg/ml, P = 0.02). In peripheral blood of sepsis group patients, we found a significant increase of VEGF-A compared to controls (196.0 ± 70.5 pg/ml vs 59.6 ± 8.5 pg/ml, P = 0.02). In the cord blood plasma, eight miRNAs had significantly differential expression (P < 0.05), four miRNAs were up-regulated and four miRNAs down-regulated. In peripheral blood plasma, all nine miRNAs with significant differential expression were up-regulated. In conclusion, in early-onset neonatal sepsis, IL-18 and VEGF-A might be considered in diagnostic workup. Early-onset sepsis in preterm newborns is associated with significant changes in the circulating miRNA pattern.

Delivery-Associated Changes in the Levels of Inflammatory Molecules in Newborns.

Inflammation is considered a fundamental process accompanying physiological human birth, also playing a role in perinatal pathologies. The goal of the study was to assess the concentrations of inflammatory molecules with respect to the mode of delivery and dynamics of inflammatory molecules in neonatal samples in the first 48-72 hours of life. The concentrations of inflammatory cytokines were measured using the Luminex®xMAP multi-analyte profiling platform in cord blood and peripheral neonatal blood. Study groups included newborns delivered spontaneously (spontaneous group) and via elective caesarean section (elective group). Cord blood concentrations of interleukin 6 (IL-6) and procalcitonin were significantly higher (P < 0.0001) in the spontaneous group compared to the elective group. Neonatal blood concentrations of tumour necrosis factor (TNF) from the elective group were significantly higher com-pared to the spontaneous group (P = 0.0077). The concentrations of procalcitonin and TNF significantly increased within the first 48 to 72 hours following either mode of delivery. IL-6 and IL-18 were significantly higher in neonatal compared to umbilical cord blood in the elective group only, while the increase in the spontaneous group did not reach statistical significance. The concentrations of IL-1α, IL-1ß, IL-17A and IL-22 did not show significant differen-ces between the spontaneous and elective groups as well as between umbilical cord and neonatal blood. Our findings show physiological differences in the levels of inflammatory molecules following spontaneous vaginal delivery and elective caesarean section. The results can be used as baseline values for the research of various pathologies in newborns.

Obesity pharmacotherapy - update 2023.

The increasing prevalence of obesity and its associated complications leads to the need to intensify its prevention and treatment. The treatment of obesity is currently based on lifestyle modification, which often fails in the long term. For the next decade, the long-term administration of anti-obesity drugs, i.e. drugs that have a positive effect not only on the reduction of excess weight but also on the health risks associated with obesity, seems to be a necessary part of obesity treatment, along with surgical approaches. This text provides an overview of the current options for the pharmacotherapy of obesity, including their indications, appropriate patient selection and adverse effects of treatment. It also provides an overview of studies that demonstrate the long-term efficacy and safety of these treatments. Although effective and safe anti-obesity drugs are currently available, it is not even partially covered by general health insurance. However, the cost of treatment is unaffordable in the long term for a large proportion of the obese. The virtual unavailability of effective antiobesity drugs for indicated patients has serious health-economic consequences. Failure to take advantage of effective therapeutic options, confirmed by evidence-based medicine, results in a high prevalence of obesity-related diseases, which are even more costly to treat economically and, in the case of type 2 diabetes, even less effective. We consider at least partial reimbursement of antiobesity drugs from general health insurance for cooperating patients under clearly defined conditions to be a necessary step towards improving the situation, and clearly cost-effective in its consequences.

The Effect of GLP-1 Receptor Agonists on Postprandial Lipaemia.

PURPOSE OF REVIEW: To review the currently available data on the effect of Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on postprandial lipaemia. RECENT FINDINGS: Out of the available studies that examined the respective lipid parameter, exenatide reduced postprandial triacyglycerol (TAG) in 4/6, apolipoprotein B-48 in 3/3, non-esterified fatty acids in 2/2, and apolipoprotein C-III and very low-density lipoprotein cholesterol (VLDL-C) in 1/1 studies. Liraglutide reduced postprandial TAG in 2/2, apolipoprotein B-48 in 3/3 and apolipoprotein C-III, chylomicron-TAG and VLDL1-TAG in 1/1 studies. Lixisenatide reduced postprandial chylomicron-TAG and apolipoprotein B-48 in 1 study. Semaglutide reduced postprandial TAG, apolipoprotein B-48 and VLDL in 1 study. Dulaglutide reduced postprandial apolipoprotein B-48 in 1 study. GLP-1 RAs have consistent beneficial effects on postprandial lipaemia with most of the data coming from studies with exenatide and liraglutide. Reduction of postprandial lipaemia might be one of the mechanisms behind the pleiotropic effects of GLP-1 RAs.

Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme.

AIMS: To evaluate the efficacy and safety of oral semaglutide versus comparators by patient characteristic subgroups in patients with type 2 diabetes. MATERIALS AND METHODS: Change from baseline in glycated haemoglobin (HbA1c) and body weight, and achievement of HbA1c <7.0% with oral semaglutide 7 mg, oral semaglutide 14 mg, flexibly dosed oral semaglutide (flex) and comparators were assessed across baseline subgroups (age, race, ethnicity, diabetes duration, body mass index and HbA1c) from the PIONEER programme. Treatment differences were analysed using a mixed model for repeated measurements for continuous variables and a logistic regression model for the binary endpoint. Pooled safety data were analysed descriptively. RESULTS: Changes from baseline in HbA1c and body weight, and the odds of achieving HbA1c <7.0%, were greater with oral semaglutide 14 mg/flex (n = 1934) and higher or similar with oral semaglutide 7 mg (n = 823) versus comparators (n = 2077) across most subgroups. Changes in HbA1c with oral semaglutide 14 mg/flex were greater for patients with higher baseline HbA1c (HbA1c >9.0%: -1.7% to -2.6%; HbA1c <8.0%: -0.7% to -1.2%). In some trials, Asian patients experienced greater HbA1c reductions with oral semaglutide 14 mg/flex (-1.5% to -1.8%) than other racial groups (-0.6% to -1.6%). The overall incidence of adverse events (AEs) with oral semaglutide was similar to that with comparators and was consistent across subgroups. More gastrointestinal AEs were observed with oral semaglutide, versus comparators, across subgroups. CONCLUSIONS: Oral semaglutide demonstrated consistently greater HbA1c and body weight reductions across a range of patient characteristics, with greater HbA1c reductions seen at higher baseline HbA1c levels.

Decreased Epicardial CTRP3 mRNA Levels in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease Undergoing Elective Cardiac Surgery: A Possible Association with Coronary Atherosclerosis.

(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.

The Role of Physicians' Digital Tools in Pharmacological Management of Type 2 Diabetes Mellitus.

Background and Objectives: The constantly increasing prevalence of type 2 diabetes mellitus (T2DM) and the advent of new treatment options have made management of T2DM patients more demanding. We aimed to (a) estimate the familiarity of general practitioners with novel T2DM treatment options, (b) determine whether a digital tool can aid in their treatment decisions and (c) demonstrate that an evidence-based digital clinical support tool can be made using an existing digital platform. Materials and methods: This proof-of-concept study consisted of two parts: We first conducted a simple online survey among general practitioners of three European countries to estimate their familiarity with novel T2DM treatment options and to determine whether they believe that a digital tool can aid in their T2DM treatment decisions. We then proceeded to develop a new digital tool that provides quick, evidence-based support for treatment of patients with T2DM using an existing digital platform. Results: The online survey was completed by 129/5278 physicians (94 from Italy, 22 from Czech Republic and 13 from Slovenia). Only 30.7% of all general practitioners reported to be either very or extremely familiar with novel T2DM treatments; the vast majority of participating general practitioners (82.8%) reported that they would find a digital clinical decision support tool for treating T2DM patients either very or extremely useful. A digital tool which features the characteristics deemed most important by the polled physicians was subsequently developed. Conclusions: The results of the online survey showed that familiarity of general practitioners with novel T2DM treatment options is relatively low and that there is a need for digital clinical decision support tools intended to facilitate treatment decisions in T2DM patients. We demonstrated that such a tool can easily be developed using an existing digital platform.

Expert opinion on the cooperation of diabetologists and internists with nephrologists in the care of patients with chronic kidney diseases.

Chronic kidney disease (CKD) affects 10% of the population of developed countries and significantly affects the population health. In addition to the well-known renoprotection tools slowing down the progression of CKD, SGLT2 inhibitors have been newly introduced into clinical practice based on the results of extensive studies, both in diabetics and non-diabetics. This expert opinion discusses the classification of CKD, current renoprotection options, and the recent role of SGLT2 inhibitors in the care of patients with CKD.

In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia.

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.

Different Expression of Mitochondrial and Endoplasmic Reticulum Stress Genes in Epicardial Adipose Tissue Depends on Coronary Atherosclerosis.

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

Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress.

(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.

Pregnancy of women with type 1 diabetes mellitus - the effect of preconception care on perinatal results. Ten years of experience.

INTRODUCTION: Despite the ever-improving medical care, pregnancies of women with type 1 diabetes mellitus (T1DM) are at increased risk of complications for both mother and child. Optimal compensation of diabetes before and during pregnancy is an essential protective factor reducing the risk of congenital malformations, pregnancy loss, and other complications. The pregnancy of women with T1DM should be planned, ideally at a time of optimal diabetes compensation. Target glycated hemoglobin (HbA1c) values until the range of 42-48 mmol/mol should be achieved at least three months before pregnancy. Our work aimed to evaluate the perinatal results of pregnancies in women with T1DM and the eff ect of preconception counseling and adequate T1DM compensation before pregnancy on perinatal outcomes. METHODS AND RESULTS: Retrospective analysis of pregnancy and perinatal outcomes of women with T1DM were followed up at the Department of Gynecology and Obstetrics, General University Hospital in Prague and First Faculty of Medicine, Charles University between 2008 to 2018. A total of 221 women with T1DM were included in the analysis. Adequate (HbA1c  48 mmol/mol at least 3 months before conception) and inadequate diabetes compensation at the beginning of the pregnancy had 59 (26.7%) and 162 (72.3%) women, respectively. Pregnancies of women with adequate diabetes compensation were more often planned (55.9 vs. 24.7%; P  95th percentile; 22.0 vs. 35.8%; P = 0.027). CONCLUSION: The pregnancy of women with T1DM is burdened by a number of perinatal and neonatal complications. In the study group, most women with T1DM became pregnant unintentionally at a time of inadequate diabetes compensation. Women who achieved adequate diabetes compensation before pregnancy had a lower incidence of perinatal complications. Therefore, it is advised that women with T1DM should plan their pregnancy, attend preconception and antenatal care, and give birth in perinatal centers, which provide coordinated care from diabetologists, gynecologists, obstetricians, and neonatologists.

Expert consensus on the practical aspects of the cooperation of cardiologist and diabetologist in the management of the patients with chronic heart failure and reduced ejection fraction.

Diabetes mellitus is an important risk factor for the development of heart failure and presence of diabetes significantly worsens heart failure outcome. Introduction of gliflozins to the therapy of heart failure is one of the most important novelty. Gliflozins reduce glucose level by the sodium-glucose contransporter 2 inhibition in proximal tubulus in the kidney. Gliflozins are used as effective antidiabetic drugs with improvement of glycemic control without risk of hypoglycemia, gliflozins decrease blood pressure and patients weight. Recent studies have shown that gliflozins significantly reduce risk of cardiovascular complications and heart failure hospitalizations in diabetic patients. Clinical trials with dapagliflozin and empagliflozin have shown reduction of the risk of cardiovascular death and heart failure hospitalization in the patients with heart failure and reduced ejection fraction both in the patients with diabetes and in the patients without diabetes. The aim of the expert consenzus is to summarize practical aspects in the cooperation of cardiologist and diabetologist in the management of the patients with heart failure and reduced ejection fraction in the context of the current guidelines and other treatment options.

Lipid Profiling in Epicardial and Subcutaneous Adipose Tissue of Patients with Coronary Artery Disease.

Coronary artery disease is one of the most frequent causes of morbidity and mortality worldwide. It is even more prevalent in patients with type 2 diabetes mellitus who suffer from obesity and increased accumulation of epicardial fat with a possible contributing role in the development of coronary artery disease. We performed an MS-based lipidomic analysis of subcutaneous and epicardial adipose tissue in 23 patients with coronary artery disease stratified for the presence/absence of type 2 diabetes mellitus and a control group of 13 subjects aiming at identification of factors from epicardial fat contributing to the development of coronary artery disease. The samples of adipose tissues were obtained during elective cardiac surgery. They were extracted and analyzed with and without previous triacylglycerols separation by high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Multivariate and univariate analyses were performed. Lipidomics data were correlated with biochemical parameters. We identified multiple changes in monoacylglycerols, diacylglycerols, triacylglycerols, glycerophosphatidylserines, glycerophosphatidylethanolamines, glycerophosphatidylcholines, ceramides, sphingomyelins, and derivatives of cholesterol. Observed changes included molecules with fatty acids with odd (15:0, 15:1, 17:0, 17:1) and even (10:0, 12:0, 14:0, 16:0, 16:1, 18:0, 18:1, 18:2, 20:4, 20:1, 22:0) fatty acids in both types of adipose tissue. More pronounced changes were detected in epicardial adipose tissue compared to subcutaneous adipose tissue of patients with coronary artery disease and type 2 diabetes. Lipidomic analysis of subcutaneous and epicardial adipose tissue revealed different profiles for patients with coronary artery disease and type 2 diabetes, which might be related to coronary artery disease and the presence of type 2 diabetes.

Nuclear transport of nicotinamide phosphoribosyltransferase is cell cycle-dependent in mammalian cells, and its inhibition slows cell growth.

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 (424RSKK to ASGA), which did not affect its enzymatic activity, blocked nuclear NAMPT transport, slowed cell growth, and increased histone H3 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.

Influence of glucometric 'dynamical' variables on duodenal-jejunal bypass liner (DJBL) anthropometric and metabolic outcomes.

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.