[Show abstract][Hide abstract] ABSTRACT: Bile acids (BA), long believed to only have lipid-digestive functions, have emerged as novel metabolic modulators. They have important endocrine effects through multiple cytoplasmic, as well as nuclear receptors in various organs and tissues. BA affect multiple functions to control energy homeostasis, as well as glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor (FXR), and cytoplasmic G protein-coupled BA receptor TGR5 in a variety of tissues. However, BA also are aimed at many other cellular targets in a wide array of organs and cell compartments. Their role in the pathogenesis of diabetes, obesity, and other 'diseases of civilization' becomes even more clear. They also interact with the gut microbiome, with important clinical implications, further extending the complexity of their biological functions. Therefore, it is not surprising that BA metabolism is substantially modulated by bariatric surgery, a phenomenon contributing favorably to the therapeutic effects of these surgical procedures. Based on these data, several therapeutic approaches to ameliorate obesity and diabetes have been proposed to affect BA cellular targets.
Preview · Article · Jan 2016 · Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Recent studies focused on epicardial fat, formerly relatively neglected component of the heart, have elucidated some of its key roles. It possesses several properties that can distinguish it from other adipose tissue depots. Its unique anatomical location in the heart predisposes the epicardial fat to be an important player in the physiological and biochemical regulation of cardiac homeostasis. Obesity is associated with an increase in epicardial fat mass. Excess of cardiac fat can contribute to greater left ventricular mass and work, diastolic dysfunction and attenuated septal wall thickening. Imbalance in adipokines levels secreted in autocrine or paracrine fashion by epicardial fat can contribute to the activation of the key atherogenic pathways in the setting of metabolic syndrome. Epicardial fat has also been identified as an important source of pro-inflammatory mediators worsening endothelial dysfunction, eventually leading to coronary artery disease. Increased production of pro-inflammatory factors by epicardial fat can also contribute to systemic insulin resistance in patients undergoing cardiac surgery. Here we review the most important roles of epicardial fat with respect to heart disease in the context of other underlying pathologies such as obesity and type 2 diabetes mellitus.
No preview · Article · Nov 2015 · Physiological research / Academia Scientiarum Bohemoslovaca
[Show abstract][Hide abstract] ABSTRACT: Obesity with related complications represents a widespread health problem. The etiopathogenesis of obesity is often studied using numerous rodent models. The mouse model of monosodium glutamate (MSG)-induced obesity was exploited as a model of obesity combined with insulin resistance. The aim of this work was to characterize the metabolic status of MSG mice by NMR-based metabolomics in combination with relevant biochemical and hormonal parameters. NMR analysis of urine at 2, 6, and 9 months revealed altered metabolism of nicotinamide and polyamines, attenuated excretion of major urinary proteins, increased levels of phenylacetylglycine and allantoin, and decreased concentrations of methylamine in urine of MSG-treated mice. Altered levels of creatine, citrate, succinate, and acetate were observed at 2 months of age and approached the values of control mice with aging. The development of obesity and insulin resistance in 6-month-old MSG mice was also accompanied by decreased mRNA expressions of adiponectin, lipogenetic and lipolytic enzymes and peroxisome proliferator-activated receptor-gamma in fat while mRNA expressions of lipogenetic enzymes in the liver were enhanced. At the age of 9 months, biochemical parameters of MSG mice were normalized to the values of the controls. This fact pointed to a limited predictive value of biochemical data up to age of 6 months as NMR metabolomics confirmed altered urine metabolic composition even at 9 months.
No preview · Article · Nov 2015 · Analytical and Bioanalytical Chemistry
[Show abstract][Hide abstract] ABSTRACT: Primary aldosteronism (PA) is the most common cause of endocrine hypertension with a high frequency of cardiovascular complications. The unfavorable cardiometabolic profile may be due to aldosterone-mediated activation of inflammatory cells, circulatory cytokines and activation of collagen synthesis in the vessel wall. Aim of our study was to evaluate differences in the levels of hsCRP, IL-6, TNF-alpha and N-terminal propeptide of collagen I (PINP) in patients with PA and essential hypertension (EH) as a control group, and between the subtypes of PA (aldosterone producing adenoma-APA, idiopathic hyperaldosteronism-IHA). We studied 28 patients with PA (IHA-10 patients, APA-12 patients, 6 unclassified) and 28 matched patients with EH. There were no differences in the levels of inflammatory markers between the followed groups [EH vs. PA: TNF-alpha (5.09[3.68-6.32] vs. 4.84[3.62-6.50]pg/ml), IL-6 (0.94[0.70-1.13] vs. 0.97[0.71-1.28]pg/ml), hsCRP (0.53[0.25-1.54] vs. 0.37[0.31-0.61]mg/l), leukocytes (6.35+/-1.42 vs. 5.97+/-1.29 10(9)l); APA vs. IHA: TNF-alpha (4.54[3.62-7.03] vs. 5.19[4.23-5.27]pg/ml), IL-6 (0.96[0.63-1.21] vs. 0.90[0.65-1.06]pg/ml), hsCRP (0.34[0.29-0.47] vs. 0.75[0.36-1.11]mg/l), leukocytes (6.37+/-1.41 vs. 5.71+/-1.21 10(9)l)]. Significant differences in the levels of PINP between PA and EH group were observed (35.18[28.46-41.16] vs. 45.21[36.95-62.81]ug/l, p</=0.003). No differences in inflammatory markers were observed between the followed groups, we confirmed higher levels of PINP in patients with PA.
No preview · Article · Oct 2015 · Physiological research / Academia Scientiarum Bohemoslovaca
[Show abstract][Hide abstract] ABSTRACT: Cardiovascular risk reduction is the major aim of type 2 diabetes mellitus treatment. The effects of various antidiabetics on the cardiovascular complications are currently under careful scrutiny. Incretin-based therapy that utilizes the effects of glucagon-like peptide 1 (GLP-1) or stimulation of its receptor by GLP-1 receptor agonists represents one of the most promising approaches from the potential cardiovascular risk reduction point of view. Experimental studies have shown that the GLP-1 and GLP-1 agonists treatment improves endothelial function, decrease blood pressure and protects myocardium during experimentally-induced ischemia. Clinical studies with GLP-1 receptor agonists consistently show that, in addition to good antidiabetic efficacy, its long-term administration decreases blood pressure, body weight and improves circulating lipid levels while slightly increasing heart rate. In this paper, we focus on the cardiovascular effects of GLP-1 receptor agonist liraglutide. Preliminary analyses of cardiovascular complications in phase III trials with liraglutide indicate its good cardiovascular safety. A possibility of cardioprotective effects of liraglutide remains still open and is currently studied within a prospective cardiovascular trial LEADER.Key words: cardiovascular complications - diabetes mellitus - GLP-1 agonists - glucagon-like peptide 1 - liraglutide.
No preview · Article · Sep 2015 · Vnitr̆ní lékar̆ství
[Show abstract][Hide abstract] ABSTRACT: Tight glucose control (TGC) reduces morbidity and mortality in patients undergoing elective cardiac surgery, but only limited data about its optimal timing are available to date.
To compare the effects of perioperative (PERI) versus postoperative (POST) initiation of TGC on postoperative adverse events in cardiac surgery patients.
Single center, single-blind, parallel-group, randomized controlled trial.
Academic tertiary hospital.
2383 hemodynamically stable patients undergoing major cardiac surgery with expected postoperative ICU treatment for at least 2 consecutive days.
Perioperatively or postoperatively initiated intensive insulin therapy with target glucose range 4.4-6.1 mmol/l.
Adverse events from any cause during postoperative hospital stay.
In the whole cohort, perioperatively initiated TGC markedly reduced the number of postoperative complications (23.2 vs. 34.1%, 95% CI 0.60-0.78) in spite of only minimal improvement in glucose control (blood glucose 6.6±0.7 vs. 6.7±0.8 mmol/l, p<0.001; time in target range 39.3±13.7 vs. 37.3±13.8%, p<0.001). The positive effects of TGC on postoperative complications were driven by non-diabetic subjects (21.3 vs. 33.7%, 95% CI 0.54-0.74; blood glucose 6.5±0.6 vs. 6.6±0.8 mmol/, n.s.; time in target range 40.8±13.6 vs. 39.7±13.8%, n.s.), while no significant effect was seen in diabetic patients (29.4 vs. 35.1%, 95% CI 0.66-1.06) despite significantly better glucose control in the PERI group (blood glucose 6.9±1.0 vs. 7.1±0.8 mmol/l, p<0.001; time in target range 34.3±12.7 vs. 30.8±11.5%, p<0.001).
Perioperative initiation of intensive insulin therapy during cardiac surgery reduces postoperative morbidity in non-diabetic patients while having minimal effect in diabetic subjects.
No preview · Article · Jun 2015 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Diabetes mellitus is a progressive disease that may eventually lead to the development of chronic complications. In patients with type 2 diabetes, a simultaneous occurrence of liver or renal impairment is quite frequent. The presence of these diseases significantly increases the risk of hypoglycemia and in case of the renal impairment also the cardiovascular risk. At the same time, the options of antidiabetic treatment are markedly limited in particular in patients with more advanced impairment owing to the fact that numerous antidiabetic drugs are either metabolized or excreted by the liver or the kidney. In this paper, we focus on the treatment of diabetes in patients with renal or liver impairment including limitations of particular drugs and drug classes. We also briefly summarize the risks associated with renal or liver impairment with respect to antidiabetic treatment.Key words: diabetes mellitus - hypoglycemia - liver impairment - renal impairment.
No preview · Article · Apr 2015 · Vnitr̆ní lékar̆ství
[Show abstract][Hide abstract] ABSTRACT: Objectives
Obesity is a frequent metabolic disorder but an effective therapy is still scarce. Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity but are ineffective after peripheral application. We have designed lipidized analogs of prolactin-releasing peptide (PrRP) which is involved in energy balance regulation as demonstrated by obesity phenotypes of both PrRP- and PrRP-receptor-knockout mice.ResultsLipidized PrRP analogs showed binding affinity and signaling in PrRP receptor-expressing cells similar to natural PrRP. Moreover, these analogs showed high binding affinity also to anorexigenic neuropeptide FF (NPFF)-2 receptor. Peripheral administration of myristoylated and palmitoylated PrRP analogs to fasted mice induced strong and long-lasting anorexigenic effects and neuronal activation in the brain areas involved in food intake regulation. Two-week-long subcutaneous administration of palmitoylated-PrRP31 and myristoylated-PrRP20 lowered food intake, body weight and improved metabolic parameters and attenuated lipogenesis in mice with diet-induced obesity.Conclusions
Our data suggest that the lipidization of PrRP enhances stability and mediates its effect in central nervous system. Strong anorexigenic and body-weight-reducing effects make lipidized PrRP an attractive candidate for anti-obesity treatment.International Journal of Obesity accepted article preview online, 16 March 2015. doi:10.1038/ijo.2015.28.
No preview · Article · Mar 2015 · International journal of obesity (2005)
[Show abstract][Hide abstract] ABSTRACT: Numerous epidemiological and experimental studies have demonstrated that patients who suffer from metabolic disorders, such as type 2 diabetes mellitus (T2DM) or obesity, have higher risks of cognitive dysfunction and of Alzheimer's disease (AD). Impaired insulin signaling in the brain could contribute to the formation of neurofibrillary tangles, which contain an abnormally hyperphosphorylated tau protein. This study aimed to determine whether potential tau hyperphosphorylation could be detected in an obesity-induced pre-diabetes state and whether anorexigenic agents could affect this state. We demonstrated that 6-month-old mice with monosodium glutamate (MSG) obesity, which represent a model of obesity-induced pre-diabetes, had increased tau phosphorylation at Ser396 and Thr231 in the hippocampus compared with the controls, as determined by western blots. Two weeks of subcutaneous treatment with a lipidized analog of prolactin-releasing peptide (palm-PrRP31) or with the T2DM drug liraglutide, which both had a central anorexigenic effect, resulted in increased phosphorylation of the insulin cascade kinases PDK1 (Ser241), Akt (Thr308), and GSK-3β (Ser9). Furthermore, these drugs attenuated phosphorylation at Ser396, Thr231, and Thr212 of tau and of the primary tau kinases in the hippocampi of 6-month-old MSG-obese mice. We identified tau hyperphosphorylation in the obesity-induced pre-diabetes state in MSG-obese mice and demonstrated the beneficial effects of palm-PrRP31 and liraglutide, both of known central anorexigenic effects, on hippocampal insulin signaling and on tau phosphorylation.
No preview · Article · Jan 2015 · Journal of Alzheimer's disease: JAD
[Show abstract][Hide abstract] ABSTRACT: Incretin-based therapies either increase endogenous levels of glucagon-like peptide-1 by prolonging its half-life (DPP-4 inhibitors) or directly stimulate its receptor (glucagon-like peptide-1 analogues; GLP-1 RA). They are currently widely used for the treatment of patients with type 2 diabetes mellitus owing to good antidiabetic efficacy, low risk of hypoglycemia, and relatively few other side effects. They also offer potential additional benefits such as weight neutrality or weight loss, positive effects on blood pressure and lipid levels, and potential cardio- and neuroprotectivity. Some experimental and clinical studies have raised concerns with respect to potential cardiovascular and pancreatic side effects of these therapies such as increased risk of heart failure with DPP-4 inhibitors as well as acute pancreatitis and pancreatic cancer with both classes. The available data are at present not robust enough to enable firm conclusions regarding these potential associations. Nevertheless, some recent data suggest a possibility of slightly increased risk of acute pancreatitis with GLP-1 RAs while they do not indicate increased risk of pancreatic cancer. Ongoing cardiovascular outcome trials will shed more light on the possible cardioprotective effects of incretin-based therapies as well as on the possible interconnection of DPP-4 inhibitors and heart failure.
[Show abstract][Hide abstract] ABSTRACT: Background
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of a metabolic syndrome. To date, liver biopsy has been the gold standard used to differentiate between simple steatosis and steatohepatitis/fibrosis. Our aim was to compare the relevance of serum non-invasive parameters and scoring systems in the staging of liver fibrosis and non-alcoholic steatohepatitis (NASH) in patients with NAFLD.
Methods and Findings
A total of 112 consecutive patients diagnosed with NAFLD were included. A liver biopsy was performed on 56 patients. The Kleiner score was used for the staging and grading of the histology. Non-invasive parameters for fibrosis (hyaluronic acid; AST/ALT; fibrosis scoring indexes OELF, ELF, BARD score, APRI, NAFLD fibrosis score); and inflammation (M30 and M65 cytokeratin-18 fragments) were measured and calculated. The same analyses were performed in 56 patients diagnosed with NAFLD, who were not indicated for liver biopsy. Based on the liver histology, NASH was diagnosed in 38 patients; simple steatosis in 18 patients. A cut-off value of 750 U/L of serum M65 discriminated patients with and without NASH with a 80% sensitivity and 82% specificity (95% CI:57–95). Fibrosis stage F0–F2 was present in 39 patients; F3–F4 in 17 patients. Serum concentrations of hyaluronic acid were higher in patients with advanced fibrosis (p<0.01); a cut-off value of 25 µg/l discriminated patients with F3–F4 with a 90% sensitivity and 84% specificity from those with F0–F2 (95% CI:59–99). When applying the non-invasive criteria to those patients without a liver biopsy, NASH could only be diagnosed in 16%; however, advanced fibrosis could be diagnosed in 35% of them.
In patients with NAFLD, non-invasive serum parameters with a high accuracy can differentiate those patients with NASH and/or advanced fibrosis from those with simple steatosis. A substantial portion of those patients not indicated for liver biopsy might have undiagnosed advanced fibrosis.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to explore the changes in the adipokines leptin and adiponectin in obese patients with type 1 diabetes mellitus (T1DM) who underwent seven days of fasting and 21 days of low-calorie diet (LCD). The plasma leptin and adiponectin concentrations were measured in 14 obese patients with T1DM at baseline, immediately after 7 days of fasting, and after 21 days of LCD. 13 non-obese patients with T1DM were studied only after an overnight fasting. Bioimpedance technique was used for determination of body composition. Obese T1DM patients lost 6.0 kg (6.0; 6.8) (median, 25%; 75%) and decreased their fat tissue after fasting and LCD. Plasma leptin in obese T1DM was significantly higher than in non-obese T1DM patients: 9.10 (5.06; 25.89) vs 1.71 (1.12; 7.08) ug · l(-1) and transiently decreased immediately after fasting: 3.45 ug · l(-1) (1.47; 7.00), (P<0.05). Adiponectin/leptin ratio in obese T1DM was significantly lower than in non-obese T1DM patients: 0.67 (0.57; 1.49) vs 3.50 (2.46; 6.30) · l0(3) and transiently increased immediately after fasting: 2.22 (1.26; 3.24) · l0(3), (P< 0.05). We conclude that obese patients with T1DM are characterized by hyperleptinemia that is reduced by prolonged fasting, but only slightly affected by low calorie diet.
[Show abstract][Hide abstract] ABSTRACT: Objective: The aim of our study was to analyze the results of oral glucose tolerant test (oGTT) of pregnant woman with currently used Czech criteria for diagnosis of GDM, to find out the prevalence of GDM if the measurement of glycemia in 1 hour of oGTT is included and to compare the prevalence of GDM using the new IADPSG (International Association of Diabetes and Pregnancy Study Groups) criteria versus the currently used Czech criteria. Design: Retrospective analysis.Settings: Department of Obstetrics and Gynecology of the First Faculty of Medicine and General Teaching Hospital, Prague.Methods: Data from the standard 75g 2-hour oral glucose tolerance test (oGTT) of 2567 pregnant females were analyzed using the currently recommended Czech cut-off values for plasma glucose at baseline and at2 hours of oGTT (5.6 and 7.7 mmol/l) and at baseline, 1 and2 hours oGTT (5.6, 8.9 and 7.7 mmol/l). The frequency of GDM using the Czech criteria was compared with the frequency of GDM using the novel IADPSG criteria (5.1, 10.0 and 8.5 mmol/l). Statistical analysis was done using the software GNU PSPP Statistical Analysis Software version 0.8.0-g0ad9f6.Results: When using the current Czech criteria (at baseline and 2 hours of oGTT) GDM was diagnosed in 362 (14.11%) females. Inclusion of glycemia at 1 hour of oGTT increased the frequency of GDM to 571 (22.26%) females (p<0.00). With the novel IADPSG criteria GDM was diagnosed in 818 (31.89%) females (p=0.038). 503 females i.e. 19.61% and 394 females i.e. 15.36% (when glycemia at 1 h of oGTT included) respectively met the IADPSG but not the Czech criteria and thus were not treated for GDM. In contrast, 47 (1.83%) resp. 147 (5.73%) of tested women who met the Czech but not the IADPSG criteria received unnecessary diabetes treatment. Conclusion: The frequency of GDM is higher with the novel IADPSG criteria when compared with the currently used Czech recommendation. Switching to IADPSG criteria might help unravel hitherto unidentified cases of GDM and thus improve outcomes for females with GDM and their offsprings. Keywords: gestational diabetes, oral glucose tolerant test, oGTT, Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study.
No preview · Article · Jul 2014 · Ceska gynekologie / Ceska lekarska spolecnost J. Ev. Purkyne
[Show abstract][Hide abstract] ABSTRACT: Adipose tissue lies at the crossroad of nutrition, metabolism and immunity and adipose tissue inflammation was proposed as a central mechanism connecting obesity with its metabolic and vascular complications. Resident immune cells constitute the second largest adipose tissue cellular component after adipocytes and as such play important roles in maintaining adipose tissue homeostasis. Obesity induced changes in their number and activity result in activation of local and later systemic inflammatory response marking the transition from simple adiposity to diseases like type 2 diabetes mellitus, arterial hypertension and ischemic heart disease. This review will focus on the various subsets of immune cells in adipose tissue and their role in the development of adipose tissue inflammation and obesity-induced insulin resistance.
Preview · Article · Jul 2014 · Journal of Endocrinology