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Metabolic Effects (metabolic + effects)
Selected AbstractsCARDIOVASCULAR AND METABOLIC EFFECTS OF OBESITYCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2008Margaret J Morris SUMMARY 1Obesity is an important risk factor for hypertension and its incidence is increasing around the world. 2The mechanisms underlying obesity-related hypertension include sympathetic activation, altered vascular responses, hormonal changes, enhanced inflammatory markers and structural changes. 3This review summarizes recent evidence of the underlying impact of obesity on blood pressure. A number of candidate mechanisms include increased sympathetic activity, activation of the renin-angiotensin system, altered vasoconstrictor or dilator responses and the attendant systemic inflammatory state. 4While adult lifestyle factors undoubtedly contribute to the incidence of obesity and its attendant hypertension, evidence suggests that the programming of obesity may occur following over-nutrition during development. A growing body of evidence links maternal obesity, offspring obesity and hypertension. 5Finally, epigenetic modification of genes relevant to hypertension may contribute to the development of hypertension following a suboptimal intrauterine environment. To date the cardiovascular effects of early nutritional changes have been largely investigated following maternal under-nutrition or protein restriction; further work is necessary to determine the impact of maternal obesity. [source] Cardiovascular and Metabolic Effects of High-dose Insulin in a Porcine Septic Shock ModelACADEMIC EMERGENCY MEDICINE, Issue 4 2010Joel S. Holger MD Abstract Objectives:, High-dose insulin (HDI) has inotropic and vasodilatory properties in various clinical conditions associated with myocardial depression. The authors hypothesized that HDI will improve the myocardial depression produced by severe septic shock and have beneficial effects on metabolic parameters. In an animal model of severe septic shock, this study compared the effects of HDI treatment to normal saline (NS) resuscitation alone. Methods:, Ten pigs were randomized to an insulin (HDI) or NS group. All were anesthetized and instrumented to monitor cardiovascular function. In both arms, Escherichia coli endotoxin lipopolysaccharide (LPS) and NS infusions were begun. LPS was titrated to 20 ,g/kg/hour over 30 minutes and continued for 5 hours, and saline was infused at 20 mL/kg/hour throughout the protocol. Dextrose (50%) was infused to maintain glucose in the 60,150 mg/dL range, and potassium was infused to maintain a level greater than 2.8 mmol/L. At 60 minutes, the HDI group received an insulin infusion titrated from 2 to 10 units/kg/hour over 40 minutes and continued at that rate throughout the protocol. Survival, heart rate (HR), mean arterial pressure (MAP), pulmonary artery and central venous pressure, cardiac output, central venous oxygen saturation (SVO2), and lactate were monitored for 5 hours (three pigs each arm) or 7 hours (two pigs each arm) or until death. Cardiac index, systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), O2 delivery, and O2 consumption were derived from measured data. Outcomes from the repeated-measures analysis were modeled using a mixed-effects linear model that assumed normally distributed errors and a random effect at the subject level. Results:, No significant baseline differences existed between arms at time 0 or 60 minutes. Survival was 100% in the HDI arm and 60% in the NS arm. Cardiovascular variables were significantly better in the HDI arm: cardiac index (p < 0.001), SVR (p < 0.003), and PVR (p < 0.01). The metabolic parameters were also significantly better in the HDI arm: SVO2 (p < 0.01), O2 delivery (p < 0.001), and O2 consumption (p < 0.001). No differences in MAP, HR, or lactate were found. Conclusions:, In this animal model of endotoxemic-induced septic shock that results in severe myocardial depression, HDI is associated with improved cardiac function compared to NS resuscitation alone. HDI also demonstrated favorable metabolic, pulmonary, and peripheral vascular effects. Further studies may define a potential role for the use of HDI in the resuscitation of septic shock. ACADEMIC EMERGENCY MEDICINE 2010; 17:429,435 © 2010 by the Society for Academic Emergency Medicine [source] Metabolic effects of metformin in patients with impaired glucose toleranceDIABETIC MEDICINE, Issue 7 2001M. Lehtovirta Abstract Aims To assess the effect of metformin on insulin sensitivity, glucose tolerance and components of the metabolic syndrome in patients with impaired glucose tolerance (IGT). Methods Forty first-degree relatives of patients with Type 2 diabetes fulfilling WHO criteria for IGT and participating in the Botnia study in Finland were randomized to treatment with either metformin 500 mg b.i.d. or placebo for 6 months. An oral glucose tolerance test (OGTT) and a euglycaemic hyperinsulinaemic clamp in combination with indirect calorimetry was performed at 0 and 6 months. The patients were followed after stopping treatment for another 6 months in an open trial and a repeat OGTT was performed at 12 months. Results Metformin treatment resulted in a 20% improvement in insulin-stimulated glucose metabolism (from 28.7 ± 13 to 34.4 ± 10.7 µmol/kg fat-free mass (FFM)/min) compared with placebo (P = 0.01), which was primarily due to an increase in glucose oxidation (from 16.6 ± 3.6 to 19.1 ± 4.4 µmol/kg FFM; P = 0.03) These changes were associated with a minimal improvement in glucose tolerance, which was maintained after 12 months. Conclusions Metformin improves insulin sensitivity in subjects with IGT primarily by reversal of the glucose fatty acid cycle. Obviously large multicentre studies are needed to establish whether these effects are sufficient to prevent progression to manifest Type 2 diabetes and associated cardiovascular morbidity and mortality. Diabet. Med. 18, 578,583 (2001) [source] Metabolic effects of carbenoxolone in rat liverJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 5 2006Leandro Silva Pivato The action of carbenoxolone on hepatic energy metabolism was investigated in the perfused rat liver and isolated mitochondria. In perfused livers, carbenoxolone (200,300 ,M) increased oxygen consumption, glucose production and glycolysis from endogenous glycogen. Gluconeogenesis from lactate or fructose, an energy-dependent process, was inhibited. This effect was already evident at a concentration of 25 ,M. The cellular ATP levels and the adenine nucleotide content were decreased by carbenoxolone, whereas the AMP levels were increased. In isolated mitochondria, carbenoxolone stimulated state IV respiration and decreased the respiratory coefficient with the substrates ,-hydroxybutyrate and succinate. The ATPase of intact mitochondria was stimulated, the ATPase of uncoupled mitochondria was inhibited, and the ATPase of disrupted mitochondria was not altered by carbenoxolone. These results indicate that carbenoxolone acts as an uncoupler of oxidative phosphorylation and, possibly, as an inhibitor of the ATP/ADP exchange system. The inhibitory action of carbenoxolone on mitochondrial energy metabolism could be contributing to induce the mitochondrial permeability transition (MPT), a key phenomenon in apoptosis. The results of the present study can explain, partly at least, the in vivo hepatotoxic actions of carbenoxolone that were found in a previous clinical evaluation. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:230,240, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20139 [source] Metabolic effects of p -coumaric acid in the perfused rat liverJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 1 2006Leonardo C.N. Lima The p -coumaric acid, a phenolic acid, occurs in several plant species and, consequently, in many foods and beverages of vegetable origin. Its antioxidant activity is well documented, but there is also a single report about an inhibitory action on the monocarboxylate carrier, which operates in the plasma and mitochondrial membranes. The latter observation suggests that p -coumaric acid could be able to inhibit gluconeogenesis and related parameters. The present investigation was planned to test this hypothesis in the isolated and hemoglobin-free perfused rat liver. Transformation of lactate and alanine into glucose (gluconeogenesis) in the liver was inhibited by p -coumaric acid (IC50 values of 92.5 and 75.6 ,M, respectively). Transformation of fructose into glucose was inhibited to a considerably lower degree (maximally 28%). The oxygen uptake increase accompanying gluconeogenesis from lactate was also inhibited. Pyruvate carboxylation in isolated intact mitochondria was inhibited (IC50 = 160.1 ,M); no such effect was observed in freeze,thawing disrupted mitochondria. Glucose 6-phosphatase and fructose 1,6-bisphosphatase were not inhibited. In isolated intact mitochondria, p -coumaric acid inhibited respiration dependent on pyruvate oxidation but was ineffective on respiration driven by succinate and ,-hydroxybutyrate. It can be concluded that inhibition of pyruvate transport into the mitochondria is the most prominent primary effect of p -coumaric acid and also the main cause for gluconeogenesis inhibition. The existence of additional actions of p -coumaric acid, such as enzyme inhibitions and interference with regulatory mechanisms, cannot be excluded. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:18,26, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20114 [source] Manganese-guided cellular MRI of human embryonic stem cell and human bone marrow stromal cell viabilityMAGNETIC RESONANCE IN MEDICINE, Issue 4 2009Mayumi Yamada Abstract This study investigated the ability of MnCl2 as a cellular MRI contrast agent to determine the in vitro viability of human embryonic stem cells (hESC) and human bone marrow stromal cells (hBMSC). Basic MRI parameters including T1 and T2 values of MnCl2 -labeled hESC and hBMSC were measured and viability signal of manganese (Mn2+)-labeled cells was validated. Furthermore, the biological activity of Ca2+ -channels was modulated utilizing both Ca2+ -channel agonist and antagonist to evaluate concomitant signal changes. Metabolic effects of MnCl2 -labeling were also assessed using assays for cell viability, proliferation, and apoptosis. Finally, in vivo Mn2+ -guided MRI of the transplanted hESC was successfully achieved and validated by bioluminescence imaging. Magn Reson Med, 2009. © 2009 Wiley-Liss, Inc. [source] Metabolic effects of static magnetic fields on streptococcus pyogenesBIOELECTROMAGNETICS, Issue 6 2007A.C. Morrow Abstract This study aimed to develop a simple experimental system utilising bacterial cells to investigate the dose responses resulting from exposures to static magnetic flux densities ranging from 0.05 to 0.5 T on viability, bacterial metabolism and levels of DNA damage in Streptococcus pyogenes. Exposure of S. pyogenes to a field of 0.3 T at 24 °C under anaerobic conditions resulted in a significant (P,<,0.05) decrease in growth rate, with an increased mean generation time of 199,±,6 min compared to the control cells at 165,±,6 min (P,<,0.05). Conversely, exposure to magnetic fields of 0.5 T significantly accelerated the growth rate at 24 °C compared to control cells, with a decreased mean generation time of 147,±,4 min (P,<,0.05). The patterns of metabolite release from cells incubated in phosphate buffered saline (PBS) at 24 °C and exposed to different magnetic flux densities (0.05,0.5 T) were significantly (P,<,0.05) altered, compared to non-exposed controls. Concentrations of metabolites, with the exception of aspartic acid (r,=,0.44), were not linearly correlated with magnetic flux density, with all other r,<,0.20. Instead, "window" effects were observed, with 0.25,0.3 T eliciting the maximal release of the majority of metabolites, suggesting that magnetic fields of these strengths had significant impacts on metabolic homeostasis in S. pyogenes. The exposure of cells to 0.3 T was also found to significantly reduce the yield of 8-hydroxyguanine in extracted DNA compared to controls, suggesting some possible anti-oxidant protection to S. pyogenes at this field strength. Bioelectromagnetics 28:439,445, 2007. © 2007 Wiley-Liss, Inc. [source] Metabolic effects of ,-3 fatty acidsBIOFACTORS, Issue 1-4 2000Harald Osmundsen Some metabolic effects of dietary marine oils, or of dietary eicosapentaenoic or docosahexaenoic acid are reviewed. It is pointed out that docosahexaenoic acid appears more effective as regards induction of peroxisomal ,-oxidation. Similarly, docosahexaenoic appears more powerful in terms of suppression of hepatic ,9 -desaturase activity and mRNA-levels. The potential inhibitory effect of polyunsaturated fatty acids, particularly docosahexaenoic acid, on mitochondrial ,-oxidation is discussed. Experiments with rats suggesting that the hypolipidaemic response of eicosapentaenoic acid is more marked when the fatty acid was given to fed rats, as compared to fasted rats, are discussed. [source] Metabolic effects and the methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with neural tube defects in southern Brazil,BIRTH DEFECTS RESEARCH, Issue 7 2004Têmis Maria Félix Abstract BACKGROUND The importance of metabolic factors in neural tube defects (NTDs) has been the focus of many investigations. Several authors have suggested that abnormalities in homocysteine metabolism, such as hyperhomocysteinemia, folate deficiency, and low vitamin B12, may be responsible for these malformations and that both nutritional factors and genetic abnormalities are associated with them. METHODS We conducted a case-control study to investigate the influence of biochemical and genetic factors in NTDs in infants in southern Brazil. Levels of folate, vitamin B12, total homocysteine (t-Hcy) and the 677C>T and 1298A>C polymorphisms of the MTHFR gene were analyzed in 41 NTD child,mother pairs and 44 normal child,mother control pairs. RESULTS Subjects in the case group had a higher mean blood folate level than those in the control group. The level of vitamin B12 was lower in mothers in the NTD group than in control mothers (p = 0.004). The level of t-Hcy was not different in the two groups, but t-Hcy and vitamin B12 were correlated (p = 0.002). There was no difference in the genotype distribution for 677C>T and 1298A>C polymorphisms of MTHFR in the case and control pairs. The level of t-Hcy was correlated with 677TT. CONCLUSIONS Despite the small sample in this study, we suggest that low vitamin B12 and, consequently, hyperhomocysteinemia are important risk factors for NTDs in our population. Birth Defects Research (Part A), 2004. © 2004 Wiley-Liss, Inc. [source] Metabolic effects in neonates receiving intravenous medium-chain triglyceridesACTA PAEDIATRICA, Issue 2 2002G Angsten The effects of two lipid emulsions, one with 50% each of medium-chain and long-chain triglycerides, and a long-chain triglycerides lipid emulsion as a control, were evaluated for lipid and carnitine metabolism and respiratory quotient when given to neonates after major surgery during a short period of total parenteral nutrition. Each group included 10 neonates, and all tolerated the total parenteral nutrition well. The relative contents of linoleic acid and ,-linolenic acid increased in all lipid esters in plasma and adipose tissue in both groups, indicating that the content of these fatty acids is sufficient even in the medium-chain triglycerides emulsion. The serum concentration of ketones was within normal limits. Free fatty acids in plasma did not increase in either group. The total plasma carnitine concentration decreased in both groups but the distribution of free carnitine and acylcarnitine did not change. The total muscle carnitine did not change significantly but the ratio of acylcarnitine to free carnitine tended to increase in muscle in the treatment group, probably an effect of the medium-chain triglyceride supplementation. Conclusions: The two groups displayed the same fatty acid pattern in plasma and adipose tissue and the same respiratory quotient during the treatment period. Regarding carnitine status, essentially the same changes were seen in the two groups. However, discrete changes were seen in muscle tissue in the treatment group. [source] Influence of herring (Clupea harengus) and herring fractions on metabolic status in rats fed a high energy dietACTA PHYSIOLOGICA, Issue 3 2009H. Lindqvist Abstract Aim:, Few dietary studies have looked beyond fish oil to explain the beneficial metabolic effects of a fish-containing diet. Our aim was to study whether addition of herring, or sub-fractions of herring, could counteract negative metabolic effects known to be induced by a high-fat, high-sugar diet. Methods:, Rats were given six different diets: standard pellets; high energy diet with chicken mince (HiE control); high energy diet with herring mince (HiE herring); and high energy diet with chicken mince and either herring oil (HiE herring oil), herring press juice, PJ (HiE PJ) or herring low molecular weight PJ (HiE LMW-PJ). Factors associated with the metabolic syndrome were measured. Results:, There were no differences in energy intake or body weight between the groups, but animals fed high energy diets had a higher body fat content compared with the pellet group, although not statistically significant in all groups. Mesenteric adipocyte size was smaller in the HiE herring oil group compared with the HiE control. Glucose clamp studies showed that, compared with the pellet group, the HiE control and HiE herring diets, but not the HiE herring oil diet, induced insulin resistance. Addition of herring or herring oil to the high energy diet decreased total cholesterol levels, triacylglycerols and the atherogenic index compared with the HiE control group. Conclusions:, The results suggest that addition of herring or herring oil counteracts negative effects on blood lipids induced by a high energy diet. The lipid component of herring thus seems to be responsible for these beneficial effects. [source] Mitogen-activated protein kinase signal transduction in skeletal muscle: effects of exercise and muscle contractionACTA PHYSIOLOGICA, Issue 3 2001U. Widegren Exercise has numerous growth and metabolic effects in skeletal muscle, including changes in glycogen metabolism, glucose and amino acid uptake, protein synthesis and gene transcription. However, the mechanism(s) by which exercise regulates intracellular signal transduction to the transcriptional machinery in the nucleus, thus modulating gene expression, is largely unknown. This review will provide insight on potential intracellular signalling mechanisms by which muscle contraction/exercise leads to changes in gene expression. Mitogen-activated protein kinase (MAPK) cascades are associated with increased transcriptional activity. The MAPK family members can be separated into distinct parallel pathways including the extracellular signal-regulated kinase (ERK) 1/2, the stress-activated protein kinase cascades (SAPK1/JNK and SAPK2/p38) and the extracellular signal-regulated kinase 5 (ERK5). Acute exercise elicits signal transduction via MAPK cascades in direct response to muscle contraction. Thus, MAPK pathways appear to be potential physiological mechanisms involved in the exercise-induced regulation of gene expression in skeletal muscle. [source] The subjective experience of taking antipsychotic medication: a content analysis of Internet dataACTA PSYCHIATRICA SCANDINAVICA, Issue 2 2009J. Moncrieff Objective:, We explored the subjective effects associated with olanzapine, risperidone and older antipsychotics. Method:, We conducted a content analysis of an Internet database of comments about prescribed medications. Results:, We analysed 223 comments on risperidone, 170 on olanzapine and 46 relating to three older antipsychotics. The predominant subjective effects produced by all drugs consisted of sedation, cognitive impairment and emotional flattening or indifference. Connections appeared between these effects and Parkinsonian-like symptoms with the older drugs, sexual impairment with risperidone and metabolic effects with olanzapine. The experience of akathisia was frequently linked to suicidal thoughts. Some respondents described how the drugs' subjective effects helped to reduce symptoms of mania, psychosis and anxiety. Conclusion:, The generalisability of Internet data is uncertain. However, the data suggest that adverse subjective effects play a central role in the experience of taking antipsychotic drugs and may be related to the drugs' desired benefits. [source] Hyperphagia and obesity of OLETF rats lacking CCK1 receptors: Developmental aspectsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 5 2006Timothy H. Moran Abstract Otsuka Long Evans Tokushima Fatty (OLETF) rats have a deletion in the gene encoding the cholecystokinin,1 (CCK1) receptor. This deletion prevents protein expression, making the OLETF rat a CCK1 receptor knockout model. Consistent with the absence of CCK1 receptors, OLETF rats do not reduce their food intake in response to exogenously administered CCK and consume larger than normal meals. This deficit in within-meal feedback signaling is evident in liquid as well as solid meals. Neonatal OLETF rats show similar differences in independent ingestion tests. Intake is higher and is reflected in greater licking behavior. Neonatal OLETF rats also have diminished latencies to consume and higher initial ingestion rats. Adult OLETF rats are hyperphagic and obese. Although arcuate nucleus peptide gene expression is apparently normal in OLETF rats, when obesity is prevented through pair-feeding to amounts consumed by control Long Evans Tokushima Otsuka (LETO) rats, dorsomedial hypothalamic NPY mRNA expression is significantly elevated in OLETF rats. NPY overexpression is also evident in preobese, juvenile OLETF rats suggesting a causal role for this overexpression in the hyperphagia and obesity. Running wheel exercise normalizes food intake and body weight in OLETF rats. When access to exercise is provided at a time when OLETF rats are obese, the effects are limited to the period of exercise. When running wheel access is available to younger, preobese OLETF rats, exercise results in long lasting reductions in food intake and body weight and improved glucose regulation. These lasting metabolic effects of exercise may be secondary to an exercise induced reduction in DMH NPY mRNA expression. © 2006 Wiley Periodicals, Inc. Dev Psychobiol 48: 360,367, 2006. [source] Effects of insulin resistance on endothelial function: possible mechanisms and clinical implicationsDIABETES OBESITY & METABOLISM, Issue 10 2008D Tousoulis Insulin resistance (IR) is defined as a reduced responsiveness of peripheral tissues to the effects of the hormone, referring to abated ability of insulin in stimulating glucose uptake in peripheral tissues and in inhibiting hepatic glucose output. Insulin has both a vasodilatory effect, which is largely endothelium dependent through the release of nitric oxide, and a vasoconstrictory effect through the stimulation of the sympathetic nervous system and the release of endothelin-1. IR and endothelial dysfunction (ED) are not only linked by common pathogenetic mechanisms, involving deranged insulin signalling pathways, but also by other, indirect to the hormone's actions, mechanisms. Different treatment modalities have been proposed to affect positively both the metabolic effects of insulin and ED. Weight loss has been shown to improve sensitivity to insulin as a result of either altered diet or exercise. Exercise has favourable effects on endothelial function in normal states and in states of disease, in men and women, and throughout the age spectrum and, hence, in IR states. Metformin improves sensitivity to insulin and most likely affects positively ED. Studies have shown that inhibitors of the renin,angiotensin system alter IR favourably, while Angiotensin converting enzyme (ACE) inhibitors and Angiotensin receptor type II (ATII) inhibitors improve ED. Ongoing studies are expected to shed more light on the issue of whether treatment with the thiazolidinediones results in improvement of endothelial function, along with the accepted function of improving insulin sensitivity. Finally, improved endothelial function by such treatments is not in itself proof of reduced risk for atherosclerosis; this remains to be directly tested in clinical trials. [source] Pomegranate flower: a unique traditional antidiabetic medicine with dual PPAR-,/-, activator propertiesDIABETES OBESITY & METABOLISM, Issue 1 2008Yuhao Li PPARs are transcription factors belonging to the superfamily of nuclear receptors. PPAR-, is involved in the regulation of fatty acid (FA) uptake and oxidation, inflammation and vascular function, while PPAR-, participates in FA uptake and storage, glucose homeostasis and inflammation. The PPARs are thus major regulators of lipid and glucose metabolism. Synthetic PPAR-, or PPAR-, agonists have been widely used in the treatment of dyslipidaemia, hyperglycaemia and their complications. However, they are associated with an incidence of adverse events. Given the favourable metabolic effects of both PPAR-, and PPAR-, activators, as well as their potential to modulate vascular disease, combined PPAR-,/-, activation has recently emerged as a promising concept, leading to the development of mixed PPAR-,/-, activators. However, some major side effects associated with the synthetic dual activators have been reported. It is unclear whether this is a specific effect of the particular synthetic compounds or a class effect. To date, a medication that may combine the beneficial metabolic effects of PPAR-, and PPAR-, activation with fewer undesirable side effects has not been successfully developed. Pomegranate plant parts are used traditionally for the treatment of various disorders. However, only pomegranate flower has been prescribed in Unani and Ayurvedic medicines for the treatment of diabetes. This review provides a new understanding of the dual PPAR-,/-, activator properties of pomegranate flower in the potential treatment of diabetes and its associated complications. [source] ,-Blocker use and diabetes symptom score: results from the GEMINI studyDIABETES OBESITY & METABOLISM, Issue 3 2007J. B. McGill Aim:, The Glycemic Effect in Diabetes Mellitus: Carvedilol,Metoprolol Comparison in Hypertensives (GEMINI) trial compared the metabolic effects of two ,-blockers in people with type 2 diabetes and hypertension treated with renin,angiotensin system (RAS) blockade and found differences in metabolic outcomes. In this paper, we report the results of a prespecified secondary analysis of GEMINI that sought to determine the effect of these two ,-blockers on commonly reported symptoms. Methods:, The Diabetes Symptom Checklist (DSC), a self-report questionnaire measuring the occurrence and perceived burden of diabetes-related symptoms, was completed by GEMINI participants at baseline and at the end of the study (maintenance month 5). The DSC assessed symptoms in eight domains: psychology (fatigue), psychology (cognitive), neuropathy (pain), neuropathy (sensory), cardiology, ophthalmology, hyperglycaemia and hypoglycaemia. Results:, Comparison of the mean change in self-reported diabetes-related symptoms indicated a significant treatment difference favouring carvedilol over metoprolol tartrate in overall symptom score (,0.08; 95% CI ,0.15, ,0.01; p = 0.02) and in the domains for hypoglycaemia symptoms (,0.12; 95% CI ,0.23, ,0.02; p = 0.02) and hyperglycaemia symptoms (,0.16; 95% CI ,0.27, ,0.05; p = 0.005). Carvedilol resulted in fewer perceived diabetes-related symptoms in patients with diabetes and hypertension. Conclusion:, Carvedilol resulted in a lower perceived burden of diabetes-related symptoms in patients with type 2 diabetes and hypertension. The addition of a well-tolerated ,-blocker to RAS blockade may improve hypertension treatment and quality of life in patients with diabetes. [source] Role of leptin in the cardiovascular and endocrine complications of metabolic syndromeDIABETES OBESITY & METABOLISM, Issue 6 2006Marcelo L. G. Correia Aim:, To review the potential role of leptin, hyperleptinaemia and leptin resistance in the cardiovascular and endocrine complications of metabolic syndrome. Methods:, Review of literature listed in Medline. Results:, Hyperleptinaemia is common in obesity and reflects increased adiposity and leptin resistance. Nevertheless, leptin resistance may not be complete as several actions of leptin, such as cardiovascular sympatho-activation, might be preserved in obese subjects known to be resistant to the metabolic effects of leptin (i.e. selective leptin resistance). Notably, the renal and sympathetic actions of leptin may play an important role in the pathogenesis of hypertension related to obesity and metabolic syndrome. Furthermore, the lipotoxic effect of leptin resistance may cause insulin resistance and , cell dysfunction, increasing the risk of type 2 diabetes. Leptin has also been shown to possess proliferative, pro-inflammatory, pro-thrombotic, and pro-oxidative actions. Conclusion:, Hyperleptinaemia and leptin resistance may contribute to hypertension, impaired glucose metabolism, and pro-atherogenic state in obesity and metabolic syndrome. [source] Ten-Year Echo/Doppler Determination of the Benefits of Aerobic Exercise after the Age of 65 YearsECHOCARDIOGRAPHY, Issue 1 2010Alexander J. Muster M.D. As the human lifespan becomes progressively extended, potential health-related effects of intense aerobic exercise after age 65 need evaluation. This study evaluates the cardiovascular (CV), pulmonary, and metabolic effects of competitive distance running on age-related deterioration in men between 69 (±3) and 77 (±2) years (mean ± SD). Twelve elderly competitive distance runners (ER) underwent oxygen consumption and echo/Doppler treadmill stress testing (Balke protocol) for up to 10 years. Twelve age-matched sedentary controls (SC) with no history of CV disease were similarly tested and the results compared for the initial three series of the study. CV data clearly separated the ER from SC. At entry, resting and maximal heart rate, systolic/diastolic blood pressure, peak oxygen consumption (VO2max), and E/A ratio of mitral inflow were better in the ER (P < 0.05 vs. SC). With aging, ER had a less deterioration of multiple health parameters. Exceptions were VO2max and left ventricular diastolic function (E/A, AFF, IVRT) that decreased (P < 0.05, Year 10 vs. Year 1). Health advantages of high-level aerobic exercise were demonstrated in the ER when compared to SC. Importantly, data collected in ER over 10 years confirm the benefit of intensive exercise for slowing several negative effects of aging. However, the normative drop of exercise capacity in the seventh and eighth decades reduces the potential athleticism plays in prevention of CV events. (Echocardiography 2010;27:5-10) [source] Development of a bacterial challenge test for gnotobiotic sea bass (Dicentrarchus labrax) larvaeENVIRONMENTAL MICROBIOLOGY, Issue 2 2009K. Dierckens Summary The use of probiotic microorganisms in aquaculture is gaining a lot of interest. Gnotobiotic model systems are required in order to fully understand the effects and modes-of-action of these microorganisms, as the native microbial communities present in non-sterile animals can lead to false conclusions. In this study, a gnotobiotic sea bass larvae (Dicentrarchus labrax) test system was developed. In order to obtain bacteria-free animals, the eggs were disinfected with glutaraldehyde and subsequently incubated in a solution of rifampicin and ampicillin. Axenity was confirmed using culture-dependent and -independent techniques. The gnotobiotic larvae were fed axenic Artemia sp. from 7 days after hatching onwards. In the challenge test, one of the three opportunistic pathogens, Aeromonas hydrophila, Listonella anguillarum serovar O1 and O2a, was added to the model system via the water and encapsulated in Artemia sp. Only serovar O2a led to increased mortality in the sea bass larvae. The presented gnotobiotic model can be used for research on, among others, reciprocal metabolic effects between microorganisms and the host (e.g. as measured by gene expression), immunostimulants, pharmacological research and the histological development of the gastrointestinal tract and growth of larvae. [source] Region-specific changes in gene expression in rat brain after chronic treatment with levetiracetam or phenytoinEPILEPSIA, Issue 9 2010Bjørnar Hassel Summary Purpose:, It is commonly assumed that antiepileptic drugs (AEDs) act similarly in the various parts of the brain as long as their molecular targets are present. A few experimental studies on metabolic effects of vigabatrin, levetiracetam, valproate, and lamotrigine have shown that these drugs may act differently in different brain regions. We examined effects of chronic treatment with levetiracetam or phenytoin on mRNA levels to detect regional drug effects in a broad, nonbiased manner. Methods:, mRNA levels were monitored in three brain regions with oligonucleotide-based microarrays. Results:, Levetiracetam (150 mg/kg for 90 days) changed the expression of 65 genes in pons/medulla oblongata, two in hippocampus, and one in frontal cortex. Phenytoin (75 mg/kg), in contrast, changed the expression of only three genes in pons/medulla oblongata, but 64 genes in hippocampus, and 327 genes in frontal cortex. Very little overlap between regions or drug treatments was observed with respect to effects on gene expression. Discussion:, We conclude that chronic treatment with levetiracetam or phenytoin causes region-specific and highly differential effects on gene expression in the brain. Regional effects on gene expression could reflect regional differences in molecular targets of AEDs, and they could influence the clinical profiles of AEDs. [source] Topical treatment with thiazolidinediones, activators of peroxisome proliferator-activated receptor-,, normalizes epidermal homeostasis in a murine hyperproliferative disease modelEXPERIMENTAL DERMATOLOGY, Issue 3 2006Marianne Demerjian Abstract:, In a murine model of epidermal hyperplasia reproducing some of the abnormalities of several common skin disorders, we previously demonstrated the antiproliferative and pro-differentiating effects of peroxisome proliferator-activated receptor (PPAR),, PPAR,/,, and liver X receptor activators. Unlike other subgroups of PPAR activators, thiazolidinediones (TZDs), a family of PPAR, ligands, did not inhibit keratinocyte proliferation in normal murine skin. Here, we studied the effects of two TZDs, namely ciglitazone (10 mM) and troglitazone (1 mM), in the same murine model where epidermal hyperproliferation was reproduced by repeated barrier abrogation with tape stripping. Topical treatment with ciglitazone and troglitazone resulted in a marked and significant decrease in epidermal thickness. Furthermore, in all TZD-treated groups, we observed a significant decrease in keratinocyte proliferation using proliferating cell nuclear antigen, 5-bromo-2,-deoxyuridine, and tritiated thymidine incorporation. However, using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, we found no difference in apoptosis between different treatments, emphasizing that it is the antiproliferative role of these activators that accounts for the decrease of epidermal thickness. Finally, using immunohistochemical methods, we determined the effects of ciglitazone on keratinocyte differentiation in this hyperproliferative model. We observed an increased expression of involucrin and filaggrin following ciglitazone treatment, suggesting a pro-differentiating action of TZDs in this model. In summary, topical TZDs significantly reduce epidermal keratinocyte proliferation while promoting differentiation in a murine model of hyperproliferative epidermis. Together, these results suggest that in addition to their metabolic effects currently in use in the treatment of type 2 diabetes, topical TZDs could be considered as potential alternative therapeutic agents in hyperproliferative skin diseases such as psoriasis. [source] Sleep and the metabolic syndromeEXPERIMENTAL PHYSIOLOGY, Issue 1 2007Robert Wolk The metabolic syndrome represents a clustering of several interrelated risk factors of metabolic origin that are thought to increase cardiovascular risk. It is still uncertain whether this clustering results from multiple underlying risk factors or whether it has a single cause. One metabolic abnormality that may underlie several clinical characteristics of the metabolic syndrome is insulin resistance. This review discusses the evidence that sleep disturbances (obstructive sleep apnoea, sleep deprivation and shift work) may independently lead to the development of both insulin resistance and individual clinical components of the metabolic syndrome. The converse may also be true, in that metabolic abnormalities associated with the metabolic syndrome and insulin resistance may potentially exacerbate sleep disorders. The notion that sleep disturbances exert detrimental metabolic effects may help explain the increasing prevalence of the metabolic syndrome and insulin resistance in the general population and may have important implications for population-based approaches to combat the increasing epidemic of metabolic and cardiovascular disease. [source] Microglia express functional 11,-hydroxysteroid dehydrogenase type 1,GLIA, Issue 10 2010Andres Gottfried-Blackmore Abstract Glucocorticoids are potent regulators of inflammation exerting permissive, stimulatory, and suppressive effects. Glucocorticoid access to intracellular receptors is regulated by the activity of two distinct enzymes known as 11,-hydroxysteroid dehydrogenase (11,HSD) Type 1 and Type 2, which catalyze the activation or deactivation of glucocorticoids. Although expression of these enzymes in major organ systems and their roles in the metabolic effects of glucocorticoids have been described, their role in the inflammatory response has only recently started to be addressed. In this report, we have studied the expression and activity of 11,HSD Type 1 and Type 2 in microglia cells. Microglia, the brain's resident macrophages, initiate and orchestrate CNS inflammatory responses. Importantly, activated microglia are implicated in most neurodegenerative conditions, making them key subjects of study. We found that microglia expressed 11,HSD-1, but not 11,HSD-2, both in ex vivo FACS-sorted adult cells and in vitro primary cultures. 11,HSD-1 expression was increased in LPS-activated microglia. Moreover, 11,HSD-1 catalyzed the metabolic conversion of 11-dehydro-corticosterone into corticosterone (CORT), which potently reduced cytokine production in activated microglia. We propose that 11,HSD-1 may provide microglia with an intrinsic mechanism to autoregulate and inhibit proinflammatory mediator production through CORT formation. © 2010 Wiley-Liss, Inc. [source] Primary care physician beliefs about insulin initiation in patients with type 2 diabetesINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 6 2008R. P. Hayes Summary Background:, Insulin is the most effective drug available to achieve glycaemic goals in patients with type 2 diabetes. Yet, there is reluctance among physicians, specifically primary care physicians (PCPs) in the USA, to initiate insulin therapy in these patients. Aims:, To describe PCPs' attitudes about the initiation of insulin in patients with type 2 diabetes and identify areas in which there is a clear lack of consensus. Methods:, Primary care physicians practicing in the USA, seeing 10 or more patients with type 2 diabetes per week, and having > 3 years of clinical practice were surveyed via an internet site. The survey was developed through literature review, qualitative study and expert panel. Results:, Primary care physicians (n = 505, mean age = 46 years, 81% male, 62% with > 10 years practice; 52% internal medicine) showed greatest consensus on attitudes regarding risk/benefits of insulin therapy, positive experiences of patients on insulin and patient fears or concerns about initiating insulin. Clear lack of consensus was seen in attitudes about the metabolic effects of insulin, need for insulin therapy, adequacy of self-monitoring blood glucose, time needed for training and potential for hypoglycaemia in elderly patients. Conclusions:, The beliefs of some PCPs are inconsistent with their diabetes treatment goals (HbA1c , 7%). Continuing medical education programmes that focus on increasing primary care physician knowledge about the progression of diabetes, the physiological effects of insulin, and tools for successfully initiating insulin in patients with type 2 diabetes are needed. [source] Maximising antihypertensive effects of angiotensin II receptor blockers with thiazide diuretic combination therapy: focus on irbesartan/hydrochlorothiazideINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 12 2007J. M. Flack Summary Background:, Evidence-based guidelines for the management of hypertension are now well established. Studies have shown that more than 60% of patients with hypertension will require two or more drugs to achieve current treatment targets. Discussion:, Combination therapy is recommended as first-line treatment by the JNC-7 guidelines for patients with a blood pressure > 20 mmHg above the systolic goal or 10 mmHg above the diastolic goal, while the International Society of Hypertension in Blacks recommends combination therapy when BP exceeds targets by > 15/10 mmHg. Current European Society of Hypertension-European Society of Cardiology guidelines also recommend the use of low-dose combination therapy in the first-line setting. Furthermore, JNC-7 recommends that a thiazide-type diuretic should be part of initial first-line combination therapy. Thiazide/diuretic combinations are available for a variety of classes of antihypertensive, including ACE inhibitors, angiotensin receptor blockers (ARBs), beta blockers and centrally acting agents. This article focuses on clinical data investigating the combination of an ARB, irbesartan, with the diuretic, hydrochlorothiazide. Conclusions:, These data indicate that the ARB/HCTZ combination has greater potency and a similar side effect profile to ARB monotherapy and represents a highly effective approach for attaining goal BP levels using a therapeutic strategy that very effectively lowers BP, is well tolerated and minimises diuretic-induced metabolic effects. [source] Schizophrenia, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and number needed to treat: how can CATIE inform clinicians?INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 8 2006L. CITROME Summary The schizophrenia medication study conducted as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) provided a large quantity of data. However, placing these data into a clinically meaningful context for the individual practitioner has been challenging. Effectiveness and safety outcome data were extracted from the three principal publications that documented the results of phases 1 and 2 of the CATIE schizophrenia study. Number needed to treat (NNT) and number needed to harm (NNH) were calculated from the categorical results, together with their confidence intervals. Olanzapine and clozapine demonstrated advantages over comparators in terms of all-cause discontinuation, largely driven by efficacy advantages. NNT for olanzapine compared with perphenazine, quetiapine, risperidone and ziprasidone ranged from 5.5 to 10.1 in phase 1. NNT for clozapine compared with risperidone or quetiapine was approximately 3 in phase 2. There were marked differences in association with weight gain and metabolic effects, with olanzapine demonstrating a NNH ranging from 12.4 to 17.7 in terms of discontinuation of treatment in phase 1 because of these effects. Results from phase 2 reflect phase 1 in this regard, and demonstrated an advantage for ziprasidone in terms of discontinuation because of weight gain or metabolic effects, with NNT ranging from 10.6 to 20.8. However, these notable differences in association with weight gain and metabolic effects did not seem to drive the differences in overall time to all-cause discontinuation. NNT and NNH can help place the wide array of CATIE results into clinical context, and permits quantification of the differences observed between the antipsychotics that were tested. [source] The role of PAS kinase in regulating energy metabolismIUBMB LIFE, Issue 4 2008Huai-Xiang Hao Abstract Metabolic disorders, such as diabetes and obesity, are fundamentally caused by cellular energy imbalance and dysregulation. Therefore, understanding the regulation of cellular fuel and energy metabolism is of great importance to develop effective therapies for metabolic disease. The cellular nutrient and energy sensors, AMPK and TOR, play a key role in maintaining cellular energy homeostasis. Like AMPK and TOR, PAS kinase (PASK) is also a nutrient responsive protein kinase. In yeast, PAS kinase phosphorylates the enzyme Ugp1 and thereby shifts glucose partitioning toward cell wall glucan synthesis at the expense of glycogen synthesis. Consistent with this function, yeast PAS kinase is activated by both cell integrity stress and growth in non-fermentative carbon sources. PASK is also important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular level. In cultured pancreatic ,-cells, PASK is activated by elevated glucose concentrations and is required for glucose-stimulated transcription of the insulin gene. PASK knockdown in cultured myoblasts causes increased glucose oxidation and elevated cellular ATP levels. Mice lacking PASK exhibit increased metabolic rate and resistance to diet-induced obesity. Interestingly, PGC-1 expression and AMPK and TOR activity were not affected in PASK deficient mice, suggesting PASK may exert its metabolic effects through a new mechanism. We propose that PASK plays a significant role in nutrient sensing, metabolic regulation, and energy homeostasis, and is a potential therapeutic target for metabolic disease. © 2008 IUBMB IUBMB Life, 60(4): 204,209, 2008 [source] In vivo metabolic effects of naringenin in the ethanol consuming rat and the effect of naringenin on adipocytes in vitroJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 3-4 2007K. Szkudelska Summary Naringenin is a bioactive flavanone involved in the inhibition of drug metabolism which exhibits antioxidant, anti-inflammatory and anticancerogenic properties and which recently appeared to be a factor mitigating the hyperlipidaemic effects in rats and rabbits. In the performed experiment, the effect of naringenin, administered intragastrically (50 mg/kg) for 2 weeks to normal and ethanol drinking rats, on insulin and leptin levels and on some metabolic parameters was investigated. Naringenin did not change the hormone levels in any group of rats. Blood glucose, triglyceride, total, esterified and free cholesterol and high-density lipoprotein-cholesterol concentrations were also unaffected by this compound. Only free fatty acids were elevated after the naringenin treatment in the water-drinking rats. In spite of unchanged glucose and insulin concentrations in blood, the tested flavanone reduced the glucose/insulin ratio in ethanol-receiving rats. Liver triglycerides, elevated due to ethanol ingestion, were partially normalized by naringenin. Other tested parameters like liver glycogen and cholesterol, muscle triglycerides and glycogen were not altered in any group of rats. The influence of naringenin (62.5, 125, 250 and 500 ,m) on basal and insulin-stimulated glucose conversion to lipids (lipogenesis) as well as on basal and epinephrine-stimulated glycerol release (lipolysis) in the isolated rat adipocytes was also tested. The basal and the stimulated lipogenesis tended to be decreased in the presence of the flavanone (250 ,m). This inhibitory effect intensified and was statistically significant at the highest concentration of naringenin. The tested compound did not evoke any effect on basal lipolysis while the epinephrine-stimulated process was limited at the highest concentration of the flavanone. Naringenin (62.5, 125, 250 and 500 ,m) had no effect on leptin secretion from the isolated rat adipocytes. Results obtained in our studies demonstrate that naringenin exerts a very weak influence on carbohydrate and lipid metabolism of normal and ethanol-consuming rats and on metabolism of isolated rat adipocytes. [source] Nateglinide and glibenclamide metabolic effects in naïve type 2 diabetic patients treated with metforminJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2009G. Derosa MD PhD Summary Background and objective:, Most antidiabetic agents target only one of several underlying causes of diabetes. The complementary actions of the glinides and the biguanides may give optimal glycemic control in patients with type 2 diabetes mellitus. The aim of the present study was to compare the effects of nateglinide plus metformin with glibenclamide plus metformin on glucose and lipid metabolism, and haemodynamic parameters in patients with type 2 diabetes mellitus. Methods:, We enrolled 248 type 2 diabetic patients. Patients were randomly assigned to receive nateglinide (n = 124) or glibenclamide (n = 124), after 6 months of run-in, in which we titrated nateglinide (starting dose 180 mg/day), glibenclamide (starting dose 7·5 mg/day), and metformin (starting dose 1500 mg/day). The final doses were (mean ± standard deviation), 300 ± 60, 12·5 ± 2·5, and 2500 ± 500 mg/day, respectively. We followed these patients for 1 year after titration. We assessed body mass index (BMI), fasting (FPG) and post-prandial (PPG) plasma glucose, glycosylated haemoglobin (HbA1c), fasting (FPI) and post-prandial (PPI) plasma insulin, homeostasis model assessment (HOMA) index, and lipid profile [total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), apolipoprotein A-I (Apo A-I), and apolipoprotein B (Apo B)], systolic blood pressure (SBP), and diastolic blood pressure (DBP). All variables were evaluated at baseline and after 3 and 6 months in the run-in period, and at baseline, and after 3, 6, 9 and 12 months for both treatment groups. Results and discussion:, Body mass index did not show any significant change during the study. We observed a significant improvement from baseline to 1 year on HbA1c (P < 0·01 vs. baseline and vs. glibenclamide group, respectively), FPG (P < 0·01 vs. baseline), PPG (P < 0·01 vs. baseline), and on HOMA index (P < 0·05 vs. baseline) in the nateglinide group. In the glibenclamide group, we found significant changes in HbA1c (P < 0·05 vs. baseline), FPG (P < 0·01 vs. baseline), PPG (P < 0·05 vs. baseline), and HOMA index (P < 0·05 vs. baseline). No significant change was observed in TC, LDL-C, HDL-C, Tg, Apo A-I, Apo B, SBP, DBP and HR in either group after 3, 6, 9 and 12 months. These effects of nateglinide and glibenclamide on insulin-resistance parameters are in agreement with previous reports. Contrarily to previous reports, we did not observe any significant BP change in patients treated with glibenclamide. Although both nateglinide and glibenclamide attenuated PPG and HOMA index, they did not have significant effects on lipid metabolism, as already shown in subjects with type 2 diabetes and good glycemic control. Conclusion:, Nateglinide improved glycemic control better than glibenclamide in combination with metformin. [source] | ||||||||||||||||||||||||||||||||||