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Molecular Genetics and Genomics : MGG Feb 2016Peroxisome proliferator-activated receptors (PPARγ), adiponectin (ADIPOQ) and fat mass and obesity-associated gene (FTO) have been reported as a key candidate genes for... (Meta-Analysis)
Meta-Analysis
Peroxisome proliferator-activated receptors (PPARγ), adiponectin (ADIPOQ) and fat mass and obesity-associated gene (FTO) have been reported as a key candidate genes for obesity, type 2 diabetes (T2D) susceptibility and insulin resistance, and we hypothesize that in the background of obesity, the effect of PPARγ2 (rs1801282), ADIPOQ (rs16861194) and FTO (rs9939609) variant could potentially influence T2D susceptibility. To decipher a more accurate estimation toward its population-specific impact of these variants toward susceptibility to T2D, a case-control study, systematic review and a meta-analysis was performed in a South Asian population. A case-control analysis of 518 T2D cases and 518 controls of Karnataka origin were performed to analyze the association of PPARγ2 (rs1801282), ADIPOQ (rs16861194) and FTO (rs9939609) on the risk of T2D. In addition, a systematic review and meta-analysis for PPARγ2 (rs1801282) and FTO (rs9939609) was elucidated from Asian population. Our investigation showed that PPARγ2 (rs1801282) and FTO (rs9939609) are associated with T2D susceptibility. When T2D cohort was further stratified according to the obesity status, PPARγ2 (rs1801282) and FTO (rs9939609) showed association with T2D only in the obese diabetic group and ADIPOQ (rs16861194) showed no difference in risk of susceptibility to the disease. The meta-analysis of PPARγ2 (rs1801282) showed population-specific association for T2D susceptibility as opposed to FTO (rs9939609) which showed no difference in population effect toward T2D susceptibility. In conclusion, our study showed that PPARγ2 (rs1801282) and FTO (rs9939609) variants are associated with T2D susceptibility when associated with adiposity in Indian population.
Topics: Adiponectin; Adiposity; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Asian People; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Humans; India; Male; Middle Aged; Obesity; PPAR gamma; Polymorphism, Single Nucleotide; Proteins
PubMed: 26243686
DOI: 10.1007/s00438-015-1097-4 -
Atherosclerosis May 2015The aim of this systematic review was to perform a meta-analysis of randomized controlled trials (RCTs) examining the efficacy of fibrate therapy in reducing plasma... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The aim of this systematic review was to perform a meta-analysis of randomized controlled trials (RCTs) examining the efficacy of fibrate therapy in reducing plasma concentration or activity of plasminogen activator inhibitor 1 (PAI-1).
METHODS
Scopus and MEDLINE databases were searched (up to October 15, 2014) to identify RCTs investigating whether fibrates lower plasma PAI-1 concentration or activity. A random-effects model and the generic inverse variance method were used for quantitative data synthesis. Sensitivity analyses were conducted using the one-study remove approach. Random-effects meta-regression was performed to assess the impact of potential moderators on the estimated effect sizes.
RESULTS
A total of 14 RCTs examining the effects of gemfibrozil (6 trials), bezafibrate (4 trials), and fenofibrate (5 trials) were included. Meta-analysis suggested that fibrate therapy did not significantly reduce plasma PAI-1 concentration (weighed mean difference [WMD]: -11.39 ng/mL, 95% CI: -26.64, 3.85, p=0.143) or activity (WMD: 2.02 U/mL, 95% CI: -0.87, 4.90, p=0.170). These results remained unchanged after subgroup analysis according to duration of treatment (<12 and ≥12 weeks) and type of fibrate administered (fenofibrate, bezafibrate or gemfibrozil). The estimated effects of fibrate therapy on plasma concentration and activity of PAI-1 were independent of treatment duration and changes in plasma triglyceride levels in the meta-regression analysis.
CONCLUSION
This meta-analysis of RCTs suggested that fibrate therapy does not reduce plasma concentration or activity of PAI-I. The putative benefits of fibrate therapy in patients with cardiovascular disease appear to be exerted via mechanisms independent of effects on PAI-1.
Topics: Biomarkers; Cardiovascular Diseases; Down-Regulation; Dyslipidemias; Fibric Acids; Humans; Plasminogen Activator Inhibitor 1; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome
PubMed: 25828270
DOI: 10.1016/j.atherosclerosis.2015.03.016 -
Sports Medicine (Auckland, N.Z.) May 2015Vascular dysfunction is a precursor to the atherosclerotic cascade, significantly increasing susceptibility to cardiovascular events such as myocardial infarction or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Vascular dysfunction is a precursor to the atherosclerotic cascade, significantly increasing susceptibility to cardiovascular events such as myocardial infarction or stroke. Previous studies have revealed a strong relationship between vascular function and cardiorespiratory fitness (CRF). Thus, since high-intensity interval training (HIIT) is a potent method of improving CRF, several small randomized trials have investigated the impact on vascular function of HIIT relative to moderate-intensity continuous training (MICT).
OBJECTIVE
The aim of this study was to systematically review the evidence and quantify the impact on vascular function of HIIT compared with MICT.
METHODS
Three electronic databases (PubMed, Embase, and MEDLINE) were searched (until May 2014) for randomized trials comparing the effect of at least 2 weeks of HIIT and MICT on vascular function. HIIT protocols involved predominantly aerobic exercise at a high intensity, interspersed with active or passive recovery periods. We performed a meta-analysis to compare the mean difference in the change in vascular function assessed via brachial artery flow-mediated dilation (FMD) from baseline to post-intervention between HIIT and MICT. The impact of HIIT versus MICT on CRF, traditional cardiovascular disease (CVD) risk factors, and biomarkers associated with vascular function (oxidative stress, inflammation, and insulin resistance) was also reviewed across included studies.
RESULTS
Seven randomized trials, including 182 patients, met the eligibility criteria and were included in the meta-analysis. A commonly used HIIT prescription was four intervals of 4 min (4 × 4 HIIT) at 85-95% of maximum or peak heart rate (HRmax/peak), interspersed with 3 min of active recovery at 60-70% HRmax/peak, three times per week for 12-16 weeks. Brachial artery FMD improved by 4.31 and 2.15% following HIIT and MICT, respectively. This resulted in a significant (p < 0.05) mean difference of 2.26%. HIIT also had a greater tendency than MICT to induce positive effects on secondary outcome measures, including CRF, traditional CVD risk factors, oxidative stress, inflammation, and insulin sensitivity.
CONCLUSION
HIIT is more effective at improving brachial artery vascular function than MICT, perhaps due to its tendency to positively influence CRF, traditional CVD risk factors, oxidative stress, inflammation, and insulin sensitivity. However, the variability in the secondary outcome measures, coupled with the small sample sizes in these studies, limits this finding. Nonetheless, this review suggests that 4 × 4 HIIT, three times per week for at least 12 weeks, is a powerful form of exercise to enhance vascular function.
Topics: Blood Pressure; Body Fat Distribution; Brachial Artery; C-Reactive Protein; Humans; Insulin Resistance; Lipids; Oxidative Stress; Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Physical Fitness; Regional Blood Flow; Resistance Training; Transcription Factors
PubMed: 25771785
DOI: 10.1007/s40279-015-0321-z -
Drugs & Aging Jan 2015Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, and close associations between AD and diabetes have been found. Peroxisome... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, and close associations between AD and diabetes have been found. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists, as newly-developed oral hypoglycaemic agents, were evaluated as a possible therapy for AD.
AIM
We systematically evaluated the efficacy and safety of PPAR-γ agonists in the treatment of AD and amnestic mild cognitive impairment (aMCI), the prodromal stage of AD.
METHODS
A search of the electronic databases PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure (until July 2014) was conducted, and included randomized controlled trials. Dichotomous data were expressed as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous data were expressed as mean differences (MD) with 95% CIs. The results were pooled using a random-effects model.
RESULTS
Nine eligible studies were identified, with 4,327 participants. Using the Alzheimer's Disease Assessment Scale-Cognitive subscale, pioglitazone was found to be efficacious, especially for patients with comorbid diabetes (MD -3.47, 95% CI -4.40 to -2.54). Rosiglitazone was not efficacious, even for apolipoprotein E (APOE) ε4 non-carriers (MD -0.31, 95% CI -1.12 to 0.51). There was no increase in any adverse events (AEs) or serious AEs compared with placebo. Peripheral edema was the most frequent AE related to PPAR-γ agonist treatment (RR 4.14, 95% CI 2.37-7.23).
CONCLUSIONS
There is insufficient evidence to support the use of rosiglitazone in aMCI and AD patients in order to improve cognitive performance. Nonetheless, the efficacy of pioglitazone seems to be promising, particularly for patients with comorbid diabetes, however this needs to be further confirmed by well-designed trials with large sample sizes. PPAR-γ agonists such as rosiglitazone and pioglitazone are generally well-tolerated in AD and aMCI patients.
Topics: Alzheimer Disease; Cognitive Dysfunction; Humans; Hypoglycemic Agents; PPAR gamma; Pioglitazone; Randomized Controlled Trials as Topic; Rosiglitazone; Thiazolidinediones
PubMed: 25504005
DOI: 10.1007/s40266-014-0228-7 -
Current Atherosclerosis Reports Dec 2014The aim of this report is to perform a systematic review and qualitative synthesis of the literature to address whether, and to what extent, diet modulates the effects... (Review)
Review
The aim of this report is to perform a systematic review and qualitative synthesis of the literature to address whether, and to what extent, diet modulates the effects of the Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma 2 (PPARγ2) on body weight and other measures of adiposity. A systematic search of the literature was conducted, wherein both observational and experimental studies of adults were reviewed. Overall, the results of the observational studies show little consistency. Methodological differences in their design, conduct and analysis may largely account for the apparently discrepant findings. This notwithstanding, the main picture that emerges is that the energy content and composition of the diet may affect BMI, body composition and metabolic parameters in Ala allele carriers more than in Pro/Pro homozygotes. In most studies, carriers of the Ala allele with an obesogenic lifestyle (i.e. high-energy, high-carbohydrate and, to some extent, high-fat diets) are more obese than Pro homozygotes. Well-designed intervention studies with a sufficiently large sample size consistently show that carriers of the Ala allele are more prone to weight loss when exposed to a healthy lifestyle; however, these individuals do not seem to retain these benefits when returning to a sedentary lifestyle and inadequate dieting behaviours. Some key questions in this area of research have emerged. Carefully designed and adequately powered studies are needed, particularly involving the development and validation of standardized tools for the assessment of dietary exposure, including the use of biomarkers, to move the field forward.
Topics: Adult; Body Mass Index; Diet, Fat-Restricted; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Obesity; Obesity, Morbid; PPAR gamma; Phenotype; Polymorphism, Genetic; Randomized Controlled Trials as Topic; Risk Assessment; Sensitivity and Specificity; Treatment Outcome
PubMed: 25342491
DOI: 10.1007/s11883-014-0462-9 -
The Cochrane Database of Systematic... Jan 2014Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists are insulin-sensitising drugs used for the treatment of insulin resistance. In addition to lowing... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists are insulin-sensitising drugs used for the treatment of insulin resistance. In addition to lowing glucose in diabetes, these drugs may also protect against hyperlipidaemia and arteriosclerosis, which are risk factors for stroke.
OBJECTIVES
To assess the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events for people with stroke or transient ischaemic attack (TIA).
SEARCH METHODS
We searched the Cochrane Stroke Group Trials Register (August 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 9), MEDLINE (1949 to October 2013), EMBASE (1980 to October 2013), CINAHL (1982 to October 2013), AMED (1985 to October 2013) and 11 Chinese databases (October 2013). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted authors and pharmaceutical companies. There were no language restrictions.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) evaluating PPAR-γ agonists versus placebo for the secondary prevention of stroke and related vascular events in people with stroke or TIA, with the outcomes of recurrent stroke, vascular events and adverse events.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy and assessed the methodological quality.
MAIN RESULTS
We identified four eligible studies with 1163 participants; only one study had a low risk of bias for all domains. The participants in different studies were heterogeneous. The number of participants with recurrent stroke was evaluated in two studies, where PPAR-γ agonists reduced the recurrence of stroke compared with placebo (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.34 to 0.80). PPAR-γ agonists given over a mean duration of 34.5 months in a single trial were found to reduce a composite outcome of total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (RR 0.73, 95% CI 0.54 to 0.99). Data on additional composite outcomes reflecting serious adverse events (all-cause death and other major vascular events; all-cause mortality, non-fatal myocardial infarction or non-fatal stroke) were similar although the confidence intervals were wider and the effects were not statistically significant. In addition, two studies respectively measured insulin sensitivity and the ubiquitin-proteasome activity in carotid plaques with significant differences in these outcomes between PPAR-γ agonists and placebo. None of the studies reported the number of participants with disability due to vascular events or improvement in quality of life. Three RCTs reported information about adverse events. Frequent adverse events included oedema, cardiac failure and anaemia. Evidence that adverse events occurred more frequently in participants treated with PPAR-γ agonists when compared with placebo was imprecise and inconsistent (risk difference (RD) 10%, 95% CI -8% to 28%, I² = 86%).
AUTHORS' CONCLUSIONS
PPAR-γ agonists were demonstrated to reduce recurrent stroke and total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, and improve insulin sensitivity and the stabilisation of carotid plaques. There is evidence of limited quality that they are well-tolerated. However, the conclusions should be interpreted with caution considering the small number and the quality of the included studies. In future, well-designed, double-blind RCTs with large samples are required to test the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events in people with stroke or TIA.
Topics: Cardiovascular Diseases; Humans; Hypoglycemic Agents; Ischemic Attack, Transient; Myocardial Infarction; PPAR gamma; Pioglitazone; Rosiglitazone; Secondary Prevention; Stroke; Thiazolidinediones
PubMed: 24399670
DOI: 10.1002/14651858.CD010693.pub2 -
Nutrition Research (New York, N.Y.) Sep 2013Diet is one factor that plays a part in coronary heart disease risk through multiple biological mechanisms including subclinical inflammation. In this review, we aimed... (Review)
Review
Diet is one factor that plays a part in coronary heart disease risk through multiple biological mechanisms including subclinical inflammation. In this review, we aimed to systematically assess and summarize evidence regarding the association of saturated fatty acids (SFAs) with inflammatory markers and adipokines. An electronic search of the literature was conducted up to September 2010 using Medline, Scopus, Web of Science, and Science Direct (updated from September 2010 to August 2011 through Medline). Original studies that were written in Portuguese, English, Spanish, or French, and addressed the effects of SFA (not dietary sources or SFA-rich diets) on inflammatory markers or adipokines in adult populations were considered eligible. Data from 15 studies providing adjusted estimates were extracted. The publication year varied from 1995 to 2010 and the sample size from 54 to 4900. Most studies were cross sectional, with 3 studies using a prospective design. Twelve studies assessed total SFA, and 3 studies considered their subtypes, which were measured through dietary assessments (11 studies) or in blood samples (4 studies). Significant positive associations were observed between SFA and soluble intercellular adhesion molecule-1 and interleukin-6, whereas no significant associations were observed with E-selectin, tumor necrosis factor α, granulocyte-macrophage colony-stimulating factor, fibrinogen, and adiponectin. For high-sensitivity C-reactive protein, 2 studies showed significant positive associations, whereas 3 studies reported no significant associations. One study reported a significant inverse association of SFA with leptin, although the other 3 found no significant associations. Based on this systematic review, a potential positive association of SFA with high-sensitivity C-reactive protein but not with adipokines is suggested, which should be confirmed by future research.
Topics: Adipokines; Biomarkers; C-Reactive Protein; Cell Adhesion; Diet; E-Selectin; Fatty Acids; Feeding Behavior; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Leptin; Tumor Necrosis Factor-alpha
PubMed: 24034567
DOI: 10.1016/j.nutres.2013.07.002 -
PPAR Research 2013Pregnancy is a state of immunotolerance, and pregnancy outcome is strongly linked to the correct activation and balancing of the maternal immune system. Besides abortion...
Pregnancy is a state of immunotolerance, and pregnancy outcome is strongly linked to the correct activation and balancing of the maternal immune system. Besides abortion as possible result of improper early pregnancy development, other pregnancy associated conditions like preeclampsia (PE), intrauterine growth retardation (IUGR), preterm labour, or gestational diabetes mellitus (GDM) are linked to immunologic overactivation and dysregulation. Both the innate and the adaptive immune system, and therefore B and T lymphocytes, natural killer cells (NK), macrophages and dendritic cells (DCs) are all involved in trophoblast invasion, pregnancy maintenance, and development of pregnancy disorders. Peroxisome proliferator activated receptors (PPARs) are nuclear transcription factors with three known isotypes: PPARα, PPAR β / δ , and PPAR γ . They are expressed in most human organs and their function extends from regulating metabolism, homeostasis, and carcinogenesis to immune response. In the recent years, PPARs have been identified in most reproductive tissues and in all lines of immune cells. Only in few cases, the role of PPARs in reproductive immunology has been elucidated though the role of PPARs in immune answer and immunotolerance is evident. Within this paper we would like to give an update on today's knowledge about PPARs and immune cells in reproduction and highlight interesting interferences in regard of future therapeutic targets.
PubMed: 23554810
DOI: 10.1155/2013/970276 -
Therapeutic Advances in Musculoskeletal... Feb 2013Fibrates are used as lipid-lowering drugs to prevent cardiovascular pathology. Fibrates are ligands of peroxisome proliferator-activated receptor α (PPARα). Besides...
Fibrates are used as lipid-lowering drugs to prevent cardiovascular pathology. Fibrates are ligands of peroxisome proliferator-activated receptor α (PPARα). Besides altering lipid metabolism, PPARα ligands exert anti-inflammatory effects on various cell types. In this study, we hypothesized that PPARα agonists exert beneficial effects on osteoarthritis (OA) and rheumatoid arthritis (RA) by their local anti-inflammatory effects, but also by their systemic influences. A systematic literature search of Medline and EMBASE databases was performed up to August 2011. The main search items were osteoarthritis, rheumatoid arthritis, peroxisome proliferator-activated receptor alpha and fibrates. Inclusion criteria were in vivo or in vitro studies regarding humans or animals in which the effects of PPARα ligands were studied. Six in vivo human studies, four in vivo animal studies and seven in vitro studies were included. The in vivo human studies showed all beneficial clinical effects of PPARα ligands, but studies were small and only four were randomized. Ligands for PPARα significantly reduced pain, swelling of the joints and decreased systemic inflammatory markers. In vitro and in vivo animal studies indicate that PPARα agonists inhibit bone resorption, and reduce inflammatory and destructive responses in cartilage and synovium. PPARα agonists such as fibrates should be considered as potential therapeutic strategy for RA. There is no clinical evidence for their use in OA, although in vitro studies indicate that PPARα agonists demonstrate different joint-protective effects locally, and systemic effects on inflammation, serum lipid levels and vascular pathology. Animal studies should be performed and after confirmation of the protective effects of PPARα, large randomized controlled trials could investigate fibrates in OA and RA.
PubMed: 23515070
DOI: 10.1177/1759720X12468659 -
Molecular Genetics and Metabolism Mar 2012Intellectual disability ('developmental delay' at age<5 years) affects 2.5% of population worldwide. Recommendations to investigate genetic causes of intellectual... (Review)
Review
BACKGROUND
Intellectual disability ('developmental delay' at age<5 years) affects 2.5% of population worldwide. Recommendations to investigate genetic causes of intellectual disability are based on frequencies of single conditions and on the yield of diagnostic methods, rather than availability of causal therapy. Inborn errors of metabolism constitute a subgroup of rare genetic conditions for which an increasing number of treatments has become available. To identify all currently treatable inborn errors of metabolism presenting with predominantly intellectual disability, we performed a systematic literature review.
METHODS
We applied Cochrane Collaboration guidelines in formulation of PICO and definitions, and searched in Pubmed (1960-2011) and relevant (online) textbooks to identify 'all inborn errors of metabolism presenting with intellectual disability as major feature'. We assessed levels of evidence of treatments and characterised the effect of treatments on IQ/development and related outcomes.
RESULTS
We identified a total of 81 'treatable inborn errors of metabolism' presenting with intellectual disability as a major feature, including disorders of amino acids (n=12), cholesterol and bile acid (n=2), creatine (n=3), fatty aldehydes (n=1); glucose homeostasis and transport (n=2); hyperhomocysteinemia (n=7); lysosomes (n=12), metals (n=3), mitochondria (n=2), neurotransmission (n=7); organic acids (n=19), peroxisomes (n=1), pyrimidines (n=2), urea cycle (n=7), and vitamins/co-factors (n=8). 62% (n=50) of all disorders are identified by metabolic screening tests in blood (plasma amino acids, homocysteine) and urine (creatine metabolites, glycosaminoglycans, oligosaccharides, organic acids, pyrimidines). For the remaining disorders (n=31) a 'single test per single disease' approach including primary molecular analysis is required. Therapeutic modalities include: sick-day management, diet, co-factor/vitamin supplements, substrate inhibition, stemcell transplant, gene therapy. Therapeutic effects include improvement and/or stabilisation of psychomotor/cognitive development, behaviour/psychiatric disturbances, seizures, neurologic and systemic manifestations. The levels of available evidence for the various treatments range from Level 1b,c (n=5); Level 2a,b,c (n=14); Level 4 (n=45), Level 4-5 (n=27). In clinical practice more than 60% of treatments with evidence level 4-5 is internationally accepted as 'standard of care'.
CONCLUSION
This literature review generated the evidence to prioritise treatability in the diagnostic evaluation of intellectual disability. Our results were translated into digital information tools for the clinician (www.treatable-id.org), which are part of a diagnostic protocol, currently implemented for evaluation of effectiveness in our institution. Treatments for these disorders are relatively accessible, affordable and with acceptable side-effects. Evidence for the majority of the therapies is limited however; international collaborations, patient registries, and novel trial methodologies are key in turning the tide for rare diseases such as these.
Topics: Cost-Benefit Analysis; Humans; Intellectual Disability; Metabolism, Inborn Errors; Molecular Diagnostic Techniques
PubMed: 22212131
DOI: 10.1016/j.ymgme.2011.11.191