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Disease Markers 2019Genome-wide association study (GWAS) provides an unprecedented opportunity to reveal substantial genetic contribution to type 2 diabetes mellitus (T2DM) and glycemic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Genome-wide association study (GWAS) provides an unprecedented opportunity to reveal substantial genetic contribution to type 2 diabetes mellitus (T2DM) and glycemic identification of allelic heterogeneity and population-specific genetic variants, yet it also faces difficulty due to the vast amount of potential confounding factors and limited availability of clinical data. To identify responsible susceptibility loci and genomic polymorphism for T2DM and glycemic traits, we have systematically investigated a genome-wide association study related to T2DM. Although GWAS has captured many common genetic variations, which are related to T2DM, each risk allele (RA) of single-nucleotide polymorphisms (SNPs) at these loci is not conclusive. Therefore, it is common to present a combination of several SNPs to infer T2DM risk, yet it is still insufficient to be deterministic. To streamline the identification of a deterministic genetic variation in T2DM, we developed this meta-analysis as a showcase to comprehensively identify the association between cumulative RAs and T2DM risk by combining different studies in reported literature and databases. After all, we identified that PGC-1 rs8192678 polymorphism can be considered as a potentially deterministic biomarker in T2DM risk. Previous studies have potentially linked PGC-1 rs8192678 polymorphism to type 2 diabetes mellitus (T2DM) risk, but the results remain inconsistent in different populations and are not conclusive. We developed a new meta-analysis approach to systematically identify the association between PGC-1 rs8192678 polymorphism and T2DM, and we have comprehensively assessed different ethnic groups to validate our findings.
METHODS
We performed comprehensive information retrieval and knowledge discovery meta-analysis by searching extensively published literature and different electronic databases to acquire eligible studies for the above association study. We developed a method to use pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) in five genetic models (allelic, dominant, recessive, homozygous, and heterozygous genetic models) to identify the relationship among ethnicity subgroup analyses comprehensively.
RESULTS
We identified 20 eligible studies consisting of 16,182 subjects (8,038 cases and 8,144 controls) in our meta-analysis. PGC-1 rs8192678 polymorphisms of all subjects showed a significant association with T2DM susceptibility under all genetic models: allelic (OR: 1.24, 95% CI: 1.13-1.35), dominant (OR: 1.27, 95% CI: 1.14-1.42), recessive (OR: 1.24, 95% CI: 1.14-1.36), homozygous (OR: 1.40, 95% CI: 1.20-1.64), and heterozygous (OR: 1.20, 95% CI: 1.06-1.35). In the subgroup analysis, we identified a significant association between PGC-1 rs8192678 polymorphism and T2DM in the Caucasian and Indian populations under all genetic models we investigated. This is the most comprehensive study of the subject to date.
CONCLUSION
Our development of meta-analysis revealed that the minor allele (A) carriers, especially AA genotype carriers, can lead to risk of T2DM in the Caucasian and Indian populations. This is the first report that such risk has been confirmed. Our finding shed new light into the genetic alteration in T2DM.
Topics: Diabetes Mellitus, Type 2; Humans; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Polymorphism, Single Nucleotide
PubMed: 30944665
DOI: 10.1155/2019/2970401 -
Cardiovascular Diabetology Mar 2019Using a meta-analysis of randomized controlled trials (RCTs), this study aimed to investigate the efficacy and safety of pemafibrate, a novel selective peroxisome... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Using a meta-analysis of randomized controlled trials (RCTs), this study aimed to investigate the efficacy and safety of pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia.
METHODS
A search was performed using the MEDLINE, Cochrane Controlled Trials Registry, and ClinicalTrials.gov databases. We decided to employ RCTs to evaluate the effects of pemafibrate on lipid and glucose metabolism-related parameters in patients with dyslipidemia. For statistical analysis, standardized mean difference (SMD) or odds ratio (OR) and 95% confidence intervals (CIs) were calculated using the random effect model.
RESULTS
Our search yielded seven RCTs (with a total of 1623 patients) that satisfied the eligibility criteria of this study; hence, those studies were incorporated into this meta-analysis. The triglyceride concentration significantly decreased in the pemafibrate group (SMD, - 1.38; 95% CI, - 1.63 to - 1.12; P < 0.001) than in the placebo group, with a reduction effect similar to that exhibited by fenofibrate. Compared with the placebo group, the pemafibrate group also showed improvements in high-density and non-high-density lipoprotein cholesterol levels as well as in homeostasis model assessment for insulin resistance. Furthermore, the pemafibrate group showed a significant decrease in hepatobiliary enzyme activity compared with the placebo and fenofibrate groups; and, total adverse events (AEs) were significantly lower in the pemafibrate group than in the fenofibrate group (OR, 0.60; 95% CI, 0.49-0.73; P < 0.001). In contrast, the low-density lipoprotein cholesterol level was significantly higher in the pemafibrate group than in the placebo (P = 0.006) and fenofibrate (P < 0.001) groups.
CONCLUSIONS
The lipid profile significantly improved in the pemafibrate group than in the placebo group. In addition to the pemafibrate group having an improved lipid profile, which was comparable with that of the fenofibrate group, the AEs were significantly lower than in the fenofibrate group and an improvement in hepatobiliary enzyme activity was also recognized. However, we believe that actual clinical data as well as long-term efficacy and safety need to be investigated in the future.
Topics: Benzoxazoles; Biliary Tract; Biomarkers; Butyrates; Dyslipidemias; Female; Humans; Hypolipidemic Agents; Lipids; Liver; Male; Middle Aged; PPAR alpha; Treatment Outcome
PubMed: 30898163
DOI: 10.1186/s12933-019-0845-x -
PloS One 2019Genetics plays a role in determining potential for athletic ability (AA) and sports performance (SP). In this study, AA involves comparing sedentary controls with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Genetics plays a role in determining potential for athletic ability (AA) and sports performance (SP). In this study, AA involves comparing sedentary controls with competitive athletes in power and endurance activities as well as a mix between the two (SP). However, variable results from genetic association studies warrant a meta-analysis to obtain more precise estimates of the association between PPARGC1A Gly482Ser polymorphism and AA/SP.
METHODS
Multi-database literature search yielded 14 articles (16 studies) for inclusion. Pooled odds ratios (ORs) and 95% confidence intervals (CI) were used to estimate associations. Summary effects were modified based on statistical power. Subgroup analysis was based on SP (power, endurance and mixed) and race (Caucasians and Asians). Heterogeneity was assessed with the I2 metric and its sources examined with outlier analysis which dichotomized our findings into pre- (PRO) and post-outlier (PSO).
RESULTS
Gly allele effects significantly favoring AA/SP (OR > 1.0, P < 0.05) form the core of our findings in: (i) homogeneous overall effect at the post-modified, PSO level (OR 1.13, 95% CI 1.03-1.25, P = 0.01, I2 = 0%); (ii) initially homogeneous power SP (ORs 1.22-1.25, 95% CI 1.05-1.44, P = 0.003-0.008, I2 = 0%) which precluded outlier treatment; (iii) PRO Caucasian outcomes (ORs 1.29-1.32, 95% CI 1.12-1.54, P = 0.0005) over that of Asians with a pooled null effect (OR 0.99, 95% CI 0.72-1.99, P = 0.53-0.92) and (iv) homogeneous all > 80% (ORs 1.19-1.38, 95% CI 1.05-1.66, P = 0.0007-0.007, I2 = 0%) on account of high statistical power (both study-specific and combined). In contrast, none of the Ser allele effects significantly favored AA/SP and no Ser-Gly genotype outcome favored AA/SP. The core significant outcomes were robust and showed no evidence of publication bias.
CONCLUSION
Meta-analytical applications in this study generated evidence that show association between the Gly allele and AA/SP. These were observed in the overall, Caucasians and statistically powered comparisons which exhibited consistent significance, stability, robustness, precision and lack of bias. Our central findings rest on association of the Gly allele with endurance and power, differentially favoring the latter over the former.
Topics: Athletic Performance; Female; Genetic Association Studies; Genotype; Humans; Male; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Polymorphism, Genetic; White People
PubMed: 30625151
DOI: 10.1371/journal.pone.0200967 -
The Journal of Clinical Endocrinology... Nov 2018Adrenoleukodystrophy (ALD) is a peroxisomal disorder associated with neurologic decompensation and adrenal insufficiency. Newborn screening for ALD has recently been...
CONTEXT
Adrenoleukodystrophy (ALD) is a peroxisomal disorder associated with neurologic decompensation and adrenal insufficiency. Newborn screening for ALD has recently been implemented in five states with plans to expand to all 50 states in the United States. Adrenal insufficiency ultimately develops in most males with ALD, but the earliest age of onset is not well established.
OBJECTIVE
These clinical recommendations are intended to address screening for adrenal insufficiency in boys identified to have ALD by newborn screen.
PARTICIPANTS
Seven members of the Pediatric Endocrine Society Drug and Therapeutics/Rare Diseases Committee, with clinical experience treating children with ALD and adrenal insufficiency, and a pediatric endocrinologist and laboratory director were selected to be on the working committee.
CONSENSUS PROCESS
The authors comprised the working group and performed systematic reviews of the published literature regarding adrenal insufficiency and ALD. The recommendations were reviewed and approved by the larger Pediatric Endocrine Society Drug and Therapeutics/Rare Diseases Committee and then by the Pediatric Endocrine Society Board of Directors.
CONCLUSIONS
There is limited literature evidence regarding monitoring of evolving adrenal insufficiency in male infants and children with ALD. The recommendations suggest initiating assessment of adrenal function at diagnosis with ALD and regular monitoring to identify boys with adrenal insufficiency in a timely manner and prevent life-threatening adrenal crisis. These recommendations are intended to serve as an initial guide, with the understanding that additional experience will inform future guidelines.
Topics: Adrenal Insufficiency; Adrenocorticotropic Hormone; Adrenoleukodystrophy; Aldosterone; Diagnostic Techniques, Endocrine; Endocrinology; Humans; Hydrocortisone; Infant, Newborn; Male; Neonatal Screening; North America; Reference Values; Societies, Medical
PubMed: 30289543
DOI: 10.1210/jc.2018-00920 -
Current Medicinal Chemistry 2020The use of anti-diabetic drugs has been increasing worldwide and the evolution of therapeutics has been enormous. Still, the currently available anti-diabetic drugs do...
The use of anti-diabetic drugs has been increasing worldwide and the evolution of therapeutics has been enormous. Still, the currently available anti-diabetic drugs do not present the desired efficacy and are generally associated with serious adverse effects. Thus, entirely new interventions, addressing the underlying etiopathogenesis of type 2 diabetes mellitus, are required. Chalcones, secondary metabolites of terrestrial plants and precursors of the flavonoids biosynthesis, have been used for a long time in traditional medicine due to their wide-range of biological activities, from which the anti-diabetic activity stands out. This review systematizes the information found in literature about the anti-diabetic properties of chalcones, in vitro and in vivo. Chalcones are able to exert these properties by acting in different therapeutic targets: Dipeptidyl Peptidase 4 (DPP-4); Glucose Transporter Type 4 (GLUT4), Sodium Glucose Cotransporter 2 (SGLT2), α-amylase, α-glucosidase, Aldose Reductase (ALR), Protein Tyrosine Phosphatase 1B (PTP1B), Peroxisome Proliferator-activated Receptor-gamma (PPARγ) and Adenosine Monophosphate (AMP)-activated Protein Kinase (AMPK). Chalcones are, undoubtedly, promising anti-diabetic agents, and some crucial structural features have already been established. From the Structure-Activity Relationships analysis, it can generally be stated that the presence of hydroxyl, prenyl and geranyl groups in their skeleton improves their activity for the evaluated anti-diabetic targets.
Topics: Chalcones; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; alpha-Glucosidases
PubMed: 30277140
DOI: 10.2174/0929867325666181001112226 -
Clinical Journal of the American... Oct 2018Per- and polyfluoroalkyl substances (PFASs) are a large group of manufactured nonbiodegradable compounds. Despite increasing awareness as global pollutants, the impact...
BACKGROUND AND OBJECTIVES
Per- and polyfluoroalkyl substances (PFASs) are a large group of manufactured nonbiodegradable compounds. Despite increasing awareness as global pollutants, the impact of PFAS exposure on human health is not well understood, and there are growing concerns for adverse effects on kidney function. Therefore, we conducted a scoping review to summarize and identify gaps in the understanding between PFAS exposure and kidney health.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
We systematically searched PubMed, EMBASE, EBSCO Global Health, World Health Organization Global Index, and Web of Science for studies published from 1990 to 2018. We included studies on the epidemiology, pharmacokinetics, or toxicology of PFAS exposure and kidney-related health, including clinical, histologic, molecular, and metabolic outcomes related to kidney disease, or outcomes related to the pharmacokinetic role of the kidneys.
RESULTS
We identified 74 studies, including 21 epidemiologic, 13 pharmacokinetic, and 40 toxicological studies. Three population-based epidemiologic studies demonstrated associations between PFAS exposure and lower kidney function. Along with toxicology studies (=10) showing tubular histologic and cellular changes from PFAS exposure, pharmacokinetic studies (=5) demonstrated the kidneys were major routes of elimination, with active proximal tubule transport. In several studies (=17), PFAS exposure altered several pathways linked to kidney disease, including oxidative stress pathways, peroxisome proliferators-activated receptor pathways, NF-E2-related factor 2 pathways, partial epithelial mesenchymal transition, and enhanced endothelial permeability through actin filament modeling.
CONCLUSIONS
A growing body of evidence portends PFASs are emerging environmental threats to kidney health; yet several important gaps in our understanding still exist.
Topics: Environmental Exposure; Environmental Pollutants; Fluorocarbon Polymers; Humans; Kidney Diseases
PubMed: 30213782
DOI: 10.2215/CJN.04670418 -
Food and Chemical Toxicology : An... Nov 2018Phytol (PYT) is a diterpene member of the long-chain unsaturated acyclic alcohols. PYT and some of its derivatives, including phytanic acid (PA), exert a wide range of...
Phytol (PYT) is a diterpene member of the long-chain unsaturated acyclic alcohols. PYT and some of its derivatives, including phytanic acid (PA), exert a wide range of biological effects. PYT is a valuable essential oil (EO) used as a fragrance and a potential candidate for a broad range of applications in the pharmaceutical and biotechnological industry. There is ample evidence that PA may play a crucial role in the development of pathophysiological states. Focusing on PYT and some of its most relevant derivatives, here we present a systematic review of reported biological activities, along with their underlying mechanism of action. Recent investigations with PYT demonstrated anxiolytic, metabolism-modulating, cytotoxic, antioxidant, autophagy- and apoptosis-inducing, antinociceptive, anti-inflammatory, immune-modulating, and antimicrobial effects. PPARs- and NF-κB-mediated activities are also discussed as mechanisms responsible for some of the bioactivities of PYT. The overall goal of this review is to discuss recent findings pertaining to PYT biological activities and its possible applications.
Topics: Adjuvants, Immunologic; Analgesics; Animals; Anti-Anxiety Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Anticonvulsants; Antineoplastic Agents; Antioxidants; Apoptosis; Autophagy; Biotechnology; Drug Industry; Drug Screening Assays, Antitumor; Humans; Microbial Sensitivity Tests; Oils, Volatile; Peroxisome Proliferator-Activated Receptors; Phytol; Plant Oils
PubMed: 30130593
DOI: 10.1016/j.fct.2018.08.032 -
Current Diabetes Reports Aug 2018This systematic review describes evidence concerning medicinal plants that, in addition to exerting hypoglycemic effects, decrease accompanying complications such as...
PURPOSE OF REVIEW
This systematic review describes evidence concerning medicinal plants that, in addition to exerting hypoglycemic effects, decrease accompanying complications such as nephropathy, neuropathy, retinopathy, hypertension, and/or hyperlipidemia among individuals with diabetes mellitus (DM).
RECENT FINDINGS
Studies on the antidiabetic mechanisms of medicinal plants have shown that most of them produce hypoglycemic activity by stimulating insulin secretion, augmenting peroxisome proliferator-activated receptors (PPARs), inhibiting α-amylase or α-glucosidase, glucagon-like peptide-1 (GLP-1) secretion, advanced glycation end product (AGE) formation, free radical scavenging plus antioxidant activity (against reactive oxygen or nitrogen species (ROS/RNS)), up-regulating or elevating translocation of glucose transporter type 4 (GLUT-4), and preventing development of insulin resistance. Not only are medicinal plants effective in DM, but many of them also possess a variety of effects on other disease states, including the complications of DM. Such plants may be appropriate alternatives or adjuncts to available antidiabetic medications.
Topics: Diabetes Complications; Diabetes Mellitus; Humans; Hypoglycemic Agents; Insulin Resistance; Peroxisome Proliferator-Activated Receptors; Plants, Medicinal
PubMed: 30105479
DOI: 10.1007/s11892-018-1042-0 -
Annals of Medicine Nov 2018Apolipoprotein C-III (apo C-III) is a key regulator of triglycerides metabolism. The aim of this meta-analysis was to assess the effect of fish omega-3 polyunsaturated... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Apolipoprotein C-III (apo C-III) is a key regulator of triglycerides metabolism. The aim of this meta-analysis was to assess the effect of fish omega-3 polyunsaturated fatty acids (PUFAs) on apo C-III levels.
METHODS
Randomized placebo-controlled trials investigating the impact of omega-3 on apo C-III levels were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar. A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on glycemic parameters.
RESULTS
This meta-analysis comprising 2062 subjects showed a significant reduction of apo C-III concentrations following treatment with omega-3 (WMD: -22.18 mg/L, 95% confidence interval: -31.61, -12.75, p < .001; I: 88.24%). Subgroup analysis showed a significant reduction of plasma apo C-III concentrations by eicosapentaenoic acid (EPA) ethyl esters but not omega-3 carboxylic acids or omega-3 ethyl esters. There was a greater apo C-III reduction with only EPA as compared with supplements containing EPA and docosahexaenoic acid (DHA) or only DHA. A positive association between the apo C-III-lowering effect of omega-3 with baseline apo C-III concentrations and treatment duration was found.
CONCLUSIONS
This meta-analysis has shown that omega-3 PUFAs might significantly decrease apo C-III. Key messages Omega-3 PUFA supplements significantly reduce apo C-III plasma levels, particularly in hypertriglyceridemic patients when applied in appropriate dose (more than 2 g/day) Triglyceride (TG)-lowering effect is achieved via peroxisome proliferator-activated receptors α Further studies should address the effect of omega-3 PUFAs alone or with other lipid-lowering drugs in order to provide a final answer whether apo C-III could be an important target for prevention of cardiovascular disease New apo C-III antisense oligonucleotide drug (Volanesorsen) showed to be promising in decreasing elevated TGs by reducing levels of apo C-III mRNA.
Topics: Apolipoprotein C-III; Cardiovascular Diseases; Dietary Supplements; Fatty Acids, Omega-3; Humans; Hypertriglyceridemia; Oligonucleotides; Randomized Controlled Trials as Topic; Time Factors; Triglycerides
PubMed: 30102092
DOI: 10.1080/07853890.2018.1511919 -
International Journal of Molecular... May 2018The peroxisome proliferator-activated receptors (, , ) and their transcriptional coactivators' (, ) gene polymorphisms have been associated with muscle morphology,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The peroxisome proliferator-activated receptors (, , ) and their transcriptional coactivators' (, ) gene polymorphisms have been associated with muscle morphology, oxygen uptake, power output and endurance performance. The purpose of this review is to determine whether the PPARs and/or their coactivators' polymorphisms can predict the training response to specific training stimuli.
METHODS
In accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses, a literature review has been run for a combination of PPARs and physical activity key words.
RESULTS
All ten of the included studies were performed using aerobic training in general, sedentary or elderly populations from 21 to 75 years of age. The non-responders for aerobic training (VO₂peak increase, slow muscle fiber increase and low-density lipoprotein decrease) are the carriers of rs8192678 Ser/Ser. The negative responders for aerobic training (decrease in VO₂peak) are carriers of the rs2267668 G allele. The negative responders for aerobic training (decreased glucose tolerance and insulin response) are subjects with the rs1801282 Pro/Pro genotype. The best responders to aerobic training are rs8192678 Gly/Gly, rs1053049 TT, rs2267668 AA and rs1801282 Ala carriers.
CONCLUSIONS
The human response for aerobic training is significantly influenced by PPARs' gene polymorphism and their coactivators, where aerobic training can negatively influence glucose metabolism and VO₂peak in some genetically-predisposed individuals.
Topics: Adult; Aged; Carrier Proteins; Humans; Male; Middle Aged; Muscle, Skeletal; Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Peroxisome Proliferator-Activated Receptors; Physical Conditioning, Human; Polymorphism, Single Nucleotide; RNA-Binding Proteins
PubMed: 29762540
DOI: 10.3390/ijms19051472