Influence of metabolic syndrome on biomarkers of oxidative stress and inflammation in obese adults

Objective: Both obesity and the metabolic syndrome (MetS) have been independently linked with increased oxidative and inflammatory stress. This study tested the hypothesis that obesity with MetS is associated with greater oxidative and inflammatory burden compared with obesity alone. Research Methods and Procedures: Forty‐eight normal‐weight and 40 obese (20 without MetS; 20 with MetS) adults were studied. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria. Plasma concentrations of oxidized low‐density lipoprotein, C‐reactive protein, tumor necrosis factor‐α, interleukin (IL)‐6, and IL‐18 were determined by enzyme immunoassay. Results: Plasma biomarkers of oxidative stress and inflammation were lowest in normal‐weight controls. Of note, obese MetS adults demonstrated significantly higher plasma concentrations of oxidized low‐density lipoprotein (62.3 ± 3.2 vs. 54.0 ± 4.0 U/L; p < 0.05), C‐reactive protein (3.0 ± 0.6 vs. 1.5 ± 0.3 mg/L; p < 0.01), tumor necrosis factor‐α (2.1 ± 0.1 vs. 1.6 ± 0.1 pg/mL; p < 0.05), IL‐6 (2.8 ± 0.4 vs. 1.4 ± 0.2 pg/mL; p < 0.01), and IL‐18 (253 ± 16 vs. 199 ± 16 pg/mL; p < 0.01), compared with obese adults without MetS. Discussion: These results suggest that MetS heightens oxidative stress and inflammatory burden in obese adults. Increased oxidative and inflammatory stress may contribute to the greater risk of coronary heart disease and cerebrovascular disease in obese adults with MetS.     

Butyrylcholinesterase interactions with amylin may protect pancreatic cells in metabolic syndrome

The metabolic syndrome (MetS) is a risk factor for type 2 diabetes mellitus (T2DM). However, the mechanisms underlying the transition from MetS to T2DM are unknown. Our goal was to study the potential contribution of butyrylcholinesterase (BChE) to this process. We first determined the hydrolytic activity of BChE in serum from MetS, T2DM and healthy individuals. The ‘Kalow’ variant of BChE (BChE‐K), which has been proposed to be a risk factor for T2DM, was genotyped in the last two groups. Our results show that in MetS patients serum BChE activity is elevated compared to T2DM patients and healthy controls (P < 0.001). The BChE‐K genotype showed similar prevalence in T2DM and healthy individuals, excluding this genotype as a risk factor for T2DM. However, the activity differences remained unexplained. Previous results from our laboratory have shown BChE to attenuate the formation of β‐amyloid fibrils, and protect cultured neurons from their cytotoxicity. Therefore, we next studied the in vitro interactions between recombinant human butyrylcholinesterase and amylin by surface plasmon resonance, Thioflavine T fluorescence assay and cross‐linking, and used cultured pancreatic β cells to test protection by BChE from amylin cytotoxicity. We demonstrate that BChE interacts with amylin through its core domain and efficiently attenuates both amylin fibril and oligomer formation. Furthermore, application of BChE to cultured β cells protects them from amylin cytotoxicity. Taken together, our results suggest that MetS‐associated BChE increases could protect pancreatic β‐cells in vivo by decreasing the formation of toxic amylin oligomers.     

Irregular 24-hour activity rhythms and the metabolic syndrome in older adults

Circadian rhythms – near 24?h intrinsic biological rhythms – modulate many aspects of human physiology and hence disruption of circadian rhythms may have an important impact on human health. Experimental work supports a potential link between irregular circadian rhythms and several key risk factors for cardiovascular disease including hypertension, obesity, diabetes and dyslipidemia, collectively termed the metabolic syndrome. While several epidemiological studies have demonstrated an association between shift-work and the components of the metabolic syndrome in working-age adults, there is a relative paucity of data concerning the impact of non-occupational circadian irregularity in older women and men. To address this question, we studied 7 days of actigraphic data from 1137 older woman and men participating in the Rush Memory and Aging Project, a community-based cohort study of the chronic conditions of aging. The regularity of activity rhythms was quantified using the nonparametric interdaily stability metric, and was related to the metabolic syndrome and its components obesity, hypertension, diabetes and dyslipidemia. More regular activity rhythms were associated with a lower odds of having the metabolic syndrome (OR?=?0.69, 95% CI?=?0.60–0.80, p?=?5.8?×?10^?7), being obese (OR?=?0.73, 95% CI?=?0.63–0.85, p?=?2.5?×?10^?5), diabetic (OR?=?0.76, 95% CI?=?0.65–0.90, p?=?9.3?×?10^?4), hypertensive (OR?=?0.78, 95% CI?=?0.66–0.91, p?=?2.0?×?10^?3) or dyslipidemic (OR?=?0.82, 95% CI?=?0.72–0.92, p?=?1.2?×?10^?3). These associations were independent of differences in objectively measured total daily physical activity or rest, and were not accounted for by prevalent coronary artery disease, stroke or peripheral artery disease. Moreover, more regular activity rhythms were associated with lower odds of having cardiovascular disease (OR?=?0.83; 95% CI?=?0.73–0.95, p?=?5.7?×?10^?3), an effect that was statistically mediated by the metabolic syndrome. We conclude that irregular activity rhythms are associated with several key components of the metabolic syndrome in older community-dwelling adults, and that the metabolic syndrome statistically partially mediates the association between activity rhythms and prevalent cardiovascular disease. Although additional longitudinal and experimental studies are needed to conclusively delineate the causal relationships underlying these associations, these findings are consistent with preclinical data, and add further support for investigations of the irregularity of activity rhythms as a potential therapeutic target to decrease the burden of cardiovascular disease in older adults.     

Role of androgens in energy metabolism affecting on body composition,metabolic syndrome,type 2 diabetes,cardiovascular disease,and longevity: lessons from a meta-analysis and rodent studies

Testosterone is a sex hormone produced by testicular Leydig cells in males. Blood testosterone concentrations increase at three time-periods in male life–fetal, neonatal (which can be separated into newborn and infant periods), and pubertal stages. After peaking in the early 20s, the blood bioactive testosterone level declines by 1–2% each year. It is increasingly apparent that a low testosterone level impairs general physical and mental health in men. Here, this review summarizes recent systematic reviews and meta-analyses of epidemiological studies in males (including cross-sectional, longitudinal, and androgen deprivation studies, and randomized controlled testosterone replacement trials) in relation to testosterone and obesity, body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity. Furthermore, underlying mechanisms are discussed using data from rodent studies involving castration or androgen receptor knockout. This review provides an update understanding of the role of testosterone in energy metabolism.

Abbreviations AR: androgen receptor; CV: cardiovascular; FDA: US Food and Drug Administration; HFD: high-fat diet; KO: knockout; MetS: metabolic syndrome; RCT: randomized controlled trial; SHBG: sex hormone binding globulin; SRMA: systematic review and meta-analysis; TRT: testosterone replacement therapy; T2DM:type 2 diabetes mellitus     

环境和遗传因素与慢性代谢性疾病的人群研究

几十年来我国居民经历了快速的营养转型,与不健康的膳食和生活方式相关的＂致肥环境＂,以及遗传倾向是导致我国慢性代谢性疾病如代谢综合征和2型糖尿病快速流行的主要推手。然而,我国目前非常缺乏针对导致慢性代谢性疾病的主要遗传和环境危险因素而开展的系统研究。在过去若干年中,通过开展基于社区人群的流行病学研究,本课题组发现了多个与代谢性疾病相关的基因变异、环境因素和生物标记物。与此同时,通过对代谢综合征或2型糖尿病患者进行的营养干预,发现添加亚麻子或其衍生物木酚素、核桃,以及用糙米替代白米能不同程度地改善代谢综合征或血糖控制。总之,所有努力旨在增进对导致中国人代谢性疾病高易感性相关的病因和机制的理解,同时也希望为疾病的预测和预防提供新的思路和线索。     

Supplementation with a combination of antioxidants does not affect glycaemic control,oxidative stress or inflammation in type 2 diabetes subjects

Abstract

The present clinical trial examined the influence of a supplement, containing a combination of antioxidants extracted from fruit, berries and vegetables, on levels of plasma antioxidants (tocopherols, carotenoids and ascorbate), glycaemic control (blood glucose, HbA1c, insulin), oxidative stress biomarkers (F₂-isoprostane, malondialdehyd, nitrotyrosine, 8-oxo-7, 8-dihydro-2′-deoxyguanosine, formamidopyrimidine glycosylase sites, frequency of micronucleated erythrocytes) and inflammatory markers (interleukin-6, C-reactive protein, prostaglandin F_2α-metabolite) in type 2 diabetes. Forty subjects were randomly assigned to control, single or double dose group and completed the study. In summary, 12 weeks of antioxidant supplementation did neither affect glycaemic control nor the levels of biomarkers of oxidative stress or inflammation, despite substantially increased plasma concentrations of antioxidants. The absence of an effect may be explained by the selected study subjects with relatively well-controlled diabetes, a high intake of fruit and vegetable and levels of plasma antioxidants, biomarkers of oxidative stress and inflammatory markers comparable to those found in healthy subjects.     

Food-derived regulatory factors against obesity and metabolic syndrome

Abstract

Obesity is a key factor in metabolic syndrome. The study of metabolic syndrome focuses on the anti-weight gain properties of physiological mechanisms and food components. Abnormal energy metabolism is a major risk factor of metabolic syndrome. Chronic inflammation is a feature of obesity; cytokines from hypertrophied adipocytes cause inflammation in both adipose tissue and blood vessels, resulting in symptoms of metabolic syndrome. Tumor necrosis factor-α causes insulin resistance in adipocytes and regression of brown adipocytes, resulting in abnormal energy metabolism. Functional foods can serve as a strategy for prevention and treatment of obesity linked with metabolic processes in white and brown adipose tissues. Diet-induced thermogenesis caused by certain food components stimulates burning of stored fat within adipose tissues. A mechanistic understanding of dietary thermogenesis via the sympathetic nerve system will prove valuable for the development of precise strategies for the practical prevention of metabolic syndrome.     

Plasma fatty acid binding protein 4 is associated with atherogenic dyslipidemia in diabetes

The aim of this study was to evaluate the impact of adipocyte fatty acid binding protein 4 (FABP4) on the lipid profile in type 2 diabetic subjects. Plasma levels of FABP4 and adiponectin and an extensive lipid profile were analyzed in 169 type 2 diabetic subjects and 105 controls. Type 2 diabetic subjects were categorized according the presence of atherogenic dyslipidemia. Univariate statistical analyses, partial correlation tests, and binary logistic regression models were applied. In type 2 diabetic subjects, FABP4 was positively correlated with plasma triglycerides (P = 0.007), apolipoprotein C-III (apoC-III) (P = 0.009), and all the components of triglyceride-rich lipoproteins, including VLDL triglycerides (P = 0.002), VLDL-cholesterol (P = 0.001), and VLDL apoB (P = 0.001). FABP4 was inversely correlated with apoA-I (P = 0.038), HDL-cholesterol (P = 0.002), and HDL apoA-I (P = 0.010) in type 2 diabetic subjects. These correlations are not significantly affected by age, gender, body mass index, adiponectin, insulin, or any pharmacological treatment. The associations are even stronger when the FABP4/adiponectin ratio is considered. None of these associations were observed in controls. High FABP4 and low adiponectin levels are independent predictors of atherogenic dyslipidemia. In conclusion, FABP4 plasma concentrations hold strong potential for development as a clinical biomarker for atherogenic dyslipidemia, independent of obesity and insulin resistance, in type 2 diabetic subjects.     

Type 2 diabetes mellitus: An unusual association with Down's syndrome

Down''s syndrome (DS) is known to be associated with autoimmune disease including type 1 diabetes. To the best of our knowledge, there are no reports of DS with type 2 diabetes mellitus in the literature. We hereby report two cases of DS with type 2 diabetes.     

Multi-omics approach to socioeconomic disparity in metabolic syndrome reveals roles of diet and microbiome

The epidemy of metabolic syndrome (MetS) is typically preceded by adoption of a “risky” lifestyle (e.g., dietary habit) among populations. Evidence shows that those with low socioeconomic status (SES) are at an increased risk for MetS. To investigate this, we recruited 123 obese subjects (body mass index [BMI] ≥ 30) from Chicago. Multi-omic data were collected to interrogate fecal microbiota, systemic markers of inflammation and immune activation, plasma metabolites, and plasma glycans. Intestinal permeability was measured using the sugar permeability testing. Our results suggest a heterogenous metabolic dysregulation among obese populations who are at risk of MetS. Systemic inflammation, linked to poor diet, intestinal microbiome dysbiosis, and gut barrier dysfunction may explain the development of MetS in these individuals. Our analysis revealed 37 key features associated with increased numbers of MetS features. These features were used to construct a composite metabolic-inflammatory (MI) score that was able to predict progression of MetS among at-risk individuals. The MI score was correlated with several markers of poor diet quality as well as lower levels of gut microbial diversity and abnormalities in several species of bacteria. This study reveals novel targets to reduce the burden of MetS and suggests access to healthy food options as a practical intervention.     

Inflammations mediators and circulating levels of matrix metalloproteinases: Biomarkers of diabetes in Tunisians metabolic syndrome patients

AimsThis study investigates the relationships between matrix metalloproteinases, inflammations mediators and type 2 diabetes mellitus in Tunisians metabolic syndrome (Mets) patients.MethodsThe study has included 239 MetS patients and 247 controls. Mets was defined according to the NCEP–ATPIII report. Mets patients were also divided into two categories: 29 MetS non-diabetics and 210 MetS diabetics. Dysglycemia markers, matrix metalloproteinase-9 (MMP-9), Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), tumor necrosis factor α (TNF-α), C-reactive protein (CRP) levels and White Blood Cells (WBC) counts were determined in patients and controls.ResultsIn our study, the level of inflammatory markers WBC, TNF-α and matrix metalloproteinases (MMP-8 and MMP-9) were significantly higher in diabetic patients with MetS, as compared with non-diabetic MetS patients. Inflammation mediators and MMP-9 were significantly associated with many clinical characteristics of MetS. The use of ROC “Receiver Operating Characteristic” analysis revealed the impact of TNF alpha on diabetes patients with MetS. In fact TNF alpha was found as a sensitive parameter in these patients with a sensitivity of 85%.ConclusionInflammation, matrix metalloproteinases and dysglycemia markers are not expressed in isolation but rather concurrently and are continuously interacting with each other, in MetS and diabetics patients. These markers fit with an early stage of cardiovascular disease (CVD); and measuring them could improve the risk evaluation, an early diagnosis, and the prognosis of CVD.     

Association of neuropeptide Y receptor Y5 polymorphisms with dyslipidemia in Mexican Americans

We examined the genetic association of neuropeptide Y receptor Y5 (NPY5R) single nucleotide polymorphisms (SNPs) with measures of the insulin resistance (metabolic) syndrome. We genotyped 10 NPY5R SNPs in 439 Mexican American individuals (age=43.3+/-17.3 years and BMI=30.0+/-6.7 kg/m2) distributed across 27 pedigrees from the San Antonio Family Diabetes Study and performed association analyses using the measured genotype approach as implemented in Sequential Oligogenic Linkage Analysis Routines (SOLAR). Minor alleles for five (rs11100493, rs12501691, P1, rs11100494, rs12512687) of the NPY5R SNPs were found to be significantly (p<0.05) associated with fasting plasma triglyceride concentrations and decreased high-density lipoprotein concentrations. In addition, the minor allele for SNP P2 was significantly associated (p=0.031) with a decreased homeostasis model assessment of beta-cell function (HOMA-%beta). Linkage disequilibrium between SNP pairs indicated one haplotype block of five SNPs (rs11100493, rs12501691, P1, rs11100494, rs12512687) that were highly correlated (r2>0.98). These preliminary results provide evidence for association of SNPs in the NPY5R gene with dyslipidemia (elevated triglyceride concentrations and reduced high-density lipoprotein levels) in our Mexican American population.     

Essential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance during aging

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes (T2DM). In this study, we have evaluated the role of PTP1B in the development of aging-associated obesity, inflammation, and peripheral insulin resistance by assessing metabolic parameters at 3 and 16 months in PTP1B(-/-) mice maintained on mixed genetic background (C57Bl/6J × 129Sv/J). Whereas fat mass and adipocyte size were increased in wild-type control mice at 16 months, these parameters did not change with aging in PTP1B(-/-) mice. Increased levels of pro-inflammatory cytokines, crown-like structures, and hypoxia-inducible factor (HIF)-1α were observed only in adipose tissue from 16-month-old wild-type mice. Similarly, islet hyperplasia and hyperinsulinemia were observed in wild-type mice with aging-associated obesity, but not in PTP1B(-/-) animals. Leanness in 16-month-old PTP1B(-/-) mice was associated with increased energy expenditure. Whole-body insulin sensitivity decreased in 16-month-old control mice; however, studies with the hyperinsulinemic-euglycemic clamp revealed that PTP1B deficiency prevented this obesity-related decreased peripheral insulin sensitivity. At a molecular level, PTP1B expression and enzymatic activity were up-regulated in liver and muscle of 16-month-old wild-type mice as were the activation of stress kinases and the expression of p53. Conversely, insulin receptor-mediated Akt/Foxo1 signaling was attenuated in these aged control mice. Collectively, these data implicate PTP1B in the development of inflammation and insulin resistance associated with obesity during aging and suggest that inhibition of this phosphatase by therapeutic strategies might protect against age-dependent T2DM.     

Prevalence of the Metabolic Syndrome in a Bulgarian Female Population Referred for Bone Density Testing

Objective: To investigate the prevalence of the metabolic syndrome in Bulgarian women referred for bone density screening. Research Methods and Procedures: This was a cross‐sectional clinical study. Subjects were 444 consecutive 30‐ to 75‐year‐old Bulgarian women recruited from the outpatients referred for bone density testing (mean age, 52.67 ± 15.19 years; mean BMI, 26.10 ± 5.71 kg/m²). Height (centimeters), weight (kilograms), and blood pressure were measured. BMI and waist‐to‐hip ratio were calculated. Fasting plasma glucose, blood lipids, and immunoreactive insulinemia (Bayer Corp.‐Diagnostics Div., Tarrytown, NY) were determined. Body composition was analyzed by bioimpedance on a leg‐to‐leg analyser (Tanita TBF‐215; Tanita Corporation, Tokyo, Japan). Results: Of all women, 56.76% had a BMI > 25 kg/m², 45.95% had a waist circumference > 88 cm, and 64.64% had a waist‐to‐hip ratio > 0.8; 59.90% had hypertension; 4.05% had fasting plasma glucose > 7.0 mM, and 42.79% had fasting morning immunoreactive insulinemia = 16 UI/liter; 23.65% had hypercholesterolemia; and 26.35% had hypertriglyceridemia. The prevalence of the metabolic syndrome in this sample, as defined by the National Cholesterol and Education Program‐Adult Treatment Panel III, was 34.91%, and by the modified World Health Organization definition was 37.16%. Discussion: We concluded that Bulgarian women 30 to 75 years old referred for bone density testing have a high prevalence of the metabolic syndrome. Therefore, large‐scale prevention programs are needed in this field.     

A visfatin promoter polymorphism is associated with low-grade inflammation and type 2 diabetes

Visfatin (also known as pre-B cell colony-enhancing factor, or PBEF) is a pro-inflammatory adipokine expressed predominantly in visceral fat. We investigated whether polymorphisms at the visfatin/PBEF locus influence the risk of type 2 diabetes (T2D). Linkage disequilibrium analysis of 52 single nucleotide polymorphisms spanning the entire gene (34.7 kb) plus 20.5 kb of the upstream region and 25.5 kb of the downstream region revealed a single haplotype block that could be tagged by seven single nucleotide polymorphisms. These seven tags were typed in a group of T2D patients (n = 814) and a group of non-diabetic controls (n = 320) of white origin. A significant association was observed at -948C>A, with minor allele frequencies of 0.157 in T2D cases and 0.119 in non-diabetic controls (p = 0.021). In a non-diabetic population (n = 630), the same -948 allele that conferred increased risk of T2D was significantly associated with higher plasma levels of fibrinogen and C-reactive protein (p = 0.0022 and 0.0038, respectively). However, no significant associations were observed with BMI, waist circumference, serum glucose levels, or fasting insulin levels. Our findings suggest that the visfatin/PBEF gene may play a role in determining T2D susceptibility, possibly by modulating chronic, low-grade inflammatory responses.     

The role of apolipoprotein A5 in obesity and the metabolic syndrome

Apolipoprotein A5 (apoA5) has an important role in lipid metabolism, specifically for triglyceride‐rich lipoproteins. Recently, evidence has emerged for an association between genetic variability at the APOA5 locus and increased risk of obesity and metabolic syndrome. However, its mechanism of action remains to be fully elucidated. Importantly, an intracellular role of apoA5 has been indicated since apoA5 is associated with cytoplasmic lipid droplets and affects intrahepatic triglyceride accumulation, as well as affecting intravascular triglyceride metabolism. Given that adipocytes provide the largest storage depot for energy in the form of triglyceride within the lipid droplets, and play a crucial role in the development of obesity, we highlight recent findings discussing the interaction of apoA5 with adipocytes or adipose tissue, indicating that apoA5 may act as a novel regulator to modulate triglyceride storage in adipocytes. We review the association of APOA5 gene polymorphisms with obesity and metabolic syndrome, and propose potential mechanisms by which apoA5 may increase susceptibility to these conditions. This review provides new insights into the physiological role of apoA5 and identifies a potential therapeutic target for obesity and associated disorders.     

Lifestyle variables, non-traditional cardiovascular risk factors, and the metabolic syndrome in an Aboriginal Canadian population

Objective : To examine lifestyle factors associated with metabolic syndrome (MetS) and to explore the relationships between MetS and non‐traditional cardiovascular disease risk factors [adiponectin, leptin, C‐reactive protein (CRP), interleukin‐6 (IL‐6), and serum amyloid A (SAA)] in an isolated Aboriginal Canadian community. Research Methods and Procedures : Data were obtained from 360 non‐diabetic adults participating in a population‐based study of Aboriginal Canadians. Fasting samples were drawn for glucose, insulin, lipids, adiponectin, leptin, CRP, IL‐6, and SAA. Percentage body fat was measured using bioelectrical impedance analysis. Past year physical activity and fitness level were assessed. MetS was diagnosed according to the criteria of the National Cholesterol Education Program, the World Health Organization, and the International Diabetes Federation. Results : The results showed that older age, higher percentage body fat, and lower fitness levels were associated with increased odds of MetS regardless of MetS definition and subject gender. Past year physical activity was independently related with the World Health Organization‐MetS in male subjects. Subjects with MetS had significantly higher leptin, CRP, IL‐6, and SAA levels and lower adiponectin levels; however, only adiponectin remained significantly low after adjustment for age and percentage body fat. Discussion : The study showed that higher percentage body fat and lower physical activity and fitness were associated with a higher prevalence of MetS in this Aboriginal community and that hypoadiponectinemia was independently associated with MetS.