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1.  Comprehensive analysis of circulating adipokines and hsCRP association with cardiovascular disease risk factors and metabolic syndrome in Arabs 
Cardiovascular diseases (CVD) are a leading cause of death worldwide including the Middle East. This is caused in part by the dysregulation of adipose tissue leading to increased production of pro-inflammatory adipokines and reduction in cardio-protective adipokines such as adiponectin. Ethnicity has been recognized as a major factor in the association between CVD risk factors and the different circulating adipokines. In this study, for the first time, the relationship between traditional cardiovascular risk factors, Metabolic Syndrome (MetS) and circulating level of adipokines in Arab ethnicity was investigated.
We conducted a population-based cross-sectional survey on 379 adult Arab participants living in Kuwait. Traditional cardiovascular risk factors such as blood pressure (BP), low density lipoprotein (LDL) and triglyceride (TG) were measured. Plasma levels of circulating Leptin, Plasminogen Activator Inhibitor (PAI-1) visfatin, adiponectin, resistin and adipsin were assessed using the multiplexing immunobead-based assay.
Circulating levels of High sensitivity C-Reactive Protein (hsCRP), Leptin, PAI-1 and adiponectin were significantly higher in Arab women than men (p < 0.0001). In multi-variate analysis, the homeostasis model assessment-insulin resistance (HOMA-IR) and body mass index (BMI) showed strong association with most of the biomarkers (p < 0.05). HsCRP showed significant association with all risk factors (p < 0.05). Leptin, PAI-1 and adipsin showed significant positive correlation with BMI, unlike adiponectin which showed inverse correlation (p < 0.05). Subjects in the highest tertile of leptin, PAI-1 and hsCRP had higher odds of having Metabolic Syndrome (MetS) (odd ratio [OR] = 3.02, 95% confidence interval [CI] = 1.47 – 6.19) and (OR = 2.52, 95% CI = 1.45 – 4.35), (OR = 4.26, 95% CI = 2.39 – 7.59) respectively. On the other hand subjects with highest tertile of adiponectin had lower odds of having MetS (OR = 0.22, 95% CI = 0.12 – 0.40). Leptin, PAI-1 and hsCRP showed significant positive association with increased MetS components (P-trend <0.05), while adiponectin was negatively associated with increased MetS components (P-trend <0.0001).
Our results show positive association between hsCRP, leptin, PAI-1 with increased MetS components and increase the odds of having MetS. Adiponectin on the other hand showed inverse correlation with MetS components and associated with reduction in MetS. Overall, our data highlights the significant clinical value these markers have in MetS especially hsCRP which can be used as good marker of low grade inflammation in Arabs.
PMCID: PMC3997236  PMID: 24716628
Adipokine; Arab; Metabolic syndrome; Cardiometabolic risk factors; Lipid profile; hsCRP; Leptin; Adiponectin; Visfatin; Resistin; Adipsin; Low grade inflammation
2.  Adiponectin in eutrophic and obese children as a biomarker to predict metabolic syndrome and each of its components 
BMC Public Health  2013;13:88.
Obesity is associated with the rise of noncommunicable diseases worldwide. The pathophysiology behind this disease involves the increase of adipose tissue, being inversely related to adiponectin, but directly related to insulin resistance and metabolic syndrome (MetS). Therefore, this study aimed to determine the relationship between adiponectin levels with each component of MetS in eutrophic and obese Mexican children.
A cross sectional study was conducted in 190 school-age children classified as obese and 196 classified as eutrophic. Adiponectin, glucose, insulin, high density lipoprotein cholesterol (HDL-C) and triglycerides were determined from a fasting blood sample. Height, weight, waist circumference, systolic and diastolic blood pressures (BP) were measured; MetS was evaluated with the IDF definition. The study groups were divided according to tertiles of adiponectin, using the higher concentration as a reference. Linear regression analysis was used to assess the association between adiponectin and components of the MetS. Finally, stepwise forward multiple logistic regression analysis controlling for age, gender, basal HOMA-IR values and BMI was performed to determine the odds ratio of developing MetS according to adiponectin tertiles.
Anthropometric and metabolic measurements were statistically different between eutrophic and obese children with and without MetS (P <0.001). The prevalence of MetS in obese populations was 13%. Adiponectin concentrations were 15.5 ± 6.1, 12.0 ± 4.8, 12.4 ± 4.9 and 9.4 ± 2.8 μg/mL for eutrophic and obese subjects, obese without MetS, and obese with MetS, respectively (P <0.001). Obese children with low values of adiponectin exhibited a higher frequency of MetS components: abdominal obesity, 49%; high systolic BP, 3%; high diastolic BP, 2%; impaired fasting glucose, 17%; hypertriglyceridemia, 31%; and low HDL-C values, 42%. Adjusted odds ratio of presenting MetS according to adiponectin categories was 10.9 (95% CI 2.05; 48.16) when the first tertile was compared with the third.
In this sample of eutrophic and obese Mexican children we found that adiponectin concentrations and MetS components have an inversely proportional relationship, which supports the idea that this hormone could be a biomarker for identifying individuals with risk of developing MetS.
PMCID: PMC3570482  PMID: 23363707
Obesity; Adiponectin; Child; Insulin resistance; Metabolic syndrome; Biomarker
3.  Adipocytokines and the metabolic syndrome among older persons with and without obesity - the InCHIANTI Study 
Clinical endocrinology  2010;73(1):55-65.
Adipose tissue-derived inflammation may contribute to metabolic alterations and eventually to the metabolic syndrome (MetS). The purpose of this study was to: 1) examine the role of adipocytokines in the association between obesity and the MetS; and 2) to determine whether the association is different in obese and non-obese persons.
Cross-sectional population-based InCHIANTI study.
944 community-dwelling adults aged 65 years and older living in Tuscany, Italy.
Obesity was defined as body mass index ≥ 30 kg/m2 and MetS as ≥ 3 of the ATP-III criteria. Circulating levels of CRP, IL-6, IL-1ra, IL-18, TNF-α R1, adiponectin, resistin, and leptin were measured. Additionally, insulin resistance was determined using the homeostasis model assessment (HOMA-IR).
The prevalence of the MetS was 32%. Both overall and abdominal obesity were significantly associated with the MetS after adjusting for inflammatory cytokines, adipokines and lifestyle factors. After adjusting for multiple confounders and HOMA-IR, IL-1ra, TNF-α R1 and adiponectin (p < 0.05) remained significantly associated with the MetS. Having multiple cytokines in the highest tertile increased the likelihood of having the MetS in both obese (p for trend 0.002) and non-obese persons (p for trend 0.001) independent of insulin resistance.
Non-obese and obese individuals who develop an intense pro-inflammatory state may be more prone to develop the MetS than those with lower levels of inflammation.
PMCID: PMC2888845  PMID: 19878507
adipocytokines; adiponectin; cytokines; inflammation; metabolic syndrome; obesity
4.  The beneficial effects of exercise in rodents are preserved after detraining: a phenomenon unrelated to GLUT4 expression 
Although exercise training has well-known cardiorespiratory and metabolic benefits, low compliance with exercise training programs is a fact, and the harmful effects of physical detraining regarding these adaptations usually go unnoticed. We investigated the effects of exercise detraining on blood pressure, insulin sensitivity, and GLUT4 expression in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY).
Studied animals were randomized into sedentary, trained (treadmill running/5 days a week, 60 min/day for 10 weeks), 1 week of detraining, and 2 weeks of detraining. Blood pressure (tail-cuff system), insulin sensitivity (kITT), and GLUT4 (Western blot) in heart, gastrocnemius and white fat tissue were measured.
Exercise training reduced blood pressure (19%), improved insulin sensitivity (24%), and increased GLUT4 in the heart (+34%); gastrocnemius (+36%) and fat (+22%) in SHR. In WKY no change in either blood pressure or insulin sensitivity were observed, but there was an increase in GLUT4 in the heart (+25%), gastrocnemius (+45%) and fat (+36%) induced by training. Both periods of detraining did not induce any change in neither blood pressure nor insulin sensitivity in SHR and WKY. One-week detraining reduced GLUT4 in SHR (heart: -28%; fat: -23%) and WKY (heart: -19%; fat: -22%); GLUT4 in the gastrocnemius was reduced after a 2-week detraining (SHR: -35%; WKY: -25%). There was a positive correlation between GLUT4 (gastrocnemius) and the maximal velocity in the exercise test (r = 0.60, p = 0.004).
The study findings show that in detraining, despite reversion of the enhanced GLUT4 expression, cardiorespiratory and metabolic beneficial effects of exercise are preserved.
PMCID: PMC2984487  PMID: 21029425
5.  Decreased diabetes-induced glycemic impairment in WKY and SHR involves enhanced skeletal muscle Slc2a4/GLUT4 expression 
Hypertension has been associated to diabetes, and participates in the development of diabetic complications. The spontaneously hypertensive rat (SHR) is the gold standard model for the study of hypertension, and experimental diabetes has been currently investigated in SHR. Wistar-Kyoto rat is usually taken as control for SHR, however, regarding the glycemic homeostasis, WKY may be similar to SHR, when compared to the standard Wistar rat, importantly affecting the interpretation of data. Slc2a4 gene, which encodes the GLUT4 protein, is expressed in insulin-sensitive tissues, such as muscle cells and adipocytes, and alteration in Slc2a4/GLUT4 expression is inversely related to glycemic levels. We investigated the effect of diabetes on the expression of Slc2a4/GLUT4 and glycemic control in Wistar-Kyoto and SHR.
Slc2a4 mRNA (Northern-blotting) and GLUT4 protein (Western-blotting) were investigated in skeletal muscles (soleus and extensor digitorum longus) of Wistar, Wistar-Kyoto and SHR, rendered or not diabetic for 1 month. Non-diabetic SHR shows hyperinsulinemia, and unaltered GLUT4 expression. The hyperglycemia was significantly attenuated in diabetic Wistar-Kyoto and SHR, compared to that observed in diabetic Wistar, although all of them presented the same hypoinsulinemic levels. Besides, diabetes significantly reduced Slc2a4/GLUT4 in Wistar, as expected; however, that was not observed in diabetic Wistar-Kyoto and SHR.
Non-diabetic SHR is insulin resistant, despite unaltered GLUT4 expression. Diabetic Wistar-Kyoto and diabetic SHR presented high Slc2a4/GLUT4 expression in skeletal muscle, as compared to diabetic Wistar. This Slc2a4/GLUT4 regulation does not depend on insulin level and possibly protects the WKY and SHR from severe glycemic impairment.
PMCID: PMC4164711  PMID: 25228927
Hypertension; Soleus; EDL; Glycemic homeostasis; Hyperglycemia
6.  Plasma Adiponectin Concentration and Its Association with Metabolic Syndrome in Patients with Heart Failure 
Yonsei Medical Journal  2011;53(1):91-98.
Plasma adiponectin concentrations are inversely related with metabolic syndrome (MetS), and MetS is associated with increased risk for heart failure (HF). However, the relationship between adiponectin and MetS in HF remains undetermined. Therefore, we tested whether MetS was associated with the degree of plasma adiponectin concentrations in HF patients.
Materials and Methods
One hundred twenty eight ambulatory HF patients with left ventricular ejection fraction of <50% (80 males, 61.8±11.9 years old) were enrolled for this cross-sectional study. Echocardiographic measurements were performed, and plasma concentrations of adiponectin, lipoproteins, apolipoproteins (apoB, apoA1) and high sensitive C-reactive protein (hsCRP) were measured.
Adiponectin concentrations in HF patients with MetS (n=43) were significantly lower than those without MetS (n=85) (9.7±7.0 vs. 15.8±10.9 µg/mL, p=0.001). Higher concentrations of apoB (p=0.017), apoB/A1 ratio (p<0.001), blood urea nitrogen (p=0.034), creatinine (p=0.003), and fasting insulin (p=0.004) were observed in HF patients with MetS compared with those without MetS. In HF patients with MetS, adiponectin concentrations were negatively correlated with hsCRP (r=-0.388, p=0.015) and positively correlated with the ratio of early mitral inflow velocity to early diastolic mitral annular velocity, E/E' (r=0.399, p=0.015). There was a significant trend towards decreased adiponectin concentrations with an increasing number of components of MetS (p for trend=0.012).
Our study demonstrated that adiponectin concentrations decreased in HF patients with MetS, and that relationship between adiponectin, inflammation and abnormal diastolic function, possibly leading to the progression of HF.
PMCID: PMC3250329  PMID: 22187237
Adiponectin; metabolic syndrome; heart failure
7.  Circulating adiponectin levels in Indian patients with psoriasis and its relation to metabolic syndrome 
Adiponectin is a cytokine mainly secreted from the adipose tissue, which has insulin-sensitizing effects, antiatherosclerotic actions, and antiinflammatory properties. There are a few studies that have demonstrated that adiponectin is reduced in patients with psoriasis suggesting that this adipocytokine may have a role in the pathogenesis of psoriasis. There have been no studies so far on adiponectin in relation to psoriasis and metabolic syndrome (MetS).
This study was performed to analyze serum adiponectin and insulin levels in psoriasis patients with and without MetS and in controls with and without MetS.
Materials and Methods:
We performed a case control study on 60 psoriasis patients, 29 with MetS and 31 without MetS and 40 controls, 20 with and 20 without MetS, matched for age, sex, and body mass index (BMI). Fasting serum insulin and adiponectin levels were measured in all groups.
The overall serum adiponectin levels were significantly reduced in psoriasis patients when compared with controls (P = 0.000). A significant reduction was also observed in psoriasis patients with MetS than those without MetS in the same group (P = 0.000). Similar decrease was observed between those with MetS in the psoriasis and control groups (P = 0.001). The lowest mean value of serum adiponectin (6387.9 ng/ml) was observed in psoriasis with MetS group and highest value (12146.3 ng/ml) in controls without MetS.
Adiponectin levels are decreased in psoriasis patients irrespective of MetS thus indicating a role in its pathogenesis. This study prompts future trials on drugs increasing adiponectin levels in patients with psoriasis.
PMCID: PMC3987269  PMID: 24741515
Psoriasis; metabolic syndrome; serum adiponectin
8.  Association of metabolic syndrome with severity of coronary artery disease 
South Asians are more prone to develop metabolic syndrome (MetS). The additive predictive value of components of MetS for cardiovascular diseases is still debated. We undertook this study to evaluate the association of MetS and its components with severity of coronary artery disease (CAD).
Materials and Methods:
Three hundred patients with known coronary disease above the age of 25 years were included in this study. Blood samples were collected for biochemical markers. Patients were stratified into subjects with and without MetS (International Diabetes Federation, IDF, criteria) and severity of CAD (number of vessel involved).
Mean age of the patient in the study was 60.9 ± 12.4 years (male, M: 72%; female, F: 28%). MetS was present in 64% patients. Patients with MetS had more severe CAD compared to those without MetS. Triple vessel disease (TVD) was present in 62.5% of patients with MetS compared to 34.3% among without MetS (P < 0.0001). The percent number of patients with TVD showed increasing trend with increasing number of components of MetS (0-0%; 1-20%; 2-27.5%; 3-47.8%; 4-72.6%; 5-78.3%; Chi square for trend < 0.0001). Inflammatory markers [interleukin (IL) 6: 77.67 ± 79.48 vs. 41.21 ± 60.72 pg/ml, P < 0.0001; tumor nuclear factor (TNF)-α: 28.0 ± 47.49 vs 20.43 ± 24.5 pg/ml, P < 0.0001; high sensitive C-reactive protein (hsCRP): 14.30 ± 9.91 vs. 7.02 ± 7.18 mg/L, P < 0.0001], insulin resistance [homeostatic model analysis insulin resistance (HOMA-IR): 22.33 ± 23.37 vs. 10.86 ± 13.90, P < 0.0001] were higher and insulin sensitivity [quantitative insulin check index (QUICKI): 0.26 ± 0.03 vs. 0.30 ± 0.04, P < 0.0001] was significantly lower in subjects with MetS compared to subjects without MetS. Among lipids, total cholesterol were comparable but triglyceride (175 ± 42 vs. 179 ± 48 vs. 180 ± 47 mg/dl, P < 0.0001) was high and high-density lipoprotein (HDL; 44.72 ± 7.63 vs. 39.96 ± 8.70 vs. 36.05 ± 8.84, P < 0.0001) was low in subjects with TVD compared to others. Similarly, percentage of patients with diabetes (7.5% vs. 26.3% vs. 63.7%, P < 0.0001) and hypertension (34.3% vs. 56.6% vs. 77.7%, P < 0.0001) were higher in subjects with TVD compared to others.
There is a strong correlation of MetS and its components with severity of CAD.
PMCID: PMC4171897  PMID: 25285291
Coronary artery disease; inflammatory markers; insulin resistance; metabolic syndrome
9.  Evaluation of Adiposity-Related Biomarkers as Metabolic Syndrome Indicators 
Clinical Nutrition Research  2013;2(2):91-99.
Recent studies have suggested a relationship of the increased circulating adipokines and inflammatory cytokine, and the risk of metabolic syndrome (MetS). The objective of this study was to identify adiposity-related factors that reflect MetS in order to establish early intervention targets. We performed a cross-sectional study which included 108 MetS subjects and 91 controls. Blood adiponectin, leptin, vascular-, and intercellular adhension molecules (VCAM, ICAM), monocyte chemoattractant protein 1 (MCP1), high-sensitivity C-reactive protein (hsCRP), oxidized LDL (oxLDL), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were measured. The correlation analysis indicated that the MetS score (sum of the number of MetS risk factors) had an inverse relationship with adiponectin (p < 0.0001), and positive correlations with leptin (p < 0.05), ICAM (p < 0.01), MCP1 (p < 0.05), oxLDL (p < 0.05), TNF-α (p < 0.0001), IL-6 (p < 0.05) and hsCRP (p < 0.01). In multivariate logistic regression analyses, plasma triglyceride (TG) was independently associated with adiponectin, ICAM and TNF-α with the standardized β coefficients of -0.213, 0.197, and 0.193, respectively. Plasma HDL-cholesterol was independently associated with ICAM and hsCRP with the standardized β coefficients of -0.150 and -0.173. Adiponectin, TNF-α, and hsCRP were the most proximate markers reflecting MetS. Among MetS components, TG and HDL-cholesterol concentrations displayed the relationship with inflammatory markers measured in this study.
PMCID: PMC3728468  PMID: 23908975
Metabolic syndrome; Adiposity; Adipokines; Inflammatory cytokines; Abdominal fat
10.  Prediction of metabolic syndrome in women with polycystic ovary syndrome 
To identify biochemical factors that serve as predictors for the metabolic syndrome (MetS) in patients with polycystic ovary syndrome (PCOS) and to investigate the value of adipocytokines in the prediction of metabolic syndrome.
Material and Methods
A total of 91 pre-menopausal women with PCOS diagnosed according to the Rotterdam consensus criteria were recruited as study subjects. Waist circumference, blood pressure, body mass index (BMI), fasting glucose, serum lipids, insulin, FSH, LH, E2, total testosteron, homeostatic model assessment–insulin resistance (HOMA-IR), serum leptin and adiponectin levels were evaluated for all patients.
Of the 91 women with PCOS, 15 patients met the criteria for MetS. Body weight, BMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting glucose, total cholesterol, triglyceride, and VLDL concentrations were significantly higher and HDL was significantly lower in women with PCOS+MetS compared with those with PCOS only. However, the level of LDL, FSH, LH, E2 and total testesterone was not significantly different between these two groups. Women with PCOS+MetS had significantly higher levels of leptin and HOMA-IR, and significantly lower levels of adiponectin compared to the women with PCOS only. In the multiple logistic regression model, the association between HOMA-IR and leptin, and MetS remained statistically significant (p=0.001 and 0.018), while the association between adiponectin and MetS was no longer statistically significant.
Aside from the biochemical markers such as glucose, cholesterol and triglyceride, adipose tissue factors and insulin resistance are valuable parameters in the prediction of MetS in patients with PCOS.
PMCID: PMC3939237  PMID: 24592034
Metabolic syndrome; polycystic ovary syndrome; leptin; adiponectin; HOMA-IR
11.  Relationships between Serum Adiponectin with Metabolic Syndrome and Components of Metabolic Syndrome in Non-Diabetic Koreans: ARIRANG Study 
Yonsei Medical Journal  2011;52(2):234-241.
Growing evidence suggests that hypoadiponectinemia may play a significant role in the development of metabolic syndrome (MetS). Therefore, the relationships between serum adiponectin with MetS and components of MetS were investigated in non-diabetic samples of drawn from the Koreans general population.
Materials and Methods
We performed a cross-sectional study in samples of older Koreans (age > 40 years) including 2,471 men and 3,463 women. MetS was defined according to the Asian modified criteria of the National Cholesterol Education Program Adult Treatment Panel III report. Serum adiponectin concentrations were measured by radioimmunoassay.
The median adiponectin level in MetS was significantly lower than that in non-MetS subjects in men (6.00 vs. 8.00 µg/mL, p < 0.001) and women (10.12 vs. 11.74 µg/mL, p < 0.001). Adiponectin concentration was negatively correlated with waist circumference and levels of triglyceride, C-reactive protein (CRP), fasting glucose, and insulin, and positively correlated with high-density lipoprotein and age in both genders (p < 0.001). In a multivariate regression model after adjustment for age, body mass index, smoking, CRP, and lipid profiles, the odds ratio of MetS comparing extreme quartiles of adiponectin distribution was 0.32 [95% confidence interval (CI), 0.20 to 0.50] in men and 0.57 (95% CI, 0.43 to 0.76) in women.
Adiponectin levels are independently associated with the phenotype of MetS, as well as components of MetS in the non-diabetic Korean general population.
PMCID: PMC3051212  PMID: 21319340
Adiponectin; metabolic syndrome; Korea
12.  Acute Inhibition of Fatty Acid Import Inhibits GLUT4 Transcription in Adipose Tissue, but Not Skeletal or Cardiac Muscle Tissue, Partly Through Liver X Receptor (LXR) Signaling 
Diabetes  2010;59(4):800-807.
Insulin-mediated glucose uptake is highly sensitive to the levels of the facilitative GLUT protein GLUT4. Transcription of the GLUT4 gene is repressed in states of insulin deficiency and insulin resistance and can be induced by states of enhanced energy output, such as exercise. The cellular signals that regulate GLUT4 transcription are not well understood. We hypothesized that changes in energy substrate flux regulate GLUT4 transcription.
To test this hypothesis, we used transgenic mice in which expression of the chloramphenicol acetyltransferase (CAT) gene is driven by a functional 895-bp fragment of the human GLUT4 promoter, thereby acting as a reporter for transcriptional activity. Mice were treated with a single dose of etomoxir, which inhibits the transport of long-chain fatty acids into mitochondria and increases basal, but not insulin-mediated, glucose flux. GLUT4 and transgenic CAT mRNA were measured.
Etomoxir treatment significantly reduced CAT and GLUT4 mRNA transcription in adipose tissue, but did not change transcription in heart and skeletal muscle. Downregulation of GLUT4 transcription was cell autonomous, since etomoxir treatment of 3T3-L1 adipocytes resulted in a similar downregulation of GLUT4 mRNA. GLUT4 transcriptional downregulation required the putative liver X receptor (LXR) binding site in the human GLUT4 gene promoter in adipose tissue and 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with the LXR agonist, TO901317, partially restored GLUT4 expression in etomoxir-treated cells.
Our data suggest that long-chain fatty acid import into mitochondria in adipose tissue may produce ligands that regulate expression of metabolic genes.
PMCID: PMC2844827  PMID: 20103707
13.  Cardiac remodeling and myocardial dysfunction in obese spontaneously hypertensive rats 
The additive effects of obesity and metabolic syndrome on left ventricular (LV) maladaptive remodeling and function in hypertension are not characterized.
We compared an obese spontaneously hypertensive rat model (SHR-ob) with lean spontaneously hypertensive rats (SHR-lean) and normotensive controls (Ctr). LV-function was investigated by cardiac magnetic resonance imaging and invasive LV-pressure measurements. LV-interstitial fibrosis was quantified and protein levels of phospholamban (PLB), Serca2a and glucose transporters (GLUT1 and GLUT4) were determined by immunohistochemistry.
Systolic blood pressure was similar in SHR-lean and SHR-ob (252 ± 7 vs. 242 ± 7 mmHg, p = 0.398) but was higher when compared to Ctr (155 ± 2 mmHg, p < 0.01 for both). Compared to SHR-lean and Ctr, SHR-ob showed impaired glucose tolerance and increased body-weight. In SHR-ob, LV-ejection fraction was impaired vs. Ctr (46.2 ± 1.1 vs. 59.6 ± 1.9%, p = 0.007). LV-enddiastolic pressure was more increased in SHR-ob than in SHR-lean (21.5 ± 4.1 vs. 5.9 ± 0.81 mmHg, p = 0.0002) when compared to Ctr (4.3 ± 1.1 mmHg, p < 0.0001 for both), respectively. Increased LV-fibrosis together with increased myocyte diameters and ANF gene expression in SHR-ob were associated with increased GLUT1-protein levels in SHR-ob suggestive for an upregulation of the GLUT1/ANF-axis. Serca2a-protein levels were decreased in SHR-lean but not altered in SHR-ob compared to Ctr. PLB-phosphorylation was not altered.
In addition to hypertension alone, metabolic syndrome and obesity adds to the myocardial phenotype by aggravating diastolic dysfunction and a progression towards systolic dysfunction. SHR-ob may be a useful model to develop new interventional and pharmacological treatment strategies for hypertensive heart disease and metabolic disorders.
PMCID: PMC3508805  PMID: 22963383
SHR-ob; SHR; MRI; Metabolic syndrome; Hypertension; Remodeling
14.  Association of hormonal dysregulation with metabolic syndrome in older women: data from the InCHIANTI study 
Metabolic syndrome (MetS) is a strong risk factor for type 2 diabetes and cardiovascular disease. Conditions associated with hyperandrogenism are often associated with glucose intolerance and other features of MetS in young women. As the prevalence of MetS increases with age and is probably multifactorial, it is reasonable to hypothesize that age-related changes in androgens and other hormones might contribute to the development of MetS in older persons. However, this hypothesis has never been tested in older women. We hypothesized that high levels of testosterone, dehydroepiandrosterone sulfate (DHEA-S), and cortisol and low levels of sex hormone-binding globulin (SHBG) and IGF-I would be associated with MetS in a representative cohort of older Italian women independently of confounders (including inflammatory markers). After exclusion of participants on hormone replacement therapy and those with a history of bilateral oophorectomy, 512 women (≥65 yr) had complete data on testosterone, cortisol, DHEA-S, SHBG, fasting insulin, total and free IGF-I, IL-6, and C-reactive protein (CRP). MetS was defined according to ATP-III criteria. Insulin resistance was calculated according to HOMA. MetS was found in 145 women (28.3%). Participants with vs. those without MetS had higher age-adjusted levels of bioavailable testosterone (P < 0.001), IL-6 (P < 0.001), CRP (P < 0.001), and HOMA (P < 0.001) and lower levels of SHBG (P < 0.001). After adjustment for potential confounders, participants with decreased SHBG had an increased risk of MetS (P < 0.0001) vs. those with low SHBG. In a further model including all hormones and confounders, log SHBG was the only independent factor associated with MetS (OR: 0.44, 95% CI 0.21–0.91, P = 0.027). In older women, SHBG is negatively associated with MetS independently of confounders, including inflammatory markers and insulin resistance. Further studies are needed to support the notion that raising SHBG is a potential therapeutic target for prevention and treatment of MetS.
PMCID: PMC2645662  PMID: 16968811
sex hormone-binding globulin; hormonal dysregulation; insulin-like growth factor I; androgens
15.  Effects of Human C-Reactive Protein on Pathogenesis of Features of the Metabolic Syndrome 
Hypertension  2011;57(4):10.1161/HYPERTENSIONAHA.110.164350.
Major controversy exists as to whether increased C-reactive protein (CRP) contributes to individual components of the metabolic syndrome or is just a secondary response to inflammatory disease processes. We measured blood pressure and metabolic phenotypes in spontaneously hypertensive rats (SHR) in which we transgenically expressed human CRP in liver under control of the apoE promoter. In SHR transgenic rats, serum levels of human CRP approximated the endogenous levels of CRP normally found in the rat. Systolic and diastolic blood pressures measured by telemetry were 10–15 mmHg greater in transgenic SHR expressing human CRP than in SHR controls (P<0.01). During oral glucose tolerance testing, transgenic SHR exhibited hyperinsulinemia compared to controls (insulin area under the curve 36±7 versus 8±2 nmol/L/2h, respectively, P<0.05). Transgenic SHR also exhibited resistance to insulin stimulated glycogenesis in skeletal muscle (174±18 versus 278±32 nmol glucose/g/2h, P<0.05), hypertriglyceridemia (0.84±0.05 versus 0.64±0.03 mmol/L, P<0.05), reduced serum adiponectin (2.4±0.3 versus 4.3±0.6 mmol/L, P<0.05), and microalbuminuria (200±35 versus 26±5 mg albumin/g creatinine, respectively, P<0.001). Transgenic SHR had evidence of inflammation and oxidative tissue damage with increased serum levels of interleukin 6 (IL6) (36.4±5.2 versus 18±1.7 pg/ml, P<0.005) and increased hepatic and renal TBARS (1.2±0.09 versus 0.8±0.07 and 1.5±0.1 versus 1.1±0.05 nM/mg protein, respectively, P<0.01), suggesting that oxidative stress may be mediating adverse effects of increased human CRP. These findings are consistent with the hypothesis that increased CRP is more than just a marker of inflammation and can directly promote multiple features of the metabolic syndrome.
PMCID: PMC3060762  PMID: 21357282
C-reactive protein; metabolic syndrome; oxidative stress; transgenic; spontaneously hypertensive rat
16.  Measurement of antioxidant capacity using the biological antioxidant potential test and its role as a predictive marker of metabolic syndrome 
Oxidative stress increases the risk of cardiovascular complications of metabolic syndrome (MetS). This study was conducted to examine the difference in antioxidant capacity according to the presence of MetS, and to characterize the association between antioxidant capacity and MetS-related factors.
We used the biological antioxidant potential (BAP) test to estimate antioxidant capacity. The BAP test has recently been used as an indicator of antioxidant capacity. We measured BAP levels in 45 patients with MetS (mean age, 44.6 ± 1.1 years) and 47 age- and sex-matched controls (mean age, 42.7 ± 1.1 years). To evaluate the association between antioxidant capacity and MetS, adiponectin, high-sensitivity C-reactive protein (hs-CRP), interleukin-6, tumor necrosis factor-α, and homeostatic model assessment for insulin resistance (HOMA-IR), linear regression and logistic analyses were performed.
The mean BAP of the MetS group (1,937.3 ± 36.5 µmol/L) was significantly lower than that of the non-MetS group (2,101.7 ± 29.5 µmol/L). Also, the mean BAP was low in persons having low high density lipoprotein and high triglyceride. Reduced antioxidant capacity was significantly associated with adiponectin, HOMA-IR and hs-CRP after adjusting for age and sex. The odds ratios for MetS with BAP, log adiponectin, log HOMA-IR, and log hs-CRP were 0.63 (95% confidence interval [CI], 0.49 to 0.82), 0.22 (0.10 to 0.51), 14.24 (4.35 to 46.58), and 1.93 (1.36 to 2.75), respectively.
Persons with MetS showed reduced antioxidant capacity. We identified relationships between antioxidant capacity measured by BAP test and MetS, as well as MetS-related factors, such as insulin resistance, hs-CRP, and adiponectin.
PMCID: PMC3932393  PMID: 24574831
Metabolic syndrome; Oxidative stress; Adiponectin; Insulin
17.  Effect of Aging and Obesity on Insulin Responsiveness and Glut-4 Glucose Transporter Content in Skeletal Muscle of Fischer 344 × Brown Norway Rats 
This study investigated the metabolic changes with age in the Fischer 344 × Brown Norway rat and its suitability as an animal model of postmaturational insulin resistance. Specifically, we determined whether an age-associated decrease in glucose disposal is associated with diminished whole body insulin responsiveness and/or a decrease in glucose transporter (GLUT-4) protein and mRNA content in medial gastrocnemius muscle of male Fischer 344 × Brown Norway rats of ages 8, 18, and 28 months. Fasting plasma glucose was unchanged with age. There was a significant age effect on visceral adiposity, fasting plasma insulin levels, insulin responsiveness, and GLUT-4 protein content. Insulin responsiveness and GLUT-4 protein were lower in the 18-month-old rats than in the 8-month-old rats. The findings of age-associated increases in visceral adiposity and insulin resistance, and decreases in GLUT-4 in the Fisher 344 × Brown Norway rat, suggest that this rat strain may be an appropriate model for studying the effects of aging on glucose homeostasis.
PMCID: PMC2714732  PMID: 11682570
18.  High sensitive C-reactive protein and serum amyloid A are inversely related to serum bilirubin: effect-modification by metabolic syndrome 
Bilirubin has been implicated in cardiovascular protection by virtue of its anti-inflammatory and anti-oxidative properties. The metabolic syndrome is featured by enhanced low-grade systemic inflammation and oxidative stress. Serum amyloid A (SAA) impairs anti-oxidative properties of high-density lipoprotein (HDL). We determined relationships of high sensitive C-reactive protein (hs-CRP) and SAA with bilirubin in subjects with and without metabolic syndrome (MetS).
Serum total bilirubin, hs-CRP, SAA and homeostasis model assessment- insulin resistance (HOMA-IR) were documented in 94 subjects with and in 73 subjects without MetS (26 and 54 subjects with type 2 diabetes mellitus (T2DM), respectively).
Bilirubin was lower in MetS (P = 0.013), coinciding with higher hs-CRP (P < 0.001) and SAA levels (P = 0.002). In all subjects combined, hs-CRP was inversely related to bilirubin (r = −0.203, P = 0.008), irrespective of the presence of MetS or T2DM (interaction terms: P ≥ 0.75). The inverse relationship of bilirubin with SAA was confined to subjects without MetS (r = −0.267, P = 0.009). Furthermore, the presence of either MetS or T2DM modified the relationship of bilirubin with SAA (interaction terms: β = 0.366, P = 0.003 and β = 0.289, P = 0.025, respectively) in age- and sex-adjusted analyses. Effect modification was also found for HOMA-IR (β = 0.790, P = 0.020). Of the individual MetS components, the strongest interaction of bilirubin on SAA was observed with low HDL cholesterol (β = 0.435, P < 0.001).
hs-CRP is inversely related to bilirubin, suggesting that low bilirubin is implicated in enhanced low-grade systemic inflammation. The inverse relationship of SAA with bilirubin was found to be absent in MetS, which could be attributable to MetS-associated abnormalities in HDL characteristics.
PMCID: PMC4176750  PMID: 24209691
Metabolic syndrome; Serum amyloid A; Bilirubin
19.  Circulating Fractalkine Levels Predict the Development of the Metabolic Syndrome 
The fractalkine/CX3CR1 axis plays an important role in regulating glucose and lipid metabolism. However, the role of fractalkine in metabolic disorders remains to be fully elucidated. We selected 887 Chinese (40–65 years old) at baseline, with a subgroup of 459 participants examined again 2 years later. The relationship of serum fractalkine levels with the metabolic syndrome (MetS) and its components was investigated. At baseline, participants with MetS had higher fractalkine concentrations than their counterparts without MetS (P < 0.001). At the 2-year follow-up, participants in the highest quartile of baseline fractalkine exhibited higher values for body mass index, waist circumference, waist-to-hip ratio, body fat percentage, glucose, insulin, total cholesterol, triglycerides (TG), and homeostasis model assessment of insulin resistance (HOMA-IR) and lower value for high density lipoprotein-cholesterol (HDL-c) (all P < 0.05). Among 390 participants without MetS at baseline, 45 developed it at year 2. Even after multiple adjustments for visceral adipose tissue area, HOMA-IR, C-reactive protein (CRP), or TG and HDL-c, baseline fractalkine predicted the development of MetS (OR = 7.18, 95%CI: 2.28–18.59). In conclusion, circulating fractalkine predicts the development of the MetS independently of central obesity, CRP, insulin resistance, and dyslipidemia.
PMCID: PMC4021752  PMID: 24883062
20.  Changes in endotoxin levels in T2DM subjects on anti-diabetic therapies 
Chronic low-grade inflammation is a significant factor in the development of obesity associated diabetes. This is supported by recent studies suggesting endotoxin, derived from gut flora, may be key to the development of inflammation by stimulating the secretion of an adverse cytokine profile from adipose tissue.
The study investigated the relationship between endotoxin and various metabolic parameters of diabetic patients to determine if anti-diabetic therapies exerted a significant effect on endotoxin levels and adipocytokine profiles.
Fasting blood samples were collected from consenting Saudi Arabian patients (BMI: 30.2 ± (SD)5.6 kg/m2, n = 413), consisting of non-diabetics (ND: n = 67) and T2DM subjects (n = 346). The diabetics were divided into 5 subgroups based on their 1 year treatment regimes: diet-controlled (n = 36), metformin (n = 141), rosiglitazone (RSG: n = 22), a combined fixed dose of metformin/rosiglitazone (met/RSG n = 100) and insulin (n = 47). Lipid profiles, fasting plasma glucose, insulin, adiponectin, resistin, TNF-α, leptin, C-reactive protein (CRP) and endotoxin concentrations were determined.
Regression analyses revealed significant correlations between endotoxin levels and triglycerides (R2 = 0.42; p < 0.0001); total cholesterol (R2 = 0.10; p < 0.001), glucose (R2 = 0.076; p < 0.001) and insulin (R2 = 0.032; p < 0.001) in T2DM subjects. Endotoxin showed a strong inverse correlation with HDL-cholesterol (R2 = 0.055; p < 0.001). Further, endotoxin levels were elevated in all of the treated diabetic subgroups compared with ND, with the RSG treated diabetics showing significantly lower endotoxin levels than all of the other treatment groups (ND: 4.2 ± 1.7 EU/ml, RSG: 5.6 ± 2.2 EU/ml). Both the met/RSG and RSG treated groups had significantly higher adiponectin levels than all the other groups, with the RSG group expressing the highest levels overall.
We conclude that sub-clinical inflammation in T2DM may, in part, be mediated by circulating endotoxin. Furthermore, that whilst the endotoxin and adipocytokine profiles of diabetic patients treated with different therapies were comparable, the RSG group demonstrated significant differences in both adiponectin and endotoxin levels. We confirm an association between endotoxin and serum insulin and triglycerides and an inverse relationship with HDL. Lower endotoxin and higher adiponectin in the groups treated with RSG may be related and indicate another mechanism for the effect of RSG on insulin sensitivity.
PMCID: PMC2674418  PMID: 19368716
21.  Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity. 
Journal of Clinical Investigation  1995;96(6):2792-2801.
Glucosamine (Glmn), a product of glucose metabolism via the hexosamine pathway, causes insulin resistance in isolated adipocytes by impairing insulin-induced GLUT 4 glucose transporter translocation to the plasma membrane. We hypothesized that Glmn causes insulin resistance in vivo by a similar mechanism in skeletal muscle. We performed euglycemic hyperinsulinemic clamps (12 mU/kg/min + 3H-3-glucose) in awake male Sprague-Dawley rats with and without Glmn infusion at rates ranging from 0.1 to 6.5 mg/kg/min. After 4h of euglycemic clamping, hindquarter muscles were quick-frozen and homogenized, and membranes were subfractionated by differential centrifugation and separated on a discontinuous sucrose gradient (25, 30, and 35% sucrose). Membrane proteins were solubilized and immunoblotted for GLUT 4. With Glmn, glucose uptake (GU) was maximally reduced by 33 +/- 1%, P < 0.001. The apparent Glmn dose to reduce maximal GU by 50% was 0.1 mg/kg/min or 1/70th the rate of GU on a molar basis. Control galactosamine and mannosamine infusions had no effect on GU. Relative to baseline, insulin caused a 2.6-fold increase in GLUT 4 in the 25% membrane fraction (f), P < 0.01, and a 40% reduction in the 35%f, P < 0.05, but had no effect on GLUT 4 in the 30% f, P= NS. Addition of Glmn to insulin caused a 41% reduction of GLUT 4 in the 25%f, P < 0.05, a 29% fall in the 30%f, and prevented the reduction of GLUT 4 in the 35% f. The 30%f membranes were subjected to a second separation with a 27 and 30% sucrose gradient. Insulin mobilized GLUT 4 away from the 30%f, P < 0.05, but not the 27% f. In contrast, Glmn reduced GLUT 4 in the 27%f, P < 0.05, but not the 30%f. Thus Glmn appears to alter translocation of an insulin-insensitive GLUT 4 pool. Coinfusion of Glmn did not alter enrichment of the sarcolemmal markers 5'-nucleotidase, Na+/K+ATPase, and phospholemman in either 25, 30, or 35% f. Thus Glmn completely blocked movement of Glut 4 induced by insulin. Glmn is a potent inducer of insulin resistance in vivo by causing (at least in part) a defect intrinsic to GLUT 4 translocation and/or trafficking. These data support a potential role for Glmn to cause glucose-induced insulin resistance (glucose toxicity).
PMCID: PMC185989  PMID: 8675649
22.  Associations of Amylin with Inflammatory Markers and Metabolic Syndrome in Apparently Healthy Chinese 
PLoS ONE  2011;6(9):e24815.
Cellular and animal studies implicate multiple roles of amylin in regulating insulin action, glucose and lipid metabolisms. However, the role of amylin in obesity related metabolic disorders has not been thoroughly investigated in humans. Therefore, we aimed to evaluate the distribution of circulating amylin and its association with metabolic syndrome (MetS) and explore if this association is influenced by obesity, inflammatory markers or insulin resistance in apparently healthy Chinese.
A population-based sample of 1,011 Chinese men and women aged 35–54 years was employed to measure plasma amylin, inflammatory markers (C-reactive protein [CRP] and interleukin-6 [IL-6]), insulin, glucose and lipid profiles. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian-Americans.
Plasma amylin concentrations were higher in overweight/obese participants than normal-weight counterparts (P<0.001) without sex difference. Circulating amylin was positively associated with CRP, IL-6, BMI, waist circumference, blood pressure, fasting glucose, insulin, amylin/insulin ratio, HOMA-IR, LDL cholesterol and triglycerides, while negatively associated with HDL cholesterol (all P<0.001). After multiple adjustments, the risk of MetS was significantly higher (odds ratio 3.71; 95% confidence interval: 2.53 to 5.46) comparing the highest with the lowest amylin quartile. The association remained significant even further controlling for BMI, inflammatory markers, insulin or HOMA-IR.
Our study suggests that amylin is strongly associated with inflammatory markers and MetS. The amylin-MetS association is independent of established risk factors of MetS, including obesity, inflammatory markers and insulin resistance. The causal role of hyperamylinemia in the development of MetS needs to be confirmed prospectively.
PMCID: PMC3174205  PMID: 21935471
23.  Adipose-specific deletion of stearoyl-CoA desaturase 1 up-regulates the glucose transporter GLUT1 in adipose tissue 
Stearoyl-CoA desaturase 1 (SCD1) deficiency protects mice from diet-induced obesity and insulin resistance. To understand the tissue-specific role of SCD1 in energy homeostasis, we have generated mice with an adipose-specific knockout of Scd1 (AKO), and report here that SCD1 deficiency increases GLUT1 expression in adipose tissue of AKO mice, but not global SCD1 knockout (GKO) mice. In 3T3-L1 adipocytes treated with a SCD inhibitor, basal glucose uptake and the cellular expression of GLUT1 were significantly increased while GLUT4 expression remained unchanged. Consistently, adipose-specific SCD1 knockout (AKO) mice had significantly elevated GLUT1 expression, but not GLUT4, in white adipose tissue compared to Lox counterparts. Concurrently, adiponectin expression was significantly diminished, whereas TNF-α expression was elevated. In contrast, in adipose tissue of GKO mice, GLUT4 and adiponectin expression were significantly elevated with lowered TNF-α expression and little change in GLUT1 expression, suggesting a differential responsiveness of adipose tissue to global- or adipose-specific SCD1 deletion. Taken together, these results indicate that adipose-specific deletion of SCD1 induces GLUT1 up-regulation in adipose tissue, associated with decreased adiponectin and increased TNF-α production, and suggest that GLUT1 may play a critical role in controlling glucose homeostasis of adipose tissue in adipose-specific SCD1-deficient conditions.
PMCID: PMC2936448  PMID: 20655875
stearoyl-coenzyme A desaturase; adipose tissue; GLUT1; GLUT4; adiponectin
24.  Association Between Metabolic Syndrome and Liver Histology Among Children With Nonalcoholic Fatty Liver Disease 
Nonalcoholic steatohepatitis (NASH) is considered the hepatic manifestation of metabolic syndrome (MetS) among adults. Emerging data suggest that MetS may be associated with nonalcoholic fatty liver disease (NAFLD) in children as well. We sought to determine whether MetS or its component features are associated with specific histological features or severity of NAFLD.
Children and adolescents aged 6 – 17 years enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) with clinical data obtained within 6 months of liver biopsy were included. MetS was defined as the presence of three or more of the following features as determined by application of age-adjusted normative values: central obesity, dyslipidemia, impaired fasting glucose, and elevated blood pressure. Liver biopsies were evaluated by the Pathology Committee of the NASH CRN.
Two hundred fifty four children were included in the analysis, of whom 65 (26 %) met specified criteria for MetS. Among children with MetS, there is a higher proportion of females who were on average older in age and pubertal. The risk of MetS was greatest among those with severe steatosis (odds ratio (OR) = 2.58 for grade 3 vs. grade 1 steatosis, P = 0.001). The presence of hepatocellular ballooning was also significantly associated with MetS (OR = 2.10, P = 0.03). Those with advanced fibrosis (stage 3/4) had an OR for MetS of 3.21 (P = 0.04) vs. those without fibrosis (stage 0). Borderline zone 1 or definite NASH patterns compared with “ not NASH ” were strongly associated with MetS (OR = 4.44, P = 0.005 and OR = 4.07, P = 0.002, respectively). The mean NAFLD Activity Score (NAS) was greater among children with MetS vs. those without (4.8 ± 1.4 vs. 4.3 ± 1.4, P = 0.01). Central obesity was significantly associated with steatosis, fibrosis, hepatocellular ballooning, and NAFLD pattern. Insulin resistance was significantly associated with steatosis, fibrosis, hepatocellular ballooning, NAS, and NAFLD pattern.
MetS is common among children with NAFLD and is associated with severity of steatosis, hepatocellular ballooning, NAS, NAFLD pattern, and the presence of advanced fibrosis. Individual MetS features, particularly central obesity and insulin resistance, were also associated with severity of NAFLD. MetS features should be considered in children with NAFLD as individually and collectively they help identify children with more advanced disease.
PMCID: PMC3070291  PMID: 20372110
25.  Metabolically healthy and unhealthy obesity phenotypes in the general population: the FIN-D2D Survey 
BMC Public Health  2011;11:754.
The aim of this work was to examine the prevalence of different metabolical phenotypes of obesity, and to analyze, by using different risk scores, how the metabolic syndrome (MetS) definition discriminates between unhealthy and healthy metabolic phenotypes in different obesity classes.
The Finnish type 2 diabetes (FIN-D2D) survey, a part of the larger implementation study, was carried out in 2007. The present cross-sectional analysis comprises 2,849 individuals aged 45-74 years. The MetS was defined with the new Harmonization definition. Cardiovascular risk was estimated with the Framingham and SCORE risk scores. Diabetes risk was assessed with the FINDRISK score. Non-alcoholic fatty liver disease (NAFLD) was estimated with the NAFLD score. Participants with and without MetS were classified in different weight categories and analysis of regression models were used to test the linear trend between body mass index (BMI) and various characteristics in individuals with and without MetS; and interaction between BMI and MetS.
A metabolically healthy but obese phenotype was observed in 9.2% of obese men and in 16.4% of obese women. The MetS-BMI interaction was significant for fasting glucose, 2-hour plasma glucose, fasting plasma insulin and insulin resistance (HOMA-IR)(p < 0.001 for all). The prevalence of total diabetes (detected prior to or during survey) was 37.0% in obese individuals with MetS and 4.3% in obese individuals without MetS (p < 0.001). MetS-BMI interaction was significant (p < 0.001) also for the Framingham 10 year CVD risk score, NAFLD score and estimated liver fat %, indicating greater effect of increasing BMI in participants with MetS compared to participants without MetS. The metabolically healthy but obese individuals had lower 2-hour postload glucose levels (p = 0.0030), lower NAFLD scores (p < 0.001) and lower CVD risk scores (Framingham, p < 0.001; SCORE, p = 0.002) than normal weight individuals with MetS.
Undetected Type 2 diabetes was more prevalent among those with MetS irrespective of the BMI class and increasing BMI had a significantly greater effect on estimates of liver fat and future CVD risk among those with MetS compared with participants without MetS. A healthy obese phenotype was associated with a better metabolic profile than observed in normal weight individuals with MetS.
PMCID: PMC3198943  PMID: 21962038

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