Obesity
Original Article EPIDEMIOLOGY/GENETICS
Uric Acid Best Predicts Metabolically Unhealthy Obesity With Increased Cardiovascular Risk in Youth and Adults Harald Mangge1, Sieglinde Zelzer1, Peter Puerstner2, Wolfgang J. Schnedl3, Gloria Reeves4, Teodor T. Postolache5 and Daniel Weghuber6
Objective: The obesity prevalence is growing worldwide and largely responsible for cardiovascular disease, the most common cause of death in the western world. The rationale of this study was to distinguish metabolically healthy from unhealthy overweight/obese young and adult patients as compared to healthy normal weight age matched controls by an extensive anthropometric, laboratory, and sonographic vascular assessment. Design and Methods: Three hundred fifty five young [8 to < 18 years, 299 overweight/obese(ow/ob), 56 normal weight (nw)] and 354 adult [>18-60 years, 175 (ow/ob), 179 nw)] participants of the STYJOBS/EDECTA (STYrian Juvenile Obesity Study/Early DEteCTion of Atherosclerosis) cohort were analyzed. STYJOBS/ EDECTA (NCT00482924) is a crossectional study to investigate metabolic/cardiovascular risk profiles in normal and ow/ob people free of disease except metabolic syndrome (MetS). Results: From 299 young ow/ob subjects (8-< 18 years), 108 (36%), and from 175 adult ow/ob subjects (>18-60 years), 79 (45%) had positive criteria for MetS. In both age groups, prevalence of MetS was greater among males. Overweight/obese subjects were divided into ‘‘healthy’’ (no MetS criterion except anthropometry fulfilled) and ‘‘unhealthy’’ (MetS positive). Although percentage body fat did not differ between ‘‘healthy’’ and ‘‘unhealthy’’ ow/ob, nuchal and visceral fat were significantly greater in the ‘‘unhealthy’’ group which had also significantly higher values of carotid intima media thickness (IMT). With MetS as the dependent variable, two logistic regressions including juveniles 18 years were performed. The potential predictor variables selected with the exception of age and gender by t test comparisons included IMT, ultrasensitive c-reactive protein (US-CRP), IL-6, malondialdehyde (MDA), oxidized LDL, leptin, adiponectin, uric acid (UA), aldosterone, cortisol, transaminases, fibrinogen. In both groups, uric acid and in adults only, leptin and adiponectin, turned out as the best predictor. Conclusion: Serum levels of UA are a significant predictor of unhealthy obesity in juveniles and adults. Obesity (2013) 21, E71-E77. doi:10.1002/oby.20061
Introduction Obesity is associated with reduced life expectancy largely because obese individuals are at increased risk of cardiovascular disease (CVD) (1,2). However, an intriguing subgroup of obese individuals,
referred to as having a metabolically healthy phenotype [Metabollically Healthy Obese (MHO)], remain resilient from developing CVD. Prevalence of MHO is surprisingly high. Primeau et al. reviewed 15 studies that report MHO prevalence ranging from 18 to 44%, depending on definitions used for obesity and metabolic
1 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria. Correspondence: Harald Mangge (
[email protected]) 2 Endocrine Laboratory, Department of Obstetrics and Gynecology, Medical University of Graz, Austria 3 General Practice for Internal Medicine, Bruck an der Mur, Austria 4 Child and Adolescent Psychiatry Division, Department of Psychiatry, University of Maryland, School of Medicine, Baltimore, Maryland, USA 5 Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA 6 Department of Pediatrics, Paracelsus Medical School Salzburg, Austria
Disclosures: All authors have read the journal’s policy on disclosure of potential conflicts of interest. The authors have no potential conflicts of interest to declare. Funding agencies: This work was funded by the ‘‘Zukunftsfond Steiermark’’ Project ‘‘STYJOBS-Extension’’. Furthermore, the Austrian Nano-Initiative co-financed this €rderung der Wissenschaftlichen work as part of the Nano-Health project (no. 0200), the sub-project NANO-PLAQUE being financed by the Austrian FWF (Fonds zur Fo Forschung, Project no. N212-NAN). Financial support of a technician and consumables associated with the set up of the STYJOBS EDECTA Cohort. Abbreviations: BMI, body mass index; CHE, cholinesterase; CI, Confidence interval; AST/GOT, Aspartat-Aminotransferase; ALT/GPT, Alanin-Aminotransferase; gammaGT, Gammaglutaryltransferase; CCA, Common carotid arteries; CT, Computed tomography; CRP, C-reactive protein; HDL, High dense lipoprotein; HOMA-IR, Homeostatic model assessment insulin resistance; IL-6, Interleukin-6; IMT, Intima media thickness; MetS, Metabolic syndrome; oxLDL, Oxidized low dense lipoprotein; SAT, Subcutaneous adipose tissue; US-CRP, Ultra sensitive c-reactive protein; UA, Uric acid; VAT, Visceral adipose tissue; WHR, Waist-to-Height Ratio. Received: 24 February 2012 and in revised form 24 February 2012 Accepted: 29 June 2012 Published online 3 October 2012. doi:10.1002/oby.20061
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Obesity | VOLUME 21 | NUMBER 1 | JANUARY 2013
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Uric Acid Essential for Metabolic Risk in Obesity Mangge et al.
health, as well as the different gender/ethnic groups studied (3). A recently published large Finnish cross sectional epidemiologic study (4) reported 9.2% of obese men and 16.4% obese women met criteria for MHO using Alberti et al. (5) criteria for Metabolic Syndrome (MetS). An Italian study which focused on insulin sensitivity identified 11% (men and women) as MHO phenotypes (6). Birth weight, ethnic background, age, and physical activity have been identified as factors that influence prevalence of MHO phenotype (3). In a 15year follow-up study, subjects with MHO phenotype did not show increased all cause mortality, cancer and CVD risks (6). We completed an additional, comprehensive assessment to further characterize the metabolic profile of these two groups, and investigate if any obesity related anthropometric or laboratory parameters reliably differentiate MHO from non-MHO individuals.
Methods Study participants are from the prospective, observational study STYJOBS/EDECTA (STYrian Juvenile Obesity Study/Early DEteCTion of Atherosclerosis; ClinicalTrials.gov Identifier NCT00482924), which investigates metabolic/cardiovascular parameters in obese individuals who were free of chronic health conditions except MetS. We included individuals aged between 8 and 60 years old (Tables 1 and 2). The inclusion criterion for the ow/ob youth ( 95th) percentile, and for ow/ob adults BMI > 25 < 29.9 kg m2 (obese > 30 kg m2). Juvenile controls had a BMI between 5th and 84.9th percentile; adult controls a BMI between 18.5 and 24.9, respectively. The analysis of normal weighted controls was included in the design of this study to provide a reference for the metabolically healthy overweight/obese. Participants were excluded if they received medications or hormone replacement therapy. Written consent was obtained for all adult participants, and parental consent was obtained for youth.
Procedures Standard anthropometric data (height, weight, waist-, hip-circumference, waist to hip-, waist to height-ratio) were obtained from each subject as described elsewhere (7). Waist-circumference was measured midway between the lower costal margin and the iliac crest; hip-circumference at the maximum circumference over the buttocks (7), and resting blood pressure in a sitting position in the right arm at the end of the physical examination.
then averaged for both body sides. Calibration and evaluation were done using computed tomography (CT) as the reference method (10).
Carotid ultrasound The ultrasound protocol involved scanning of the bulbous near common carotid arteries on both sides with a 12-to-5-MHz broad-band linear transducer on a HDI 5000 (ATL, Bothell, WA, USA) as described elsewhere (11-14).
Laboratory analysis Fasting blood samples were collected from 08:00 to 10:30 h. Interleukin-6 was analyzed by an electrochemiluminescence immunoassay (Roche Diagnostics). Ultrasensitive-CRP (US-CRP) was anaR C-reactive protein latex ultrasensitive lyzed with a Tina-quantV assay (Roche diagnostics). Leptin and total adiponectin were determined in plasma by ELISA from Biovendor Laboratory Medicine (Brno, Czech Republic). Cholesterol, HDL-cholesterol, and triglycerides were measured by enzymatic photometric methods, LDL cholesterol calculated by the Friedewald formula. Oxidized low dense lipoprotein (oxLDL) was measured by ELISA (Mercodia oxidized LDL Competitive ELISA, SE-754 50 Uppsala, Sweden). Intra- and inter-assay variation coefficients for all ELISAs in our study were below 10%. Plasma glucose was measured by the glucose hexokinase method. Malondialdehyde (MDA) was determined by high-performance liquid chromatography with spectrofluorimetric detection as described elsewhere (15); myeloperoxidase (MPO) by an automated chemiluminescent microparticle immunoassay (Architect MPO assay, Abbott Diagnostics, Abbott Park, IL) (16). Homeostatic model assessment—insulin resistance (HOMA-IR) was calculated using the formula by Mathews et al. (17). A cut off >2.5 was used for identification of insulin resistance. Alkaline phosphatase (AP), aspartate transaminase (AST/GOT), alanine transaminase (ALT/GPT), gamma-GT (gGT), cholinesterase (CHE), creatinine, and UA were measured on a Cobas 8000, fibrinogen with LIATEST reagents using a STAGO STA-R Evolution coagulation analyzer (Roche Diagnostics, Germany).
Statistics
For youth MetS was determined according to the updated criteria of Alberti et al. (8) and for adults according to Zimmet et al. (9); i.e., waist circumference 90th percentile (for youth); male 94 cm, female 80 cm (for adults); and two of the four criteria fulfilled: fasting glucose 100 mg dl1 (5.6 mmol l1); triglycerides 150 mg dl1 (1.7 mmol l1); HDL-Cholesterol < 40 mg dl1 (1.03 mmol l1), males; < 50 mg dl1 (1.29 mmol l1), females; blood pressure 130 systolic or 85 mmHg diastolic.
All statistical analyses were carried out using PASW Statistics 18.0 for Windows. Normal distribution of all clinical and biochemical measures was controlled by the Kolmogorov–Smirnov test. In cases of skewed distribution of variables logarithmic transformation was applied for significance calculation. Differences between groups were analyzed by unpaired t test. When more than two groups were compared, analyses of variance (ANOVA), with a three-stage factor [normal weighted controls, healthy-ow/ob (MHO), unhealthy-ow/ob(nonMHO)] was performed. Differences were calculated by Bonferroni post-hoc test. A stepwise logistic regression analysis (with forward and backward selection, respectively) was applied to investigate association of MetS as dependent variable with laboratory measures as independent variables. Additionally, Receiver-Operator-Curve (ROC) analysis was performed to confirm the results of the binary logistic regression analysis.
R) Extended anthropometry (LipometerV
Ethics
The subcutaneous adipose tissue (SAT) distribution was analyzed by a patented optical device (EU Pat.Nr. 0516251) on 15 anatomically welldefined body sites (10) distributed from the neck to calf bilaterally, and
STYJOBS/EDECTA was approved by the ethical committee of the Medical University of Graz, and conducted in compliance of human studies with the Helsinki Declaration of 1975 as revised in 1996.
Determination of metabolic syndrome
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Original Article
Obesity
EPIDEMIOLOGY/GENETICS
TABLE 1 Baseline characteristics, anthropometric and laboratory data not included in the metabolic syndrome algorithm of normal weighted, metabolically healthy (MHO) overweight/obese (i.e., no lab criterium of MS definition fulfilled) and ‘‘unhealthy’’ (nonMHO) overweight/obese (i.e. 3 criteria IDF criteria of MS fulfilled) subjects aged 18 years
Baseline characteristics, anthropometry Age (years) Females/males Birthweight (g) BMI (kg m2) BMI mother (kg m2) BMI father (kg m2) Lipometry body fat (%) Lipometry SAT thickness neck (mm) Lipometry visceral adipose tissue (kg) Carotid IMT (cm) Organised physical activity Nonorganized physical activity Laboratory parameter Homa Index US-CRP (mg l1) IL-6 (pg ml1) LDL-cholesterol (mg dl1) Oxidized LDL (mmol l1) Malondialdehyde (lmol l1) Myeloperoxidase (ng ml1) Leptin (ng ml1) Adiponectin (lg ml1) Uric acid (mg dl1) Creatinin (mg dl1) Aldosteron (ng l1) Renin (ng l1) Cortisol (ng ml1) AST/GOT (U l1) ALT/GPT (U l1) gammaGT (U l1) Cholinesterase (U l1) Alcaline phosphatase (U l1) Fibrinogen (mg dl1) ETP (extinction)
Normal weighted controls
‘‘Healthy’’ overweight/obese MHO phenotype
‘‘Unhealthy’’ overweight/obese nonMHO phenotype
n ¼ 56
n ¼ 48
n ¼ 108
14.0 6 3.0 29/27 3252 6 437 17.9 6 2.6 23.5 6 3.6 26.4 6 2.8 18.8 6 9.3 2.0 (1.3–4.5) 1.5 (1.0–1.9) 0.05 (0.04–0.06) 50% 65.4%
11.7 6 3.3 30/18 3426 6 44 28.0 6 5.0*** 25.7 (22.3–33.9)*** 26.9 (24.6–32.1)* 37.3 6 9.7*** 11.5 (7.8–16.6)*** 3.6 (2.9–5.3)*** 0.07 (0.06–0.07)*** 28.2%* 53.2%
1.2 0.4 1.9 99.0
2.1 (1.2–3.4) 1.7 (0.6–3.4)*** 3.0 (1.8–5.4) 103 (89–123) 41.3 6 15.0* 0.4 (0.3–0.5) 16.3 (12–29) 33.1 6 16.5*** 11.7 6 5.9 5.1 6 1.1* 0.6 (0.55–0.72) 80.6 (55–120) 32.7 6 13.2 73.4 (46–103)*** 29 (25–34) 21 (17–32) 14 (11–19) 9996 (8985–11191)*** 247 (112–305)** 334 6 88.6 369 6 39
(0.7–2.3) (0.2–0.5) (1.5–2.5) (84–119) 34.4 6 9.4 0.4 (0.3–0.6) 13.7 (10–19) 1.8 (0.7–8.2) 14.0 6 6.8 4.5 6 1.0 0.7 (0.6–0.8) 76.2 (65–114) 35.2 6 30.1 181.1 6 173.3 26 (22–35) 17 (12–24) 11 (9–15) 8102 6 1728 151.2 6 91.7 301.4 6 101.6 327.2 6 7.4
12.8 6 2.7 47/61 3479.2 6 582 31.4 (28.8–36.5)***þþþ 28.8 6 7.1*** 29.1 6 4.7*** 38.8 6 10.4*** 16 (12.4–19.6)***þþþ 5.9 (4.8–7.6)***þþþ 0.08 (0.07–0.08)***þ 26.6% 46.6% 4.5 (2.5–8.2)***þþ 2.7 (1.1–5.2)*** 3.8 (2.4–5.3)*** 104 (89–116) 46.3 6 16.1*** 0.6 (0.4–0.8)*þþ 17 (13–33) 37.7 6 16.0*** 9.5 6 5.0*** 6.1 6 1.5***þþþ 0.7 (0.6–0.8) 78.9 (48.2–129.4) 25.3 6 8.1 70.0 (49.0–124.6)*** 29 (24–35) 25 (20–36)** 19 (16–25)***þþ 10172 (8948–11482)*** 210 (140–299)*** 370.6 6 66.5 386.4 6 54.6
If normally distributed, results are expressed as mean 6 SD, otherwise as median, 25th and 75th percentile. Differences between groups are analyzed by one-way ANOVA including Bonferroni post-hoc comparison. The symbols (*) are indicators of significance between controls, MHO and nonMHO subjects; (þ) indicate the significance between subjects with MHO and nonMHO phenotypes. Significance levels are given as *P < 0.05, **P < 0.01, and ***P < 0.001, respectively.IDF, international diabetes federation; BMI, body mass index; carotid IMT, SAT, subcutaneous adipose tissue; carotid intima-media thickness; US-CRP, ultra-sensitive C-reactive protein; IL-6, interleukin-6; ETP, endogenous thrombin potential.
Results We analyzed 474 overweight/obese (ow/ob) and 235 normalweight (nw) controls. Participants were categorized as juvenile
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(18). From 299 juvenile ow/ob subjects, 108 (36%), and from 175 adult ow/ob subjects, 79 (45%) had positive criteria for MetS. In both groups, more males had MetS (Tables 1 and 2).
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Uric Acid Essential for Metabolic Risk in Obesity Mangge et al.
TABLE 2 Baseline characteristics, anthropometric and laboratory data not included in the metabolic syndrome algorithm of normal weighted, metabolically healthy (MHO) overweight/obese (i.e., no lab criterium of MS definition fulfilled) and ‘‘unhealthy’’ (nonMHO) overweight/obese (i.e., 3 criteria IDF criteria of MS fulfilled) subjects aged > 18 years
Baseline characteristics, anthropometry Age, age range (years) Females/males Birthweight (g) BMI (kg m2) BMI mother (kg m2) BMI father (kg m2) Lipometry body fat (%) Lipometry SAT thickness neck (mm) Lipometry visceral adipose tissue (kg) Carotid IMT (cm) Organised physical activity Nonorganized physical activity Laboratory parameter Homa index US-CRP (mg l1) IL-6 (pg ml1) LDL-cholesterol (mg dl1) Oxidized LDL (mmol l1) Malondialdehyde (lmol l1) Myeloperoxidase (ng ml1) Leptin (ng ml1) Adiponectin (lg ml1) Uric acid (mg dl1) Creatinin (mg dl1) Aldosteron (ng l1) Renin (ng l1) Cortisol (ng ml1) AST/GOT (U l1) ALT/GPT (U l1) gammaGT (U l1) Cholinesterase (U l1) Alcaline phosphatase (U l1) Fibrinogen (mg dl1) ETP (extinction)
Normal weighted controls
‘‘Healthy’’ overweight/obese MHO phenotype
‘‘Unhealthy’’ overweight/obese nonMHO phenotype
n ¼ 176
n ¼ 31
n ¼ 79
32.5 6 10.5 (18.1–60) 125/51 3352 6 520 21.6 6 1.9 24.9 6 3.9 26.3 6 3.4 19.7 6 7.2 3.3 (2.2–5.1) 2.2 (1.7–2.7) 0.06 (0.05–0.07) 57.3% 48.3%
35.7 6 12.9 (18.1–60) 22/9 3368 6 384 27.8 (26.7–33.4)*** 26.0 6 5.6 27.0 6 3.5 27.5 6 8.1*** 7.3 (5.2–11.7)*** 4.3 (3.3–5.5)*** 0.06 (0.06–0.07) 48.3% 51.6%
37.7 6 10.5 (18.1–60) 34/45 3418 6 428 33.6 (29.9–39.4)***þþþ 26.3 (24–30)*** 29.1 6 5.4*** 24.5 6 5.3*** 9.5 (7.3–12.2)***þþ 6.2 (5.2–7.3)***þþþ 0.07 (0.07–0.08)***þþ 26.6%* 54.4%
1.3 (0.7–1.9) 0.8 (0.5–1.9) 1.5 (1.5–2.2) 96.0 (80–125) 44.1 6 16.9 0.5 (0.3–0.5) 11.5 (9–16) 8.4 6 7.9 12.0 6 5.6 4.5 6 1.1 0.84 (0.76–0.94) 88.3 (53–149) 21.4 6 30.9 181.0 (125–293) 25 (21–29) 19 (15–24) 17 (13–22) 7248 6 1412 57 6 17 282 6 60 383 6 54
1.8 (0.9–2.9) 2.6 (0.9–4.1)*** 2.2 (1.5–3.3) 121 (95–147)§§ 53.0 6 17.7 0.4 (0.4–0.5) 13.2 (9.7–20) 26.2 6 16.7*** 11.1 6 3.2 5.2 6 1.2*** 0.82 (0.70–0.92) 80.4 (65–116) 15.6 6 11.0 165.4 (126–270) 26 (22–31) 25 (19–34)** 18 (13–25) 7737 (6926–8769) 61 6 16 338.8 6 63.8** 418.5 6 53.9*
3.4 (2.0–5.0)***þþþ 3.5 (1.6–7.4)*** 2.7 (1.6–4.5)*** 125 (96–142) 69.0 6 25.1***þþþ 0.4 (0.4–0.6) 14 (10–26)** 29.2 6 17.4*** 7.3 6 3.2***þþ 6.2 6 1.3***þþþ 0.9 (0.77–1.02)*þ 72.7 (51.8–95.3)* 11.1 (6.7–21.5) 158.6 (96.4–220.5)** 30 (25–35)* 35 (24–53)***þþ 33 (25–57)***þ 9651 (8422–10747)***þþþ 69.6 6 18 353.7 6 81.6*** 430.1 6 53.7***
If normally distributed, results are expressed as mean 6 SD, otherwise as median, 25th and 75th percentile. Differences between groups are analysed by one-way ANOVA including Bonferroni post-hoc comparison. The symbols (*) are indicators of significance between controls, MHO and nonMHO subjects; (þ) indicate the significance between subjects with MHO and nonMHO phenotypes. Significance levels are given as *P < 0.05, **P < 0.01, and ***P < 0.001, respectively.IDF, international diabetes federation; BMI, body mass index; carotid IMT, SAT, subcutaneous adipose tissue; carotid intima-media thickness; US-CRP, ultra-sensitive C-reactive protein; IL-6, interleukin-6; ETP, endogenous thrombin potential.
Overweight/obese subjects were divided into a healthy (MHO) and an unhealthy ow/ob (nonMHO) subgroup. MHOs had a fasting glucose
