Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

Validation of the FNIH sarcopenia criteria and SOF frailty index as predictors of long-term mortality in ambulatory older men.

OBJECTIVE: we aimed to evaluate the Foundation for the National Institutes of Health (FNIH) criteria for weakness and low muscle mass and the Study of Osteoporotic Fractures (SOF) frailty index for prediction of long-term, all-cause mortality. DESIGN: community-based cohort study. SETTING: semi-rural community of Merelbeke (Belgium). SUBJECTS: ambulatory men aged 74 and more (n = 191). METHODS: weakness was defined on previously established criteria as low grip strength (<26 kg) or low grip strength-to-body mass index (BMI) ratio (<1.00). Low muscle mass (dual-energy x-ray absorptiometry) was categorised as low appendicular lean mass (ALM; predefined <19.75 kg) or low ALM-to-BMI ratio (predefined <0.789). Frailty status was assessed using the components of weight loss, inability to rise from a chair and poor energy (SOF index). Survival time was calculated as the number of months from assessment in 2000 until death or up to 15 years of follow-up. RESULTS: mean age of the participants was 78.4 ± 3.5 years. Combined weakness and low muscle mass was present in 3-8% of men, depending on the criteria applied. Pre-frailty and frailty were present in 30 and 7% of men, respectively. After 15 years of follow-up, 165 men (86%) died. Both the presence of combined weakness and low ALM-to-BMI ratio (age-adjusted HR = 2.50, 95% CI = 1.30-4.79) and the presence of SOF frailty (age-adjusted HR = 2.64, 95% CI = 1.44-4.86) were associated with mortality. CONCLUSIONS: our findings confirm the predictive value for mortality of the non-distribution-based FNIH criteria and SOF index in older community-dwelling Belgian men.

Glycated nail proteins: a new approach for detecting diabetes in developing countries.

OBJECTIVE: To assess glycation of nail proteins as a tool in the diagnosis of diabetes. METHODS: Glycation of nail proteins was assessed using a modified photometric nitroblue tetrazolium-based assay, which provides information about average glucose values of the last 6-9 months. Analysis is possible on 10 mg of nail clippings with a within-run coefficient of variation (CV) of 11%. The analyte is extremely stable. The reference range for glycated nail protein (0.55-3.60 µmol/g nail) increases upon ageing. RESULTS: In diabetics (n = 112), values for glycated nail protein are significantly higher (median: 4.07 µmol/g nail, IQR: 2.37-6.89 µmol/g nail, P < 0.0001) than in non-diabetics (n = 116). ROC analysis shows an AUC of 0.848 (specificity 93.1%; sensitivity 68.9%). CONCLUSION: This affordable method is a simple alternative for diagnosing diabetes in remote areas as the pre-analytical phase (including all processes from the time a laboratory request is made by a physician until the sample is ready for testing) is extremely robust.

Physical function measurements predict mortality in ambulatory older men.

BACKGROUND: To assess and compare the predictive value of physical function measurements (PFMs) for all-cause mortality in older men and to evaluate the Timed Up and Go test (TUG) as a predictor in subjects with underlying comorbidity. DESIGN: Observational study of a population-based sample of 352 ambulatory older men aged 71-86 at study baseline. The Rapid disability rating scale-2, 36-Item short form health survey, Grip strength, Five times sit-to-stand test, Standing balance, and TUG were determined at baseline. Associations with all-cause mortality were assessed using Cox proportional hazard analyses. Age, Body mass index (BMI), smoking status, education, physical activity and cognitive status were included as confounders. Follow-up exceeded 15 years. Comorbidity status was categorized into cardiovascular disease, chronic obstructive pulmonary disease (COPD) and diabetes mellitus. RESULTS: All examined PFMs were associated with all-cause mortality. TUG was the best predictor (adjusted HR per SD increase = 1·58, 95% CI = 1·40-1·79, P < 0·001) for global mortality and continued to be predictive in subjects with cardiovascular disease (adjusted HR per SD increase = 1·80, 95% CI = 1·40-2·33, P < 0·001). CONCLUSIONS: The assessment of physical functioning is important in the evaluation of older persons. We encourage the use of the TUG as a reliable, quick and feasible screening tool in clinical settings.

Sex hormone-binding globulin at the crossroad of body composition, somatotropic axis and insulin/glucose homeostasis in young healthy men.

OBJECTIVES: Sex hormone-binding globulin (SHBG) modulates the bioavailability of sex steroids at tissue level. Genetic, hormonal and lifestyle-related factors determine the SHBG levels, and low SHBG levels are a known risk factor for the development of the metabolic syndrome, diabetes and cardiovascular diseases. We investigated to what extent different determinants contribute to the variation in SHBG levels in healthy young men. DESIGN AND PATIENTS: Healthy male siblings (n = 677) aged 25-45 year were recruited in a cross-sectional, population-based study. MEASUREMENTS: Lean and fat mass were measured using dual-energy X-ray absorptiometry (DXA), and immunoassays were used to determine the serum hormonal levels. Additional information about smoking and physical activity was obtained using questionnaires. Carriers of two SHBG polymorphisms, the Asp327Asn polymorphism and the (TAAAA)(n) repeat polymorphism, were identified. RESULTS: Weight, BMI, whole body fat mass and truncal fat mass were negatively associated with SHBG levels. Body composition characteristics did not differ between SHBG genotype groups, indicating that body composition controls SHBG levels rather than the other way around. The associations may be mediated by adipokines because leptin and adiponectin were, respectively, inversely and positively associated with SHBG levels. Insulin and glucose were negatively associated with SHBG levels, as well as IGF-1 and IGF-BP3, while no associations were found with free thyroid hormone status. CONCLUSIONS: In conclusion, we found that fat mass, insulin and IGF-1 levels are important negative determinants of SHBG levels in young healthy men. The association with fat mass could be mediated by the effects of adiponectin and/or leptin on SHBG synthesis.

Guanidino compounds after creatine supplementation in renal failure patients and their relation to inflammatory status.

BACKGROUND: Specific guanidino compounds have been described as uraemic toxins and their concentrations are increased in renal failure due to dimished glomerular filtration, whereas the guanidino compound creatine is used as a performance-enhancing substance in athletes. The present study investigates the effects of creatine supplementation on plasma guanidino compounds in a chronic haemodialysis population. METHODS: Twenty male haemodialysis patients were included in a placebo-controlled cross-over trial. Patients were treated with creatine (2 g/day) or placebo during two treatment periods of 4 weeks, separated by a washout of 4 weeks. Plasma guanidino compounds and routine biochemical parameters were determined, as well as the prognostic inflammatory and nutritional index (PINI). RESULTS: Upon creatine supplementation, guanidinoacetate concentrations decreased by 15%, due to inhibition of creatine synthesis. Concentrations of alpha-keto-delta-guanidinovaleric acid increased three-fold and argininic acid concentrations doubled. Guanidinosuccinate concentrations did not change, but correlated inversely with CRP (r = -0.736; P = 0.001), PINI-score (r = -0.716; P = 0.002) and correlated positively with plasma urea concentration (r = 0.54; P = 0.02). CONCLUSIONS: Creatine supplementation in haemodialysis patients significantly altered the concentration of specific guanidino compounds. Guanidinosuccinate correlated positively with plasma urea and negatively with inflammation markers.

Vitamin D binding protein and the need for vitamin D in hemodialysis patients.

OBJECTIVE: Vitamin D binding protein (DBP) is a polymorphic serum protein with a predominant role in a spectrum of biological activities. Chronic renal failure is characterized by deficient vitamin D metabolism. The present study investigates the impact of DBP polymorphism on the need for vitamin D in hemodialysis patients. DESIGN: This was a retrospective study. SETTING: This study included hemodialysis patients from the Renal Unit of Ghent University Hospital (Ghent, Belgium) and the Algemeen Stedelijk Ziekenhuis Geraardsbergen Hospital (Geraardsbergen, Belgium). METHODS: One hundred and ninety-one hemodialysis patients and 211 healthy subjects were recruited from the hemodialysis database. The DBP phenotypes were determined by polyacrylamide gel electrophoresis. Serum DBP, parathyroid hormone, 25-hydroxyvitamin D(3), 1,25-dihydroxyvitamin D(3), calcium, albumin, and phosphate were measured. Information regarding the intake of vitamin D analogues was collected. RESULTS: The phenotypic distributions of DBP were in agreement with Hardy-Weinberg equilibrium. Comparing allele frequencies of the two groups, there was an increased proportion of the DBP 2 allele in hemodialysis patients (P < .05). The median serum DBP concentration was lowest in the DBP 2-2 group. The need for oral vitamin D differed significantly (P < .01) between DBP phenotypes, and was greatest in DBP 2-2. CONCLUSIONS: The present study demonstrates an altered DBP allele frequency in hemodialysis patients, compared with the general population. More importantly, vitamin D intake differs depending on the DBP polymorphism, and is greatest for end-stage renal disease patients with a DBP 2-2 phenotype. Therefore, vitamin D treatment deserves more careful monitoring among DBP 2-2 patients with end-stage renal disease.

Vitamin D binding protein, bone status and body composition in community-dwelling elderly men.

The vitamin D binding protein (DBP) is the major carrier protein for vitamin D metabolites in plasma. Polymorphisms in DBP have been described to be associated with an increased bone fracture risk and diabetes. The present study investigates the influence of both phenotypic and (TAAA)(n)-Alu repeat DBP-polymorphism and DBP-concentration on bone mineral density, body composition, bone turnover- and metabolic markers in a cohort of ambulatory elderly men. We included 211 men (>70 years) in this study. Bone mineral density (BMD) was determined by dual energy X-ray absorptiometry. Bone turnover was assessed by measurement of serum osteocalcin, serum and urinary C-terminal telopeptides of type I collagen and urinary deoxypyridinoline, together with 25(OH)-vitamin D and 1,25(OH)(2)-vitamin D concentrations. DBP-phenotypes were determined electrophoretically and the (TAAA)(n)-Alu repeat polymorphism was determined by polymerase chain reaction. Body composition was estimated using bioelectrical impedance analysis, together with handgrip and arm strength, fasting serum glucose and leptin concentrations. No differences in BMD or bone turnover markers among DBP-phenotypes or (TAAA)(n)-genotypes were observed in this study. Serum 25(OH)-vitamin D was comparable among DBP-variants and did not relate to DBP-concentrations, whereas 1,25(OH)(2)-vitamin D was different among DBP-phenotypes and was correlated positively with DBP-concentrations. DBP-concentrations related positively to body mass index, fat mass, leptin and glucose concentration. The correlation with leptin remained significant after correction for fat mass. Fasting glucose concentrations were different among DBP-phenotypes, whereas no difference was observed between (TAAA)(n)-genotypes. In conclusion, serum 1,25(OH)(2)-vitamin D concentrations are codetermined by DBP-phenotypes and DBP-concentrations. No major effect of DBP-polymorphism was demonstrated on BMD, bone turnover markers or body composition.

Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism.

The vitamin D binding protein (DBP) is the major plasma carrier protein of vitamin D and its metabolites. Unlike other hydrophobic hormone-binding systems, it circulates in a considerably higher titer compared to its ligands. Apart from its specific sterol binding capacity, DBP exerts several other important biological functions such as actin scavenging, fatty acid transport, macrophage activation and chemotaxis. The DBP-gene is a member of a multigene cluster that includes albumin, alpha-fetoprotein, and alpha-albumin/afamin. All four genes are expressed predominantly in the liver with overlapping developmental profiles. DBP is a highly polymorphic serum protein with three common alleles (Gc1F, Gc1S and Gc2) and more than 120 rare variants. The presence of unique alleles is a useful tool for anthropological studies to discriminate and to reveal ancestral links between populations. Many studies have discussed the link between DBP-phenotypes and susceptibility or resistance to osteoporosis, Graves' disease, Hashimoto's thyroiditis, diabetes, COPD, AIDS, multiple sclerosis, sarcoidosis and rheumatic fever. This article reviews the general characteristics, functions and clinical aspects of DBP.

Serum vitamin C concentration is influenced by haptoglobin polymorphism and iron status in Chinese.

BACKGROUND: Vitamin C is a powerful antioxidant (free radical scavenger). Apart from the diet, other factors regulating its catabolism may affect its serum concentration. Haptoglobin (Hp) is a plasma protein participating in iron metabolism. It shows a genetic polymorphism which shows marked geographical differences. We investigated the relationship between vitamin C, iron status and haptoglobin polymorphism in Chinese men and women. METHODS: Iron status markers were compared according to Hp phenotypes determined by chemiluminescence detection in 110 healthy Chinese subjects. The concentration of haptoglobin was determined using an immunoturbidimetric method. Serum vitamin C was tested by a 2,4-dinitrophenylhydrazine based method. RESULTS: In Chinese, the haptoglobin phenotype distribution was 10.0% Hp 1-1, 33.6% Hp 2-1, and 56.4% Hp 2-2. In the study group, serum vitamin C concentration was associated with haptoglobin type, showing lowest values in serum from Hp 2-2 subjects in males (p=0.028, ANOVA). In contrast to Hp phenotype, Hp concentration did not affect vitamin C concentration. Hp 2-2 shows higher haptoglobin (p=0.002 (ANOVA)) than individuals with the other types. Furthermore, vitamin C was influenced by (log)ferritin levels. In Chinese, vitamin C is influenced by haptoglobin polymorphism and iron status. CONCLUSION: The present findings support the role of non-nutritional factors in vitamin C status.

Effect of dietary creatine on skeletal muscle myosin heavy chain isoform expression in an animal model of uremia.

BACKGROUND: Chronic renal failure is accompanied with muscle dysfunction and myopathy, characterized by muscle weakness and increased fatigue. Myosin heavy chain (MHC) is the principal structural protein that controls the intrinsic contractile properties of striated muscle. Creatine is widely used as an ergogenic nutritional supplement in sportsmen. This study investigates the effect of creatine supplementation on MHC expression in the setting of uremic myopathy. METHODS: Male Wistar rats were either sham operated or subtotally nephrectomized and received a control diet or creatine (2% w/w)-supplemented diet. After 4 weeks of treatment, serum creatinine, creatine, urea and creatinine clearances were determined. MHC isoforms were determined electrophoretically in the extensor digitorum longus and soleus muscles. RESULTS: Creatinine clearances were lower in nephrectomized animals, but similar in creatine-supplemented and control diet animals. Nephrectomized animals had significantly higher MHC IIb and lower MHC IIx isoform expression in the extensor digitorum longus muscle compared to sham-operated animals. In the soleus muscle, MHC IIb expression was increased in nephrectomized animals. Creatine supplementation reversed the MHC transitions observed in uremia in the soleus muscle, but not in the extensor digitorum longus muscle. CONCLUSION: We observed altered expression of MHC isoforms in uremia. In uremic animals, fast MHC IIb isoforms were increased, whereas MHC I and IIx isoforms predominate in control animals. Dietary creatine supplementation reversed the altered MHC expression during uremia in slow-twitch, but not in fast-twitch muscles.

A multicomponent approach to identify predictors of hospital outcomes in older in-patients: a multicentre, observational study.

BACKGROUND: The identification of older patients at risk of poor hospital outcomes (e.g. longer hospital stay, in-hospital mortality, and institutionalisation) is important to provide an effective healthcare service. OBJECTIVE: To identify factors related to older patients' clinical, nutritional, functional and socio-demographic profiles at admission to an acute care ward that can predict poor hospital outcomes. DESIGN AND SETTING: The CRiteria to assess appropriate Medication use among Elderly complex patients project was a multicentre, observational study performed in geriatric and internal medicine acute care wards of seven Italian hospitals. SUBJECTS: One thousand one hundred twenty-three consecutively admitted patients aged 65 years or older. METHODS: Hospital outcomes were length of stay, in-hospital mortality, and institutionalisation. RESULTS: Mean age of participants was 81 years, 56% were women. Median length of stay was 10 (7-14) days, 41 patients died during hospital stay and 37 were newly institutionalised. Number of drugs before admission, metastasized cancer, renal failure or dialysis, infection, falls at home during the last year, pain, and walking speed were independent predictors of LoS. Total dependency in activities of daily living and inability to perform grip strength test were independent predictors of in-hospital mortality. Malnutrition and total dependency in activities of daily living were independent predictors of institutionalisation. CONCLUSIONS: Our results confirm that not only diseases, but also multifaceted aspects of ageing such as physical function and malnutrition are strong predictors of hospital outcomes and suggest that these variables should be systematically recorded.

Triiodothyronine and free thyroxine levels are differentially associated with metabolic profile and adiposity-related cardiovascular risk markers in euthyroid middle-aged subjects.

BACKGROUND: We have previously shown that in healthy young men, a less favorable body composition is associated with higher free triiodothyronine (fT3) levels within the euthyroid range. Besides, a higher free-triiodothyronine-to-free-thyroxin (fT3-to-fT4) ratio has been related to a less favorable metabolic phenotype and more placental growth in pregnant women. In the present study, we therefore investigated whether serum thyrotropin (TSH), thyroid hormone levels, and the fT3-to-fT4 ratio are associated with metabolic and adiposity-related cardiovascular risk markers in a healthy population of middle-aged euthyroid men and women. METHODS: Thyroid parameters were measured in 2524 generally healthy subjects from the Asklepios Study (35-55 years, mean age 46 years). Analyses were restricted to 2315 subjects (1138 women and 1177 men), not using thyroid medication, not having anti-TPO levels above clinical cutoff values or TSH levels outside the reference range (0.27-4.2 mU/L). Twenty-seven percent of the women and 47.5% of the men were overweight, while 13% of women and 17% of men were obese. Twenty percent of the subjects were active smokers. Serum thyroid function parameters were determined by electrochemiluminescence. RESULTS: fT3 and the fT3-to-fT4 ratio were positively related to body mass index (BMI), waist circumference, and components of metabolic syndrome, that is, triglycerides, systolic and diastolic blood pressure, and fasting plasma glucose, and negatively with HDL-cholesterol levels, whereas fT4 was negatively associated with BMI, waist circumference, and triglycerides (p<0.001). TSH related positively with total cholesterol levels (p<0.01), triglycerides, and systolic and diastolic blood pressure (p<0.001). The fT3-to-fT4 ratio was further positively associated with the adiposity-related inflammation markers interleukin-6 and high-sensitivity C-reactive protein and to pulse wave velocity. All associations were adjusted for sex, age, height, and smoking, and most associations persisted after additional adjustment for weight or waist circumference. CONCLUSION: In healthy euthyroid middle-aged men and women, higher fT3 levels, lower fT4 levels, and thus a higher fT3-to-fT4 ratio are consistently associated with various markers of unfavorable metabolic profile and cardiovascular risk.

Functional changes during hospital stay in older patients admitted to an acute care ward: a multicenter observational study.

OBJECTIVES: Changes in physical performance during hospital stay have rarely been evaluated. In this study, we examined functional changes during hospital stay by assessing both physical performance and activities of daily living. Additionally, we investigated characteristics of older patients associated with meaningful in-hospital improvement in physical performance. METHODS: The CRiteria to assess appropriate Medication use among Elderly complex patients project recruited 1123 patients aged ≥65 years, consecutively admitted to geriatric or internal medicine acute care wards of seven Italian hospitals. We analyzed data from 639 participating participants with a Mini Mental State Examination score ≥18/30. Physical performance was assessed by walking speed and grip strength, and functional status by activities of daily living at hospital admission and at discharge. Meaningful improvement was defined as a measured change of at least 1 standard deviation. Multivariable logistic regression models predicting meaningful improvement, included age, gender, type of admission (through emergency room or elective), and physical performance at admission. RESULTS: Mean age of the study participants was 79 years (range 65-98), 52% were female. Overall, mean walking speed and grip strength performance improved during hospital stay (walking speed improvement: 0.04±0.20 m/s, p<0.001; grip strength improvement: 0.43±5.66 kg, p = 0.001), no significant change was observed in activities of daily living. Patients with poor physical performance at admission had higher odds for in-hospital improvement. CONCLUSION: Overall, physical performance measurements show an improvement during hospital stay. The margin for meaningful functional improvement is larger in patients with poor physical function at admission. Nevertheless, most of these patients continue to have poor performance at discharge.

Thyroid hormone levels within reference range are associated with heart rate, cardiac structure, and function in middle-aged men and women.

BACKGROUND: Triiodothyronine (T3) has many effects on the heart, and marked changes in cardiac function and structure occur in patients with (subclinical) thyroid disease. We investigated whether between-subject variation in thyroid hormone levels within the euthyroid range is also associated with heart rate and echocardiographic heart function and structure. METHODS: Subjects were selected from the Asklepios study (n=2524), a population-representative random sample of patients aged between 35 and 55 years, free from overt cardiovascular disease at baseline. Analyses were restricted to 2078 subjects (1013 women and 1065 men), not using antihypertensive or thyroid medication nor having antithyroperoxidase antibody levels above clinical cut-off or thyrotropin (TSH) levels outside the reference range. All subjects were phenotyped in-depth and underwent comprehensive echocardiography, including diastolic evaluation. Thyroid function parameters were determined by automated electrochemiluminescence. RESULTS: Heart rate was robustly positively associated with (quartiles of) free T3 (FT3) and T3, both in subjects with TSH levels within reference (0.27-4.2 µU/L) and in narrow TSH range (0.5-2.5 µU/L; p<0.0001). FT3 and T3 were negatively associated with left ventricular (LV) end-diastolic volume but positively associated with relative wall thickness. Total T3 (TT3) was associated with enhanced ventricular contraction (as assessed by tissue Doppler imaging). Free thyroxine, FT3, and TT3 were positively associated with late ventricular filling, and TT3 was associated with early ventricular filling. CONCLUSION: We have demonstrated a strong positive association between thyroid hormone levels within the euthyroid range and heart rate, and more subtle effects on cardiac function and structure. More specifically, we suggest a smaller LV cavity size (with increased relative wall thickness), an enhanced atrial and ventricular contraction, and LV relaxation with higher circulating thyroid hormones. These results illustrate that variation in thyroid hormone levels, even within the reference range, exerts effects on the heart.

Associations between single nucleotide polymorphisms in thyroid hormone transporter genes (MCT8, MCT10 and OATP1C1) and circulating thyroid hormones.

BACKGROUND: Thyroid hormone (TH) action takes place intracellularly; therefore, transport across the plasma membrane by specific TH transporters, such as MCT8, MCT10 and OATP1C1, is necessary. Several single nucleotide polymorphisms (SNPs) in these genes were reported to be associated with TH concentrations; however, results have been inconsistent. METHODS: Six SNPs in TH transporter genes (rs5937843-G/T and rs6647476-T/C in MCT8, rs14399-C/A in MCT10, rs10444412-C/T, rs10770704-C/T and rs36010656-C/A in OATP1C1) were genotyped in 2 cohorts; one consisting of 2416 men and women aged 35-55 yrs (Asklepios), and the other of 941 men aged 25-45 yrs (Siblos), using KASPar technology. TSH, FT3, FT4 and total T3 were determined by immuno-electrochemiluminescence in both cohorts; in the second cohort additional determination of total T4 by electrochemiluminescence and of reverse T3 (rT3) and thyroid binding globulin (TBG) by radioimmunoassays was performed. RESULTS: The first SNP in MCT8 (rs5937843-G/T) was inversely associated with FT4 concentrations in men but not in women. In Siblos, this SNP showed also negative associations with TT4 and rT3; in men from Asklepios a trend for positive association with TSH was observed. The second SNP in MCT8 (rs6647476-T/C) was negatively associated with FT3 levels in men from the Siblos and the Asklepios cohort. In addition, an inverse association with TT3 levels in men from the Siblos was observed. Rs36010656 (C/A) in OATP1C1 was not in Hardy-Weinberg equilibrium and therefore excluded from further analyses. The other 2 SNPs in OATP1C1 (rs10444412-C/T and rs10770704-C/T) and the SNP in MCT10 (rs14399-C/A) were not related to TH levels in either cohort. CONCLUSION: Two SNPs in MCT8 were related to circulating thyroid hormone levels in men but not in women: the rs5937843 polymorphism (G/T) was inversely associated with FT4 levels and the rs6647476 (T/C) polymorphism related negatively to circulating FT3.

Sex steroid-induced changes in circulating monocyte chemoattractant protein-1 levels may contribute to metabolic dysfunction in obese men.

CONTEXT: Low testosterone accompanied by elevated estradiol associates with the development of metabolic dysfunction in men. OBJECTIVE: The aim of the study was to explore the hypothesis that alterations in sex steroid levels induce metabolic dysfunction through adipokines. DESIGN: Circulating levels of sex steroids and 28 adipokines were determined in a cross-sectional study of morbidly obese men and aged-matched controls, as well as in a randomized clinical trial with healthy young men in which obesity-related alterations in sex steroid levels were mimicked by treatment with an aromatase inhibitor plus estradiol patches. RESULTS: Morbidly obese men had lower testosterone levels than normal-weight controls. Estradiol levels were increased in morbidly obese men (without DM2) as compared to normal-weight controls. Circulating levels of multiple proinflammatory cytokines, including IL-1Ra, IL-5, IL-6, IL-10, leptin, monocyte chemoattractant protein 1 (MCP1), and macrophage inflammatory protein 1α, positively associated with estradiol and negatively with testosterone. The associations with estradiol, but not with testosterone, remained significant after adjusting for adipocyte cell size. In a separate clinical trial, the direct adverse effects of lowering testosterone and raising estradiol on MCP1 were substantiated in vivo. CONCLUSIONS: Initial alterations in sex steroid levels may contribute to metabolic dysfunction through adverse effects on adipokine levels in obese men. The direct adverse effects on MCP1, a chemokine highly linked to the development of metabolic dysfunction, were substantiated in a trial mimicking obesity-related alterations of sex steroid levels in healthy young males.

Combined gene and protein expression of hormone-sensitive lipase and adipose triglyceride lipase, mitochondrial content, and adipocyte size in subcutaneous and visceral adipose tissue of morbidly obese men.

AIMS: Lipotoxicity in obesity might be a failure of adipocytes to respond sufficiently adequate to persistent energy surplus. To evaluate the role of lipolytic enzymes or mitochondria in lipotoxicity, we studied expression levels of genes and proteins involved in lipolysis and mitochondrial DNA (mtDNA) content. METHODS: As differences in lipid metabolism between men and women are extremely complex, we recruited only men (lean and morbidly obese) and collected subcutaneous and visceral adipose tissue during abdominal surgery for real-time PCR gene expression, protein expression, and microscopic study. RESULTS: Although mRNA levels of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) were increased in visceral adipose tissue of morbidly obese men, this was not paralleled by alterations in protein expression and phosphorylation of HSL and ATGL. mtDNA content of visceral adipose tissue was increased in morbidly obese men as compared to lean controls (p < 0.013). Positive correlations were observed between visceral adipocyte size and serum triacylglycerol (r = 0.6, p < 0.007) as well as between visceral adipocyte size and CRP (r = 0.6, p < 0.009) in analyses performed separately in obese men. CONCLUSION: Lipotoxicity of morbidly obese men might be related to the quantitative impact of the visceral fat depot rather than to important dysregulation of involved lipolytic enzymes or adipocyte mitochondria.