Serum retinol-binding protein 4 is not increased in obesity or obesity-associated type 2 diabetes mellitus, but is reduced after relevant reductions in body fat following gastric bypass

Objective Controversy exists regarding the elevation of serum retinol‐binding protein 4 (RBP4) in human obesity and type 2 diabetes mellitus (T2DM). In the present study, we have compared serum RBP4 in lean and obese patients with or without T2DM, and analysed the effect of weight loss on serum RBP4. Design Forty‐two Caucasian subjects were included in the study. Serum RBP4 was measured by ELISA and Western blot. In addition, serum RBP4 was measured in 21 morbidly obese patients before and after 4, 8 and 15 months of weight loss following Roux‐en‐Y gastric bypass (RYGBP). Results No significant effect of either obesity or diabetes on serum RBP4 was observed. Serum RBP4 concentrations (measured by either ELISA or Western blot) did not correlate with body mass index (BMI), body fat or any indicator of glucose metabolism or insulin resistance. Weight loss following RYGBP did not modify serum RBP4 at 15 months (P = 0·472). However, the variations in serum RBP4 were significantly associated with the reduction in body fat (r = 0·48; P = 0·026). Patients loosing over 20% of fat mass (n = 11) showed significantly different RBP4 concentrations compared to those individuals exhibiting smaller adiposity reductions (n = 10) (–11·0 ± 6·4 vs.+5·8 ± 3·6 mg/l; P = 0·036). Furthermore, RBP4 levels were significantly reduced at 4 (P = 0·006) and 8 (P = 0·015) months only in those patients loosing over 20% of fat mass. Conclusion Serum RBP4 concentrations are not increased in obese patients with or without T2DM. A decrease in RBP4 levels was only observed after surgically induced weight loss accompanied by relevant reductions in body fat. RBP4 might be considered as a dynamic marker of negative energy balance being reduced during weight loss when a negative energy balance threshold is reached. Furthermore, RBP4 variation in the first month after RYGBP may be a predictor of weight loss success.     

Retinol-binding protein in nonobese women with polycystic ovary syndrome

Objective Although polycystic ovary syndrome (PCOS) is frequently associated with insulin resistance, cardiovascular disease and various metabolic diseases, the mechanisms linking PCOS to metabolic changes are not fully understood. Retinol‐binding protein (RBP) was recently reported as an adipocytokine that may link insulin resistance and lipid metabolism. The aim of this study was to investigate the potential role of RBP in women with PCOS. Research design and methods Fifty women with PCOS and 40 healthy women, all of whom were age‐ and weight‐matched, were studied. Blood was obtained to determine RBP levels as well as metabolic and hormonal parameters, and the homeostasis model assessment of insulin resistance (HOMA‐IR) was calculated for each subject. Results The RBP levels were higher (P < 0·01) in women with PCOS after adjusting for age, body mass index (BMI), mean blood pressure, triglyceride (TG), high density lipoprotein (HDL)‐cholesterol, low density lipoprotein (LDL)‐cholesterol, fasting glucose, fasting insulin, estimated glomerular filtration rate (GFR), LH/FSH, total testosterone and SHBG levels. PCOS status was the strongest predictor of elevated RBP levels. In both the PCOS and control groups, RBP levels were significantly correlated with HOMA‐IR (P = 0·03 in the PCOS group; P = 0·01 in controls). In addition, RBP levels were significantly correlated with total cholesterol, LDL‐cholesterol and TG levels in PCOS (P < 0·01, P < 0·01 and P = 0·01, respectively). Conclusions Higher RBP levels in the PCOS group, when compared to the non‐PCOS group, were observed, and this difference may play a role in the pathophysiology found in women with PCOS. Further studies are needed to clarify the role of RBP in these women.     

A paradoxical difference in relationship between anxiety, depression and thyroid function in subjects on and not on T4: findings from the HUNT study

Objective There have been conflicting reports on the relationship between thyroid function and mood between studies in subjects on T4 and the general population not on T4. We investigated this relationship in a large catchment area‐based study. Design We analysed data on serum TSH levels and Hospital Anxiety and Depression Scale (HADS) scores from the HUNT 2 study (age ≥ 40 years). Following a test for interaction, analyses were performed separately in females on T4 (n = 1265) and in people not on T4 (males n = 9319 and females n = 17 694). Results More females on T4 had high depression and anxiety scores than females not on T4 (depression 18·4%vs. 13·0%, P < 0·001, anxiety 23·4%vs. 18·7%, P < 0·001). In those not on T4, there was an inverse association between serum TSH and depression score in males (B coefficient = –0·61, 95% CI –0·91 to –0·24, P = 0·001) though not in females (B coefficient = –0·07, –0·33 to 0·19), and an inverse association between TSH and anxiety score in both genders (B coefficient for males = 0·68, 95% CI –1·04 to –0·32, P < 0·001; females –0·37, 95% CI –0·67 to –0·08, P = 0·01). In contrast, in females on T4, TSH was positively associated with both depression (B coefficient = +0·27, 95% CI 0·02 to 0·51, P < 0·05) and anxiety (B coefficient = +0·29, 95% CI 0·01 to 0·56, P < 0·05). Conclusions There is a different relationship between thyroid function and depression and anxiety in females on T4 compared with individuals with no thyroid disease. This group also has a higher prevalence of depression and anxiety.     

Effect of exercise training on A-FABP, lipocalin-2 and RBP4 levels in obese women

Objective Lipocalin family proteins, including adipocyte fatty acid‐binding protein (A‐FABP), lipocalin‐2 and retinol‐binding protein 4 (RBP4), have recently been identified as novel adipokines associated with obesity, type 2 diabetes and the metabolic syndrome. We have evaluated the effect of exercise training on lipocalin family proteins and inflammatory markers. Study subjects Thirty obese Korean women and 15 age‐matched nonobese control subjects were studied. Design Concentrations of the lipocalin family proteins were compared between obese and nonobese women and were evaluated before and 3 months after an exercise programme consisting of aerobic exercise (45 min/session, 300 kcal/day) and muscle strength training (20 min/session, 100 kcal/day) five times a week. Results Obese women exhibited higher A‐FABP levels compared to nonobese women (21·4 ± 6·4 µg/l vs. 13·6 ± 4·4 µg/l, P < 0·001). However, neither lipocalin‐2 nor RBP4 levels were significantly different between the two groups, although the difference in lipocalin‐2 was marginally significant (P = 0·054). Circulating A‐FABP levels were significantly associated with body mass index (BMI), waist circumference, triglyceride, alanine aminotransferase (ALT), lipocalin‐2 and high‐sensitivity C‐reactive protein (hsCRP) levels. After 3 months of the exercise training programme, serum A‐FABP levels decreased significantly from 21·4 ± 6·4 µg/l to 19·3 ± 6·8 µg/l (P = 0·038), along with a reduction in weight, BMI, waist circumference, fasting glucose and total cholesterol levels. There was no significant change in the lipocalin‐2 and RBP4 levels, although IL‐6 levels increased after the exercise programme. Conclusion Exercise training with weight loss induced a significant reduction in circulating A‐FABP levels in obese Korean women.     

Relation between plasma fibroblast growth factor-23, serum fetuin-A levels and coronary artery calcification evaluated by multislice computed tomography in patients with normal kidney function

Objective To examine the correlation of plasma fibroblast growth factor (FGF)‐23 and serum fetuin A levels with the coronary artery calcification score (CACS) in patients with normal kidney function. Background Vascular calcification is an active process that may be aggravated by hyperphosphataemia and hypercalcaemia. FGF‐23 and human fetuin‐A have been associated with calcifying arteriosclerosis in renal failure. Plasma FGF‐23 was identified as an independent factor negatively associated with peripheral vascular calcification. Fetuin‐A acts as a systemic inhibitor of ectopic calcification in dialysis patients and can be correlated to the survival of these patients. Very few data exists on the role of FGF‐23 and fetuin‐A in coronary calcification of patients without impaired kidney function. Materials and methods Sixty‐four patients, 21 females and 43 males, were subjected to 64‐slice coronary computed tomography (CT) to evaluate coronary artery calcification (CAC). Plasma intact FGF‐23 was determined by ELISA. Serum fetuin‐A concentration were evaluated nephelometrically. Results Mean plasma FGF‐23 level was 20·4 ± 9·1 pg/ml and serum fetuin‐A was 0·46 ± 0·09 g/l. There was no correlation between FGF‐23 (P = 0·777) and fetuin‐A (P = 0·767) levels and the CACS. No correlation was found between the presence of noncalcified plaques and coronary artery stenosis (CAS) ≥  50%, and FGF‐23 (P = 0·313 and P = 0·775) and fetuin‐A levels (P = 0·601 and P = 0·659). Conclusion Plasma intact FGF‐23 and serum fetuin‐A concentration do not correlate with the CACS, the grade of stenosis or presence of noncalcified plaques of the coronary arteries in patients with normal kidney function.     

GH sensitivity of GH-deficient adults is dependent on gender but not timing of onset

Background Females secrete 2–3‐fold greater amounts of GH compared with males despite maintaining similar IGF‐I levels. IGF‐I generation tests in healthy subjects suggest this discordancy results from relative resistance to GH in females. In GHD females the presumed relative insensitivity to GH is reflected by a lower basal IGF‐I and the need for higher GH maintenance doses during replacement. Adults with severe GHD of childhood‐onset (CO) have lower basal IGF‐I SDS and require higher GH maintenance doses compared with adult‐onset (AO) patients with GHD of equal severity. We hypothesised CO‐GHD adults to be less sensitive to GH than AO‐GHD patients. Methodology In a single site study we analysed the incremental change in IGF‐I (ΔIGF‐I) in 116 GHD adults following initiation of GH replacement. The data were corrected to provide ΔIGF‐I/mg GH because of slight variances in initial GH dose. Results Following GH replacement ΔIGF‐I was 230 ± 245 and 356 ± 278 ng/ml/mg GH in females and males, respectively (P = 0·01). In CO and AO patients ΔIGF‐I was 282 ± 206 and 294 ± 292 ng/ml/mg GH, respectively (P = 0·83). Further analysis after stratification by both gender and timing of onset of GHD showed ΔIGF‐I was 226 ± 164, 324 ± 228, 231 ± 268, and 373 ± 304 ng/ml/mg GH in the CO females, CO males, AO females, and AO males, respectively (AO males vs. AO females, P = 0·03; CO males vs. CO females, P = 0·17; AO males vs. CO males, P > 0·05; AO females vs. CO females, P > 0·05). Multiple linear regression with ΔIGF‐I as the dependent variable and age, gender, BMI, baseline IGF‐I level, and timing of onset as independent variables showed ΔIGF‐I to be dependent on gender alone (R = 0·28, P = 0·004). Age (P = 0·44), BMI (P = 0·54), baseline IGF‐I level (P = 0·63) and timing of onset (P = 0·61) had no effect on ΔIGF‐I. Conclusion We have shown gender to have a significant impact on GH sensitivity in GHD adults, which, at least in part, explains differences in maintenance dosages during replacement. None of the additional variables impacted significantly on GH sensitivity. The lower basal IGF‐I SDS and higher GH replacement requirement reported in CO compared with AO patients cannot be explained by differences in sensitivity to GH.     

Association between serum TSH, free T4 and serum liver enzyme activities in a large cohort of unselected outpatients

Objective Although overt thyroid dysfunction is associated with some liver abnormalities, there is a dearth of information on liver function tests across thyroid function tests. We assessed the relationship between serum liver enzyme activity and thyroid function tests in a cohort of adult individuals. Design, patients and measurements We performed a retrospective analysis on the database of the Clinical Chemistry Laboratory at the Verona University Hospital to retrieve results of serum liver enzyme activities [alanine aminotransferase (ALT), γ‐glutamyltransferase (GGT)] and thyroid function tests (TSH and free T4), which have been performed on the whole cohort of outpatient adults consecutively referred by general practitioners for routine blood testing during the last 3 years. Results Cumulative results for serum GGT, ALT and TSH concentrations were retrieved for 10 292 (68·3% females) outpatient adults with a wide range of age and thyroid function tests. Subjects were categorized according to serum TSH concentrations as follows: < 0·1, 0·1–0·35, 0·36–4·5, 4·6–10 and >10 mU/l. Serum GGT and ALT concentrations increased steadily across the increasing TSH categories (P < 0·0001 for trends), ranging from mean values of 36 to 62 U/l for GGT and from 29 to 41 U/l for ALT, respectively. Similarly, there was a negative, graded, relationship between serum GGT and ALT concentrations and free T4 categories. The results did not change after adjusting for gender, age, lipids and fasting glucose concentrations. Conclusions Our findings suggest that hypothyroidism and thyroid function tests, even within the reference range, are associated with slightly increased serum GGT and ALT activity concentrations.     

Association between thyroid function and nonalcoholic fatty liver disease in euthyroid elderly Chinese

Objective Thyroid dysfunction commonly occurs in the elderly population and overt thyroid dysfunction is associated with some liver abnormalities. This study aimed to investigate the association of thyroid function with nonalcoholic fatty liver disease (NAFLD) in euthyroid elderly Chinese. Methods A cross‐sectional study was performed among 878 euthyroid elderly Chinese who took their annual healthy examination at Zhenhai Lianhua Hospital, Ningbo, China. Results A total of 227 (25·85%) subjects fulfilled the diagnostic criteria of NAFLD. Patients with NAFLD had significantly lower levels of serum‐free thyroxine (FT4) than controls (11·12 ± 1·43 vs 11·58 ± 1·47 pmol/l; P < 0·001). The prevalence rate of NAFLD decreased along with progressively higher serum FT4 levels (P for trend < 0·001). Age, gender and smoking status–adjusted correlation analysis showed that serum FT4 level was negatively correlated with body mass index, waist circumference, triglyceride and serum uric acid levels (All with P < 0·05). Stepwise logistic regression analysis showed that serum FT4 level was significantly associated with the risk for NAFLD [odds ratio (OR): 0·847, 95% confidence interval (CI): 0·743 – 0·966; P = 0·013]. Conclusion Our findings suggest that thyroid function, even within the reference range, is associated with NAFLD in elderly Chinese.     

Phospholipid transfer protein activity is determined by type 2 diabetes mellitus and metabolic syndrome, and is positively associated with serum transaminases

Background The extent to which plasma phospholipid transfer protein (PLTP) activity is affected by type 2 diabetes mellitus (DM) and metabolic syndrome (MetS) is still unknown. PLTP is synthesized in the liver, and elevated serum transaminases are considered to predict nonalcoholic fatty liver disease (NAFLD). In this study, we examined the relationship between plasma PLTP activity and liver enzymes in subjects with and without DM and MetS. Design Plasma PLTP activity, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured in 71 subjects without DM or MetS, 21 without DM but with MetS, 26 with DM but without MetS and 55 with DM and MetS (WHO and NCEP‐ATP III criteria). Results After controlling for age, sex and alcohol intake, PLTP activity was positively related to both MetS (P < 0·001) and DM (P = 0·001). Serum ALT (P = 0·006) and AST (P = 0·04) were both associated with MetS, but only ALT was associated with DM (P < 0·001). In multiple linear regression models, serum ALT and AST were positively and independently associated with PLTP activity (P < 0·01 for all), even when the presence of MetS and DM was taken into account, as well as after controlling for glycated haemoglobin (HbA_1c), insulin resistance, triglycerides, free fatty acids (FFA), C‐reactive protein (CRP), leptin and adiponectin. Conclusions Plasma PLTP activity is determined by MetS and by diabetes per se. Serum transaminases are independently associated with PLTP activity. We suggest that this lipid transfer protein may be a marker for NAFLD.     

The IGF system and cytokine interactions and relationships with longitudinal growth in prepubertal patients with cystic fibrosis

Objective Growth delay is a feature of patients with cystic fibrosis (CF). CF is a condition characterized by chronic inflammation that has been shown to modify the IGF system, which is essential for normal growth, and is related to pulmonary function in CF patients. We aimed to verify whether circulating levels of tumour necrosis factor (TNF)‐α, interleukin (IL)‐6, insulin and the IGF system were related and/or had relationships with linear growth in children with CF. Design and patients Seventeen prepubertal CF patients (nine males and eight females) in a stable clinical condition were enrolled. Auxological parameters, pulmonary function and the Shwachman–Kulczycki (S‐K) score were assessed, and serum samples were drawn at baseline and after 12 months. Measurements TNF‐α, IL‐6, IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2, IGFBP‐3 and insulin were assayed using specific commercial kits. Results At baseline, TNF‐α serum concentration was related to serum IGF‐I concentration (R = 0·53), IGF‐II bioactivity (IGF‐II/IGFBP‐3 molar ratio, R = +0·52) and insulin concentration (R = +0·63). Changes in serum IL‐6 and IGFBP‐2 concentrations during the 12‐month observation were positively correlated (R = +0·63). Changes in height standard deviation score (Ht SDS) were correlated with IGF‐I serum concentrations at baseline (R =+0·67) and after 12 months (R = +0·70), with IGF‐I bioavailability and with IGFBP‐1 serum concentrations (R = –0·88). Body mass index (BMI) SDS correlated with IGF bioavailability. Conclusions This study showed a relationship between inflammatory status and the IGF system, and an effect of these interactions on longitudinal growth. Moreover, a role for insulin in growth was identified. Better control of inflammation and preservation of insulin secretion could benefit these patients.     

Polymorphism of the oestrogen receptor beta gene (ESR2) is associated with susceptibility to Graves' disease

Objective To investigate whether a polymorphism in the ESR2 gene (rs4986938, previously associated with endometriosis, ovulatory dysfunction and premature onset of coronary heart disease) increases the risk of Graves’ disease (GD). Subjects and design A cohort of 375 GD patients (300 females and 75 males) and 1001 individuals representative of the background population of Poland (502 males and 499 females) were genotyped for rs4986938 using allele‐specific polymerase chain reaction (PCR). Results We found an increased frequency of the ESR2 A allele among the patients vs. controls (38·0%vs. 32·7%, OR = 1·26, P = 0·009) that was caused by a co‐dominant (OR = 1·25, P = 0·01, P_{for model fit} = 0·127) or a recessive (OR = 1·67, P = 0·003, P_{for model fit} = 0·554) effect. The association was found in both sexes (OR = 1·21, P = 0·046 and OR = 1·53, P = 0·029, respectively, for co‐dominant and recessive models in females, and OR = 1·44, P = 0·034 and OR = 2·29, P = 0·01, respectively, for the two models in males) and was more pronounced among the DRB1*03‐negative (OR = 1·63, P = 0·0002) than DRB1*03‐positive patients (OR = 1·04, P = 0·822). No other statistically significant associations between the ESR2 genotype and GD subsets were found (age of onset, smoking, clinically evident ophthalmopathy, family history of GD, and PTPN22 and CTLA4 (CT60) genotypes were analysed). Conclusions In a Polish population the ESR2 A allele is associated with GD with a strength comparable to polymorphisms of PTPN22 and CTLA4 CT60 loci (OR ~ 1·7). The association with ESR2 is found in both sexes and may be particularly strong among the DRB1*03‐negative individuals.     

Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians

Objective Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the –420C>G putative gain‐of‐function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans. Design and methods We examined the association of three resistin polymorphisms, –852A>G, –420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C‐reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851). Results Resistin levels were higher, dose‐dependently, with the –420G allele (CC 5·9 ± 2·7 ng/ml, GC 6·5 ± 4·0 ng/ml and GG 7·2 ± 4·8 ng/ml, trend P = 0·04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1·07 (1·00–1·15), P < 0·05)]. The –852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor‐receptor 2 (sol‐TNFR2) levels in fully adjusted models [1·06 (95% CI 1·01–1·11), P = 0·01)]. The estimated resistin haplotype (GGT) was associated with sol‐TNFR2 (P = 0·04) and the AGT haplotype was related to CRP (P = 0·04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores. Conclusions Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5′ variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.     

Serum concentrations of leptin, adiponectin and resistin, and their relationship with cardiovascular disease in patients with end-stage renal disease

Background and Objective High levels of some adipocytokines have been reported in patients with chronic renal failure, but little information is available on adipocytokine concentrations in uraemic patients under different modalities of therapy. Our aims were (1) to quantify the serum concentrations of leptin, adiponectin and resistin in uraemic patients on peritoneal dialysis (PD) and haemodialysis (HD), in comparison with patients on conservative management, and (2) to study the relationships between adipocytokine levels and previous atherosclerotic vascular disease. Patients and Measurements We studied 82 dialysis patients treated by PD (n = 44, 23 males and 21 females, mean age 54·4 ± 1·8 years) or HD (n = 38, 22 males and 16 females, age 60·8 ± 1·6 years). A group of 19 uraemic patients on conservative management served as the control. Serum concentrations of leptin, adiponectin and resistin were measured in all subjects. Information on vascular disease (cerebral vascular, peripheral vascular and heart disease) was obtained from a detailed medical history. Results PD patients showed significantly higher serum leptin concentrations [median (interquartile range), 28·7 (13·0–71·9) µg/l] than those found in patients on HD [9·7 (4·7–31·9) µg/l, P < 0·01] or in conservative management [5·9 (4·3–38·6) µg/l, P < 0·05]. Adiponectin concentrations were similar in the three groups of patients (mean ± SEM, 48·0 ± 4·5 mg/l in PD, 57·7 ± 4·4 mg/l in HD, and 44·4 ± 7·0 mg/l in controls, NS). Patients treated by both PD and HD exhibited resistin concentrations significantly higher than those found in controls (26·3 ± 0·99 and 27·5 ± 1·4 µg/l, respectively, vs. 17·3 ± 1·0 µg/l, P < 0·001). Leptin concentrations were positively correlated with body mass index (BMI) (r = 0·287, P < 0·01) and adiponectin levels were negatively related to BMI (r = ?0·416, P < 0·001) and the homeostatic model assessment (HOMA‐R) index (r =?0·216, P < 0·05). Leptin, adiponectin and resistin levels in patients with previous vascular events were similar to those found in patients without these complications. Logistic regression analysis did not demonstrate any relationship between serum adipocytokine concentrations and the presence of vascular disease of any type. A significant relationship between resistin and heart disease [odds ratio (OR) 1·80 (1·03–3·15), P = 0·039] was found when analysing subgroups of patients. Conclusions These data suggest that leptin levels are higher in PD patients, and resistin levels are higher in PD and HD patients in relation to patients on conservative management, whereas adiponectin concentrations are similar in the three groups. These results do not support the presence of a clinically relevant relationship between adipocytokines and previous episodes of vascular disease in the whole population or in patients classified in subgroups, with the only exception of a relationship between resistin levels and heart disease.     

Effects of light to moderate alcohol consumption on thyroid volume and thyroid function

Objective To examine a possible relationship between alcohol consumption and thyroid volume and function. Subjects A total of 1493 subjects (599 males aged 45–60 years and 894 females aged 35–60 years) with no known thyroid disorders who were participating in the SUpplémentation en VItamines et Minéraux AntioXydants (SU.VI.MAX) study. Measures Daily dietary intakes and alcohol consumption in grams per day were based on five 24‐h dietary records. Thyroid volume and structure were measured by ultrasonography. At baseline, TSH and free T4 (FT4) were measured. Results Male and female drinkers consumed (mean ± SD), respectively, 30·6 ± 23·3 and 14·2 ± 13·4 g of ethanol per day. There was a decrease in carbohydrate intake with higher alcohol consumption among both male (P = 0·0001) and female drinkers (P = 0·06). Alcohol intake was associated with higher thyroid volume in males and females independently of iodine status. Multivariate odds ratios (ORs, with 95% confidence intervals) of thyroid enlargement (sex‐specific 85th percentile values of ≥ 20 ml for males, ≥ 14 ml for females) in males and females who drank ≥ 45 and ≥ 20 g/day, respectively, were 2·22 (1·10–4·47) and 2·11 (1·15–3·90) compared with low drinkers, and 11·75 (2·15–64·12) and 2·03 (1·04–3·96) compared with abstainers. ORs were slightly increased when smokers were excluded. Alcohol intake was associated with low FT4 levels in male drinkers independently of TSH. Conclusions An increasing dose–response relationship was found between alcohol intake levels and ORs for thyroid enlargement in both males and females. Alcohol consumption was strongly associated with a higher risk in females.     

Correlation of insulin sensitivity with bone mineral status in obese adolescents with nonalcoholic fatty liver disease

Aim The aim of this study was to investigate the relationships between bone mineral density (BMD) vs insulin resistance and metabolic risk factors in obese adolescents with nonalcoholic fatty liver disease (NAFLD). Patients and methods Eighty‐two obese adolescents [45 girls and 37 boys, mean age: 12·3 ± 1·7 years, mean body mass index‐standard deviation score (BMI‐SDS): 1·9 ± 0·2] and 30 control subjects (15 girls and 15 boys, mean age: 12·3 ± 1·45 years, mean BMI‐SDS: 0·5 ± 0·7) were enrolled the study. The obese subjects were divided into two groups based on the presence or absence of liver steatosis with high transaminases (NAFLD group and non‐NAFLD group). Insulin resistance was evaluated by homeostasis model assessment (HOMA‐IR) from fasting samples. BMD was determined by dual‐energy X‐ray absorptiometry. Results Fasting insulin levels in the NAFLD group were significantly higher than in the non‐NAFLD obese (32·3 ± 24·0 vs 11·02 ± 2·95 mU/l, P < 0·001) and control groups (8·4 ± 2·4 mU/l, P< 0·001). The NAFLD group had higher values of HOMA‐IR than the non‐NAFLD obese (7·3 ± 0·1 vs 2·3 ± 0·7, P < 0·001) and control groups (1·8 ± 0·5, P < 0·001). BMD‐SDS measurements were lower in the NAFLD group than in the non‐NAFLD (0·56 ± 0·3 vs 1·02 ± 0·9, P < 0·001) and control groups (0·56 ± 0·3 vs 1·37 ± 1·04, P < 0·001). BMD‐SDS was positively correlated with BMI‐SDS (r = 0·530, P = 0·004) and negatively correlated with HOMA‐IR (r = ?0·628, P = 0·017) in the NAFLD obese group. Conclusion This study reports the association between BMD‐SDS and insulin resistance in obese adolescents both with and without NAFLD, although the NAFLD group had a lower BMD‐SDS than the non‐NAFLD group. We suggest that NAFLD has a detrimental effect on bone health in adolescents, and it is correlated with increased insulin resistance.     

Perioperative plasma active and total ghrelin levels are reduced in acromegaly when compared with in nonfunctioning pituitary tumours even after normalization of serum GH

Objective Ghrelin is a novel gastric peptide known to stimulate GH secretion, but the relationship between ghrelin and the GH‐insulin‐like growth factor (IGF)‐1 axis in GH excess or deficiency is poorly understood. This study investigated dysregulation of ghrelin secretion in acromegaly and its short‐term postoperative recovery. Methods A prospective study was conducted on eight patients who underwent complete transsphenoidal resection of GH‐producing pituitary adenomas (acromegaly group) and 22 for endocrinologically nonfunctioning pituitary tumours (control group). Active and total plasma ghrelin levels were measured serially before and after surgery. Results Preoperative active and total plasma ghrelin concentrations (mean ± SD; fmol/ml) were significantly reduced in acromegalic patients when compared with those in the controls (9·6 ± 4·3 and 157·4 ± 65·6 vs. 21·8 ± 13·0 and 267·1 ± 111·4; P = 0·023 and P = 0·021, respectively). Both levels were still significantly suppressed on postoperative Day 7 in the acromegaly group when compared with those in the control group (11·7 ± 4·3 and 197·8 ± 68·9 vs. 22·5 ± 12·6 and 302·7 ± 100·0; P = 0·038 and P = 0·018, respectively). The ratios of active to total ghrelin were not significantly different between the two groups before and after operation. In acromegalic patients, active and total ghrelin levels remained significantly suppressed even after normalization of serum GH levels. Conclusions The putative negative feedback mechanism of GH on ghrelin secretion may in part account for the low ghrelin levels observed in acromegalic patients, and the mechanism may persist even after normalization of serum GH.     

GH and IGF-I deficiency are associated with reduced loss of fat mass after laparoscopic-adjustable silicone gastric banding

Context GH secretion is reduced in obese subjects and increases after body weight loss. It is still unclear if changes in the GH/IGF‐I axis after laparoscopic‐adjustable silicone gastric banding (LASGB) are associated with changes of body composition. Objective To analyse the relationships between changes in the GH/IGF‐I axis and those of body weight and composition before and after LASGB. Design Observational, prospective. Setting University ‘Federico II’ of Naples (Italy). Patients Seventy‐two severely obese females (BMI: 44·9 ± 4·68; mean age: 33·1 ± 11·34 years) were studied. Main outcome measures GH peak after GHRH plus arginine test, IGF‐I, IGFBP‐3 and ALS levels, fat mass (FM) and free fat mass (FFM) (by Bioelectrical Impedance Analysis) at baseline and 6 months after LASGB. The change in percentage of individual variables was calculated as well as that of excess of body weight loss (EBWL%). The FM%, FFM% and EBWL% were correlated with peak GH and IGF‐I levels changes. Results At baseline, GH deficiency (GHD) (GH peak = 4·1 µg/l) was found in 22 patients (31%), 16 of them also had IGF‐I deficiency (< –2SDS). IGF‐I levels were inversely correlated with waist circumference (r = –0·72, P < 0·001) and FM% (r = –0·75, P < 0·001). Post‐LASGB the patients were classified as follows: group (1) GH and IGF‐I sufficient (n = 44; 61·1%); group (2) GH and IGF‐I deficient (n = 14; 19·4%) and group (3) GH sufficient and IGF‐I deficient (n = 14; 19·4%). The percentage changes of EWBL (P < 0·05, P = 0·051, respectively) and FM (P < 0·001, P < 0·01, respectively) were lower in groups (2) and (3) than in group (1). At the stepwise linear regression analysis, postoperative IGF‐I levels were the strongest determinant of percent changes of FM (P < 0·0001), of FFM (P = 0·009) and of EBWL (P < 0·0001). Conclusions IGF‐I levels is the most sensitive to unfavourable changes in body composition 6 months after LASGB making investigation of the somatotropic axis useful in the evaluation of bariatric surgery outcomes.     

Insulin-like growth factor-1 deficiency determines increased intima-media thickness at common carotid arteries in adult patients with growth hormone deficiency

objective To investigate the role of IGF‐1 on intima–media thickness (IMT) at common carotid arteries by Doppler ultrasonography. subjects Thirty‐nine patients (17 women, 22 men, aged 25–70 years) with severe GH deficiency (GHD), 19 with normal and 20 with low IGF‐1 levels, and 39 sex‐, age‐ and body mass index (BMI)‐matched healthy controls. results Patients with GHD showed abnormalities in lipid profile, and increased fibrinogen levels, mean IMT (0·88 ± 0·26 vs. 0·69 ± 0·14 mm, P < 0·001), and systolic and diastolic peak velocity (P < 0·001) compared to controls. Eight patients (18%) and one control (2·1%, P = 0·04) had well‐defined plaques. In controls, but not in patients with GHD, mean carotid IMT was correlated with age (r = 0·78, P < 0·001). In both controls (r = ?0·82; P < 0·0001) and patients with GHD (r = ?0·84, P < 0·0001), serum IGF‐1 levels were inversely correlated with mean IMT at common carotid arteries. At the stepwise multiple regression, the variables most significantly related to IMT in GH‐deficient patients were total cholesterol levels (t = 5·2, P < 0·001), followed by disease duration (t = 2·4, P = 0·02), while in controls the variables most significantly related to IMT were IGF‐1 levels (t = ?9·9, P < 0·001), followed by low density lipoprotein (LDL)‐cholesterol levels (t = ?2·3, P = 0·02). Compared to patients with normal IGF‐1 levels, those with low IGF‐1 levels had lower high density lipoprotein (HDL)‐cholesterol levels (1·0 ± 0·2 vs. 1·3 ± 0·2 mmol/l, P = 0·0002), and higher glucose (54·3 ± 6·1 vs. 48·9 ± 5·9 mmol/l, P = 0·008), insulin (25·2 ± 6·8 vs. 18·8 ± 6·0 mUl/l, P = 0·004), total cholesterol (7·1 ± 1·1 vs. 4·9 ± 0·6 mmol/l, P < 0·0001), total/HDL‐cholesterol ratio (7·2 ± 1·8 vs. 3·9 ± 0·7, P < 0·0001), fibrinogen levels (319·8 ± 56·9 vs. 241·8 ± 53·0 mg/dl, P < 0·0001) and mean IMT at common carotid arteries (1·05 ± 0·25 vs. 0·69 ± 0·07 mm, P < 0·0001). Atherosclerotic plaques were found only in GH‐deficient patients with low IGF‐1 levels. conclusions GH‐deficient patients have alterations in lipid profile with an increase in the total/HDL‐cholesterol ratio, which is an index of increased cardiovascular risk, but only patients with IGF‐1 deficiency have increased IMT.     

Coronary artery disease is associated with higher epicardial retinol-binding protein 4 (RBP4) and lower glucose transporter (GLUT) 4 levels in epicardial and subcutaneous adipose tissue

Objective Retinol‐binding protein 4 (RBP4), produced by adipocytes and hepatocytes, contributes to an unfavourable lipid profile and insulin resistance, which can contribute to the development of coronary artery disease (CAD). Recently, several studies have shown that epicardial adipose tissue (EAT) differs from subcutaneous adipose tissue (SAT) and plays a role on the physiopathology of CAD because of its proximity to the coronary arteries. We aimed to study the expression and secretion levels of RBP4 in both fat tissues and explore its possible association with CAD. Research Design and Methods Fifty‐eight patients undergoing heart surgery were included in the study. We analysed RBP4 mRNA expression by real‐time PCR, protein expression by Western blot and immunohistochemistry, and secretion of EAT and SAT explants from CAD and non‐CAD patients by Enzyme Immunoassay. Results Retinol‐binding protein 4 is expressed at similar levels in EAT and SAT, mainly from adipocytes. Protein levels were higher in EAT from CAD than non‐CAD patients (0·63 ± 0·09 arbitrary units (a.u).; n = 10) vs (0·41 ± 0·04 a.u.; n = 13, P = 0·039). In contrast, GLUT4 mRNA levels were lower in EAT from CAD than non‐CAD patients (6·55 ± 0·16 a.u.; n = 13) vs (7·21 ± 0·18 a.u.; n = 14, P = 0·012). We also found differential expression in SAT between samples from CAD and non‐CAD patients [(6·63 ± 0·16 a.u.; n = 14) vs (7·21 ± 0·14 a.u.; n = 14, P = 0·009)]. Besides, EAT releases higher RBP4 levels than SAT after 3, 6, 24 and 48 h of culture. These levels were independent of CAD but significantly higher in diabetic than nondiabetic patients. Conclusion Retinol‐binding protein 4 levels behave differently in EAT and SAT with respect to CAD. However, both adipose tissues have lower GLUT4 levels in patients with CAD. These findings suggest a differential regulation of RBP4 production in EAT and SAT that may be influenced by local factors.     

Relationship between serum free T4 (FT4) levels and metabolic syndrome (MS) and its components in healthy euthyroid subjects

Background The metabolic syndrome (MS) is associated with increased life‐time risk for atherosclerotic cardiovascular disease. While some reports suggest that MS and/or insulin resistance is associated with low serum free T4 (FT4) level in euthyroid subjects, this remains a controversial issue. Objective To clarify the association of serum FT4 level with presence of MS and its components in healthy euthyroid subjects. Subjects and measurements For 44 196 euthyroid subjects (including 25 147 males) not taking thyroid hormone or antithyroid‐drug and without liver or renal disease who participated in a routine health screening examination, we measured serum FT4, high‐density lipoprotein cholesterol (HDL‐C), triglycerides (TG), fasting glucose, blood pressure (BP), height, weight, and waist circumference. Subjects were categorized into five groups according to their serum FT4 concentration. The association of FT4 quintiles with clinical and metabolic parameters of MS was analysed by significance test for linearity, and logistic regression analysis was used to calculate odds ratios (ORs) for risk of MS and each of its components, before and after adjustment for age. Results In males, serum FT4 concentrations were positively associated with BP, fasting glucose, HDL‐C, and TG levels, and negatively associated with waist circumference after adjustment for age (P for trend = 0·033 to < 0·001). Females also showed similar findings except that FT4 had no correlation with TG after adjustment for age (all P for trend < 0·001 except TG). The negative association between FT4 and waist circumference was not present in younger male subjects (< 50 years), and the positive association between FT4 and BP was more prominent in younger female subjects (< 50 years) than in older females (P < 0·05). In both sexes, the ORs for elevated BP and elevated fasting glucose were significantly higher in subjects in the highest FT4 quintile than those in the lowest FT4 quintile, while the ORs for abdominal obesity and low HDL‐C were significantly lower. Subjects in the higher FT4 quintiles had a significantly lower prevalence of MS than those in the lowest FT4 quintile, but such differences disappeared after adjustment for age in both males and in females. Conclusion These results suggest that the interaction between serum FT4 and MS components could be different according to age as well as gender in euthyroid subjects. Although thyroid hormone significantly affected each component of MS, there was no association between serum FT4 level and presence of MS after adjustment for age in healthy euthyroid subjects.