Reduced levels of adiponectin in sleep apnea syndrome.

BACKGROUND: To investigate adiponectin levels in an obese population with and without obstructive sleep apnea syndrome (OSAS) and the acute modifications in adiponectin after a whole-night control by auto continuous positive air pressure (CPAP). METHODS: 46 obese subjects [22 males, 24 females, age 55.1+/-11.4 yr, body mass index (BMI) 38.9+/-6.5 kg/m2]: 11 OSAS with apnea/hypopnea index (AHI) from 10/h to 30/h, 14 OSAS with AHI >30/h and 21 without OSAS. Thirty-seven normal weight healthy subjects (20 males, 17 females, age 31.3+/-9.5 yr, BMI 21.5+/-1.8 kg/m2). Serum adiponectin levels, biochemical parameters, anthropometric measurements, pulmonary function, pulse-oxymetry and polisomnography. RESULTS: The 3 groups of obese patients were comparable for gender, BMI, age, fat mass, fat free mass, hip and waist circumference, waist-to-hip ratio (WHR), systolic and diastolic blood pressure and glycometabolic parameters. Adiponectin levels were significantly reduced in obese patients compared to healthy normal weight subjects (8.1+/-3.5 vs 11.3+/-4.8 microg/ml p<0.001) In particular, adiponectin showed a trend to decrease according to the severity of OSAS. No differences in adiponectin levels were found after a whole-night control by Auto CPAP. CONCLUSIONS: OSAS is associated with reduced levels of adiponectin independently of insulin-resistance and BMI. These low adiponectin levels may contribute to the increased mortality seen in such patients.

Ghrelin in human medullary thyroid carcinomas.

OBJECTIVE: Ghrelin is a novel gastrointestinal hormone involved in several metabolic functions. It has been identified previously in several normal and tumoral neuroendocrine tissues, including human medullary thyroid carcinomas (MTCs). The aim of the study was to evaluate ghrelin levels in patients with MTC and nontoxic goitre (NTG) with elevated calcitonin (CT) levels, as an additional marker of the disease. PATIENTS AND DESIGN: The study included 22 patients with MTC (four before and 18 after thyroidectomy), 12 patients with NTG with basal CT levels exceeding 10 ng/l and 15 healthy subjects matched for age, sex and body mass index (BMI). After thyroidectomy, MTC patients were considered cured when basal and pentagastrin-stimulated CT levels were < 0.2 and < 10 ng/l, respectively. A pentagastrin-induced CT peak over 50 ng/l was considered as an abnormal response while 100 ng/l was the cut-off accepted for the diagnosis of C-cell hyperplasia or tumour. Circulating ghrelin and CT levels were evaluated at baseline in patients and controls and at -10, 0, 1, 2, 5 and 15 min after pentagastrin injection (0.5 microg/kg body weight) in 12 patients with MTC and nine with NTG. Four surgically removed MTCs were tested for ghrelin expression. MEASUREMENTS: Total plasma ghrelin and CT levels were measured with a commercially available radioimmunoassay (RIA) and two-site chemiluminescence immunometric assays, respectively. In paraffin-embedded MTC samples ghrelin immunostaining was performed with a polyclonal antibody (1:1000) and the reaction visualized by an indirect immunoperoxidase system. RESULTS: Plasma ghrelin levels found in cured or not cured MTC and in NTG patients were similar to those of BMI-matched healthy controls. No correlation between ghrelin and CT levels, thyroid disease or previous thyroidectomy was observed. The administration of pentagastrin caused a 17% increase in ghrelin levels (basal ghrelin vs. peak: 162 +/- 62 pmol/l vs. 189 +/- 58 pmol/l, P < 0.05) that was particularly evident (33% increase) in patients with an abnormal CT response to the test (CT > 50 ng/l). Immunohistochemistry showed positivity for ghrelin in a small proportion of CT positive cells from the four MTCs removed. CONCLUSIONS: Patients with MTC, NTG and controls showed similar ghrelin levels, ruling out this parameter as a marker of MTC. The increase in ghrelin levels in patients with a positive CT response to pentagastrin, together with the immunopositivity for ghrelin in some MTC cells, suggests C cells as minor source of ghrelin production.

Aminotransferase and gamma-glutamyltranspeptidase levels in obesity are associated with insulin resistance and the metabolic syndrome.

Fatty liver at ultrasounds, with/ without raised plasma levels of hepatic enzymes, is common in obesity. In most cases, it is the hallmark of non-alcoholic fatty liver disease (NAFLD), a potentially progressive disease associated with insulin resistance and the metabolic syndrome (MS). We tested the hypothesis that insulin resistance per se might be associated with hepatocellular necrosis. Alanine and aspartate aminotransferases (ALT and AST; no.=799) and gamma-glutamyltranspeptidase (GGT; no.=459) were analyzed in a group of treatment-seeking obese patients recruited in 12 Italian medical centers. Insulin resistance was calculated by the homeostasis model assessment method (HOMA-IR; no.=522). Median ALT and AST increased with increasing obesity class (p=0.001 and p=0.005) and exceeded normal limits in 21.0% of cases. Also HOMA-IR increased with the obesity class (p<0.0001), and was higher in subjects with elevated ALT (median, 4.93 vs 2.89; p<0.0001). A significant correlation was observed between HOMA-IR and ALT (R2=0.208; p<0.0001), as well as between HOMA-IR and AST or GGT (R2=0.112 and R2=0.080; p<0.0001). The correlation was maintained when cases with elevated enzyme levels were omitted from analysis. Diabetes and hypertriglyceridemia were the features of the MS most commonly associated with raised liver enzymes. In logistic regression, after correction for age, gender, BMI and features of the MS, HOMA-IR maintained a highly predictive value for raised ALT, AST and GGT. We conclude that in obesity insulin resistance is a risk factor for raised liver enzyme levels, possibly related to NAFLD.

Circulating levels of inhibin A, inhibin B and activin A in normal and intrauterine growth restricted (IUGR) fetuses.

OBJECTIVE: To evaluate the relationships between circulating levels of inhibin A, inhibin B and activin A, and sex, gestational age and gonadotropins in normal and pathological fetuses. STUDY DESIGN: The study included 31 normal fetuses and 12 affected with intrauterine growth restriction (IUGR) of gestational age ranging 20-40 weeks. RESULTS: No gender difference in inhibin A and activin A levels were observed. Inhibin B levels were significantly higher in males than in females (P < 0.05). Fetuses with the highest levels of inhibin A and B were found in the IUGR group that also showed activin A levels significantly higher than normal. No correlations were observed between inhibin A, inhibin B, activin A and both gonadotropins. CONCLUSION: Plasma inhibin A, inhibin B and activin A are detectable in both genders during intrauterine life. The different gender pattern of inhibin B suggests that inhibin B may contribute to the assessment of the hypothalamic-pituitary-gonadal set-point at least in males.

Circulating adiponectin levels and cardiovascular risk factors in acromegalic patients.

OBJECTIVE: Adiponectin (ApN) is an adipocytokine expressed in human adipose cells with anti-atherogenic and anti-inflammatory properties that plays a role in the pathophysiology of insulin resistance, metabolic syndrome and coronary artery disease. The aim of the study was to evaluate ApN secretion in patients with acromegaly, a chronic disease associated with insulin resistance and increased cardiovascular mortality, and to correlate ApN levels with hormonal, metabolic and cardiovascular parameters. DESIGN AND METHODS: The study included 32 patients with active acromegaly (11 male and 21 female, aged 48+/-11 years, duration of disease: 8+/-6 years, GH: 9.2+/-9.8 microg/l, IGF-I: 80+/-33 nmol/l (means+/-s.d.)) and 38 control subjects sex- and body mass index (BMI)-matched. In all subjects, serum ApN, leptin and ghrelin levels, BMI, waist circumference, insulin resistance (assessed by homeostasis model assessment and the quantitative insulin check index), lipid profile and blood pressure values were evaluated. RESULTS: Acromegalic patients and control subjects had similar ApN levels (9.4+/-3.5 vs 9.5+/-4.0 mg/l, NS), while when considering obese subjects acromegalic patients had ApN levels significantly higher than controls (10.2+/-4 vs 7.5+/-3 mg/l, P<0.05). No significant correlation between ApN and GH/IGF-I levels or duration of disease was found. ApN concentrations negatively correlated with BMI, waist circumference, glucose and diastolic blood pressure and positively with high-density lipoprotein cholesterol and ghrelin in controls, while all these correlations were lost in acromegalic patients. CONCLUSIONS: We provide evidence that, although metabolic and cardiovascular abnormalities are present in most acromegalic patients, in these subjects ApN levels are not reduced and, contrary to what is found in BMI-matched controls, do not correlate with cardiovascular risk factors. These data support the view that atherosclerosis is not the main determinant of cardiovascular mortality in acromegaly and suggest a permissive action of GH and/or IGF-I excess on ApN secretion.

Ghrelin secretion in severely obese subjects before and after a 3-week integrated body mass reduction program.

Ghrelin, the endogenous ligand of GH-secretagogue receptors, has been implicated in the regulation of feeding behavior and energy balance. Aim of the study was to investigate ghrelin levels in fasting conditions and after a standard meal test in obese subjects before and after a 3-week integrated body weight reduction (BWR) program (consisting of energy-restricted diet, exercise training, psychological counselling and nutritional education). Weight, height, fat mass, fat free mass (by impedentiometry), circulating ghrelin, insulin and leptin levels were evaluated in 10 obese subjects (3 male, 7 female; mean age: 35 +/- 9.3 yr; body mass index BMI: 45.2 +/- 10.6 kg/m2) before and after weight reduction. At baseline, obese subjects showed significantly lower ghrelin levels than controls, which were negatively correlated with BMI, weight, insulin and leptin levels. Fasting ghrelin levels were not modified by standard meal test in obese subjects (from 110.8 +/- 69.7 to 91.8 +/- 70.2 pmol/l p=ns), while a significant reduction was observed in controls (from 352.4 +/- 176.7 to 199.0 +/- 105.2 pmol/l; p<0.01). After a 3-week integrated BWR program obese subjects significantly reduced weight, BMI and leptin levels, while no significant changes were found both in fasting ghrelin and in ghrelin response after the meal. In conclusion, 5% weight loss obtained after a short-term period of integrated BWR program is not sufficient to normalize fasting ghrelin levels nor to restore the normal ghrelin suppression after a meal in severely obese subjects.

Chronic treatment with inhaled corticosteroids does not modify leptin serum levels.

AIM: To assess the influence of a short-term treatment with low-dose inhaled corticosteroids on leptin serum levels. PATIENTS: 14 prepubertal children, mean age 5.1 +/- 2.4 years, treated with inhaled fluticasone propionate 100 microg b.d. and 16 prepubertal children, mean age 8.3 +/- 1.3 years, treated with inhaled budesonide 200 microg b.d. METHODS: All children underwent a CRH test with evaluation of leptin, cortisol and ACTH levels before and after 3 months of treatment. RESULTS: Fluticasone group: no difference was found between basal cortisol level, delta and area under the curve (AUC) before and after treatment, though cortisol peak was significantly lower following treatment. Basal ACTH level, peak and AUC were significantly lower after treatment. Budesonide group: no statistically significant difference in any of the parameters regarding cortisol and ACTH secretion was observed before and after treatment. No significant changes in basal serum leptin levels and AUC were observed following treatment in both groups. Furthermore no significant variation in leptin level was observed during both CRH tests. DISCUSSION: Leptin secretion does not seem to be affected by low-dose inhaled corticosteroids; moreover leptin does not seem to be involved in the response of the HPA axis to stress.

In vitro release of activin A from human normal and pathological thyroid tissues.

Activin A is a dimeric glycoprotein belonging to the transforming growth factor beta (TGF-beta) superfamily characterized by the ability to affect FSH secretion. Activin A was originally indicated as a gonadal product but the expression of activin A has been successively identified in several different tissues, including the thyroid gland. The aim of this study was to evaluate the release of activin A from human normal and pathological thyroid tissues in culture. Activin A concentration was evaluated in media obtained from primary culture of perinodular normal tissues (no.=2), hyperplastic hyperfunctioning thyroid tissues due to Graves' disease (no.=3) and autonomous thyroid adenomas (no.=3). Detectable levels of activin A were found in the incubation media from all tissues, without significant differences between normal and pathological samples. We conclude that activin A is secreted by follicle thyroid cells in normal and pathological conditions.

Activin A serum levels and aging of the pituitary-gonadal axis: a cross-sectional study in middle-aged and elderly healthy subjects.

Aim of the study was to investigate activin A serum concentration in healthy adult males and post-menopausal females over a wide age-range and its correlation to gonadotropins, inhibin B and testosterone concentrations. The study included 73 males (aged 30-101 years) and 42 postmenopausal females (aged 50-104 years). Blood samples were collected after an overnight fast to measure serum activin A, inhibin B, LH, FSH, and gonadal steroid levels. A significant increase in serum activin A levels over age in both genders, especially in the oldest age-groups, was observed. Serum inhibin B and testosterone concentrations showed a sharp decrease in male subjects, reflecting the age-related decrease of testicular function and by consequence serum FSH and LH significantly increased. In female subjects LH and FSH levels were very high in subjects in their 50s and showed a continuous decline due to pituitary aging. Simple and multivariable regression analyses demonstrated the lack of correlation between activin A and FSH in both males and females. In conclusion, a steep increase in activin A levels is present during aging in both genders, especially in the last decades of life. The physiologic role and site of production of activin A in old subjects remain to be clarified.

Fetal plasma leptin concentrations: relationship with different intrauterine growth patterns from 19 weeks to term.

The relationship between in utero fetal growth and fetal leptin concentrations was investigated between 19 and 41 wk in 40 normal (appropriate for gestational age, AGA) fetuses, in 25 intrauterine growth-restricted (IUGR) fetuses, and in 18 fetuses from gestational diabetic mothers (GDM), representing different intrauterine growth patterns. Umbilical venous plasma leptin concentrations were determined at the time of either in utero fetal blood sampling or delivery. Plasma leptin was measurable as early as 19 wk of gestation. A significant difference was observed between umbilical venous and arterial plasma leptin concentrations (0.6+/-0.6 ng/mL; p<0.01). In AGA and in IUGR fetuses, significant positive relationships were found between fetal leptin concentrations and both gestational age (p<0.001) and fetal weight (p<0.001). Leptin concentrations were significantly higher in AGA than IUGR only after 34 wk (p<0.05), but leptin per kilogram fetal weight (leptin/kg) was not significantly different. In IUGR with abnormal umbilical arterial Doppler velocimetry and fetal heart rate, leptin/kg significantly higher than in IUGR with normal biophysical and biochemical parameters was found (p<0.05). Both circulating plasma leptin and leptin/kg were significantly higher in GDM than in normal fetuses (p<0.001) and correlated with abdominal fat mass measured by ultrasound. No gender differences were observed in any group of fetuses. These findings indicate a clear relationship between fetal leptin concentrations and fetal fat mass. Data in severe IUGR suggest the presence of increased leptin concentrations associated with in utero signs of fetal distress.

Maternal compound W serial measurements for the management of fetal hypothyroidsm.

OBJECTIVE: The diagnosis of fetal hypothyroidism is based at present on measurements of TSH and free thyroxine (FT4) in fetal blood samples obtained by cordocentesis. The measurement of maternal serum and urinary concentrations of compound W, immunologically similar to but chromatographically distinct from diiodothyronine sulfate (T2S), has been advocated as a new possible marker for fetal hypothyroidism. DESIGN: In this paper, we measured serum compound W levels in 84 pregnant women, 20 with and 64 without thyroid disorders before and during specific treatment. Compound W was also assessed in fetal blood obtained by cordocentesis from 49 normal fetuses and 4 fetuses with suspected hypothyroidism due to transplacental passage of propylthiouracil (PTU). Compound W levels were measured by T2S RIA in maternal and fetal serum. To assess the possible usefulness of 3, 5,3'-triiodothyroacetic acid (TRIAC) for therapy of fetal hypothyroidism we evaluated the transplacental passage of TRIAC by administering the drug to four pregnant women before therapeutic abortion. RESULTS: In normal pregnancies, both maternal and fetal compound W levels increased progressively during gestation with a significant direct correlation (P<0.001, in both mothers and fetuses). Moreover, a significant positive correlation was observed between fetal compound W and fetal FT4 values (P<0.005), whereas no correlation was observed between maternal serum compound W and maternal FT4 in either euthyroid or hyperthyroid women, suggesting the fetal origin of compound W. The hypothyroid fetuses of PTU-treated mothers showed low compound W levels, and maternal compound W values were in the low normal range and did not show the typical increase during progression of gestation. A significant increase of maternal compound W was observed when the PTU dose was reduced. TRIAC was documented to cross the placental barrier and the treatment of a hyperthyroid pregnant woman on PTU caused the high fetal TSH levels and goiter to normalize. CONCLUSIONS: Serial measurements of 3,3'-T2S crossreactive materials (compound W and 3, 3'-diiodothyroacetic acid sulfate) in maternal blood and the administration of TRIAC to the mother may represent a useful and safe alternative to invasive techniques for the diagnosis and therapy of fetal hypothyroidism.