Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Chronic Stress as a Risk Factor for Type 2 Diabetes: Endocrine, Metabolic, and Immune Implications.

BACKGROUND: Chronic stress is a condition of pressure on the brain and whole body, which in the long term may lead to a frank disease status, even including type 2 diabetes (T2D). Stress activates the hypothalamus-pituitary-adrenal axis with release of glucocorticoids (GCs) and catecholamines, as well as activation of the inflammatory pathway of the immune system, which alters glucose and lipid metabolism, ultimately leading to beta-cell destruction, insulin resistance and T2D onset. Alteration of the glucose and lipid metabolism accounts for insulin resistance and T2D outcome. Furthermore, stress-related subversion of the intestinal microbiota leads to an imbalance of the gut-brain-immune axis, as evidenced by the stress-related depression often associated with T2D. Inflammatory mechanisms: A condition of generalized inflammation and subversion of the intestinal microbiota represents another facet of stress-induced disease. In fact, chronic stress acts on the gut-brain axis with multi-organ consequences, as evidenced by the association between depression and T2D. Novel Therapeutic Options: Oxidative stress with the production of reactive oxygen species and cytokine-mediated inflammation represents the main hallmarks of chronic stress. ROS production and pro-inflammatory cytokines represent the main hallmarks of stress-related disorders, and therefore, the use of natural antioxidant and anti-inflammatory substances (nutraceuticals) may offer an alternative therapeutic approach to combat stress-related T2D. Single or combined administration of nutraceuticals would be very beneficial in targeting the neuro-endocrine-immune axis, thus, regulating major pathways involved in T2D onset. However, more clinical trials are needed to establish the effectiveness of nutraceutical treatment, dosage, time of administration and the most favorable combinations of compounds. Therefore, in view of their antioxidant and anti-inflammatory properties, the use of natural products or nutraceuticals for the treatment of stress-related diseases, even including T2D, will be discussed. Several evidences suggest that chronic stress represents one of the main factors responsible for the outcome of T2D.

Thyroid and COVID-19: a review on pathophysiological, clinical and organizational aspects.

BACKGROUND: Thyroid dysfunction has been observed in patients with COVID-19, and endocrinologists are requested to understand this clinical issue. Pandemic-related restrictions and reorganization of healthcare services may affect thyroid disease management. OBJECTIVE AND METHODS: To analyze and discuss the relationship between COVID-19 and thyroid diseases from several perspectives. PubMed/MEDLINE, Google Scholar, Scopus, ClinicalTrial.gov were searched for this purpose by using free text words and medical subject headings as follows: "sars cov 2", "covid 19", "subacute thyroiditis", "atypical thyroiditis", "chronic thyroiditis", "hashimoto's thyroiditis", "graves' disease", "thyroid nodule", "differentiated thyroid cancer", "medullary thyroid cancer", "methimazole", "levothyroxine", "multikinase inhibitor", "remdesivir", "tocilizumab". Data were collected, analyzed, and discussed to answer the following clinical questions: "What evidence suggests that COVID-19 may induce detrimental consequences on thyroid function?"; "Could previous or concomitant thyroid diseases deteriorate the prognosis of COVID-19 once the infection has occurred?"; "Could medical management of thyroid diseases influence the clinical course of COVID-19?"; "Does medical management of COVID-19 interfere with thyroid function?"; "Are there defined strategies to better manage endocrine diseases despite restrictive measures and in-hospital and ambulatory activities reorganizations?". RESULTS: SARS-CoV-2 may induce thyroid dysfunction that is usually reversible, including subclinical and atypical thyroiditis. Patients with baseline thyroid diseases are not at higher risk of contracting or transmitting SARS-CoV-2, and baseline thyroid dysfunction does not foster a worse progression of COVID-19. However, it is unclear whether low levels of free triiodothyronine, observed in seriously ill patients with COVID-19, may worsen the disease's clinical progression and, consequently, if triiodothyronine supplementation could be a tool for reducing this burden. Glucocorticoids and heparin may affect thyroid hormone secretion and measurement, respectively, leading to possible misdiagnosis of thyroid dysfunction in severe cases of COVID-19. High-risk thyroid nodules require a fine-needle aspiration without relevant delay, whereas other non-urgent diagnostic procedures and therapeutic interventions should be postponed. DISCUSSION: Currently, we know that SARS-CoV-2 could lead to short-term and reversible thyroid dysfunction, but thyroid diseases seem not to affect the progression of COVID-19. Adequate management of patients with thyroid diseases remains essential during the pandemic, but it could be compromised because of healthcare service restrictions. Endocrine care centers should continuously recognize and classify priority cases for in-person visits and therapeutic procedures. Telemedicine may be a useful tool for managing patients not requiring in-person visits.

Platelet number is positively and independently associated with glycated hemoglobin in non-diabetic overweight and obese subjects.

BACKGROUND AND AIMS: A significant increase in platelet count may be a risk factor for atherosclerotic cardiovascular disease. This study investigates the association between platelet number and glucose metabolism, evaluated by glycated hemoglobin (HbA1c) levels, in a apparently healthy population represented by overweight and obese subjects with normal glucose and HbA1c levels. METHODS AND RESULTS: As many as 240 subjects, 177 women and 63 men, aged 18-70 years, were enrolled. Body mass index (BMI), waist circumference (WC), systolic and diastolic blood pressure levels, platelet count and fasting blood glucose, insulin, insulin resistance, HbA1c, uric acid, triglyceride, total cholesterol, high and low density lipoprotein cholesterol concentrations were evaluated. Concerning the univariate correlation analyses between platelets number and all other variables, platelet count was significantly (and positively) correlated only with HbA1c (P < 0.05) and female sex (P < 0.01). HbA1c (P < 0.05), female sex (P < 0.001), and diastolic blood pressure (P < 0.01), positively, and age (P < 0.05) and systolic blood pressure (P < 0.05), negatively, were significantly and independently associated to platelet count in a final multiple regression analysis. CONCLUSION: This is the first study showing a strong positive and independent relationship between HbA1c and platelet number in non-diabetic overweight and obese subjects.

Platelet number is negatively and independently associated with carotid intima-media thickness in apparently healthy overweight/obese subjects.

BACKGROUND AND AIM: A significant change of platelet number may be a risk factor for atherosclerotic cardiovascular disease. The aim of this study was to investigate the association between platelet number and early signs of atherosclerosis, evaluated by carotid intima-media thickness (c-IMT), in a apparently healthy population mainly represented by obese subjects. METHODS AND RESULTS: As many as 961 subjects, 686 women and 275 men, aged between 18 and 74 years, were enrolled in the study. Of these, 54 individuals (5.6% of all subjects) were normal weight, 259 individuals (27.0% of all subjects) were overweight, and 648 individuals (67.4% of all subjects) were obese. Waist circumference (WC) and blood glucose, insulin, total cholesterol, high and low density lipoprotein cholesterol, triglycerides and platelet count were also detected in all subjects, who underwent carotid echo color doppler ultrasound to measure c-IMT. c-IMT was significantly and positively associated to age (r = 0.204, P < 0.0001), fasting glucose (r = 0.073, P < 0.0240), total cholesterol (r = 0.096, P = 0.0031), and systolic and diastolic blood pressure (r = 0.140, P < 0.0001 and r = 0.119, P < 0.0003 respectively); c-IMT was significantly and negatively correlated with platelet count (r = -0.165, P < 0.0001). Only age (P < 0.0001) and systolic blood pressure (P = 0.0393), positively, and platelet number (P < 0.0001), negatively, were significantly and independently associated to c-IMT in a final multiple regression analysis. CONCLUSION: Lower platelet number represented an independent determinant of c-IMT in a population, mainly represented by obese patients. These results suggest that a decrease of platelet number may well be an early defensive mechanism in subjects developing the thickening of carotid artery.

Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism.

The aim of this retrospective observational study was to evaluate whether adding liraglutide to lifestyle changes, metformin (Met) and testosterone replacement therapy (TRT), by means of improving weight and glycaemic control, could boost erectile function in type 2 diabetic obese men with overt hypogonadism and erectile dysfunction (ED) in a 'real-life setting'. Forty-three obese, diabetic and hypogonadal men (aged 45-59 years) were evaluated because of complaining about the recent onset of ED. They were subdivided into two groups according to whether hypogonadism occurred after puberty (G1; n = 30: 25 with dysfunctional hypogonadism and 5 with acquired hypogonadotropic hypogonadism) or before puberty (G2; n = 13: 10 with Klinefelter's syndrome and 3 with idiopathic hypogonadotropic hypogonadism). Both G1 and G2 patients were given a combination of testosterone (T) [testosterone undecanoate (TU) 1000 mg/every 12 weeks] and Met (2000-3000 mg/day) for 1 year. In the poor responders (N) to this therapy in terms of glycaemic target (G1N: n = 16; G2N: n = 10), liraglutide (L) (1.2 µg/day) was added for a second year, while the good responders (Y) to T + Met (G1Y: 14/30 and G2Y: 3/13) continued this two drugs regimen therapy for another year. All patients were asked to fill in the International Index of Erectile Function (IIEF 15) questionnaire before starting TU plus Met (T1) and after 12 months (T2) and 24 months (T3) of treatment. Patients underwent a clinical examination and a determination of serum sex hormone binding globulin (SHBG), total testosterone (T) and glycosylated haemoglobin (HbA1c) at T1, T2 and T3. At T2, each patient obtained an improvement of ED (p < 0.01) and of the metabolic parameters without reaching, however, the glycaemic goals [HbA1c = >7.5% (>58 mmol/mol)], while T turned out to be within the range of young men. L added to TU and Met regimen in G1N and G2N allowed these patients to reach not only the glycaemic target [HbA1c = <7.5% (<58 nmol/mol)] and a significant reduction in body weight (p < 0.01), but also a further increase in SHBG (p < 0.05) and T (p < 0.01) plasma levels as well as a significant increment of IIEF score (T3). Conversely, at T3 G1Y and G2Y, who received the combined therapy with TRT and Met for the second year, showed a partial failure of that treatment given that there was no improvement of the IIEF score and they showed a significant rise in serum HbA1c (p < 0.05) and weight (p < 0.04) compared with the assessments at T2. These results suggest that TRT could improve clinical and metabolic parameters in obese, type 2 diabetic men with ED and overt hypogonadism (independently of when T deficit occurred). Furthermore, in case of insufficient metabolic control the addition of L to TRT and Met regimen allows to achieve serum T levels in the range of healthy men, as well as to reach glycaemic target and to lower weight, leading to a considerable improvement of ED.

Potential benefit of dehydroepiandrosterone supplementation for infertile but not poor responder patients in a IVF program.

AIM: The aim of this paper was to evaluate the hypothesis that pretreatment with dehydroepiandrosterone (DEHA) may improve the result on in vitro fertilization (IVF) and the pregnancy outcome among infertile women with normal ovarian reserve. METHODS: Double-blind, randomized, placebo-controlled study; 52 infertile patients received the long protocol IVF. Patients in Group 1, received 75 mg of DHEA once a day, 8 weeks before starting the IVF cycle and during treatment; control group (Group 2) received placebo. The primary endpoint was pregnancy, live birth and miscarriage rates, secondary endpoint was standard IVF parameters such us stimulation duration (hCG day), E2 on HCG-day, endometrial thickness, number of retrieved oocytes, metaphase II oocytes, embryos transferred and score of leading embryos transferred. RESULTS: Patients in the DHEA group had a significantly higher live birth rate compared with controls (P<0.05). Miscarriage rate was higher in control group (P<0.05). CONCLUSION: DHEA supplementation could have a beneficial effect on IVF outcome in infertile women with normal ovarian reserve.

Neurobehavioral studies, in transgenic F3/CONTACTIN (C57BL/6J × CBA) mice, on cognitive and anxiety aspects during late-adolescential period.

OBJECTIVE: Besides than in the control of developmental events, axonal adhesive glycoproteins may be also involved in functions requiring fine organization and connectivity of the nervous tissue. We previously demonstrated morphological alterations and functional cerebellar deficits in transgenic mice (TAG/F3 mice) ectopically expressing the F3/Contactin axonal glycoprotein under the control of a selected regulatory region from the Transient Axonal Glycoprotein (TAG-1) gene. In the present study, the hippocampal function was explored by evaluating the ability of TAG/F3 mice to encode spatial and non-spatial relationships between discrete stimuli and to analyze an anxiety-related behavior. MATERIALS AND METHODS: To the first end, mice were placed in an "open-Field" containing five objects and, after three sessions of habituation (S2-S4), their reactivity to objects displacement (S5-S4) and object substitution (S7-S6) was examined.To the second end, mice were placed in the "elevated zero maze", a standard test to explore the anxiety-related behavior, in order to study, in transgenic mice, the effects of F3 misexpression on emotional reactivity by measuring the avoidance of the unsheltered open sectors. RESULTS: Statistical evaluations of reactivity to object novelty, TAG-F3 mice showed a lower DO exploration with respect to wild-type mice and, regarding DOs, TAG/F3 mice interacted less than wild-type mice, showing an impaired spatial change response. Furthermore, the number of HDIPS in transgenic TAG/F3 mice resulted significantly lower with respect to the controls (wild type). CONCLUSIONS: These results indicate that the coordinated expression of axonal adhesive glycoproteins may be relevant for the functional maturation of the hippocampus.

Could androgen receptor gene CAG tract polymorphism affect spermatogenesis in men with idiopathic infertility?

PURPOSE: This study examined whether the AR-CAG repeat length might affect clinical characteristics (testis volume) seminal parameters (sperm count and its mobility) along with hormonal serum profile [FSH, LH, Testosterone (T) and Inhibin B (InhB)] both in idiopathic male infertility (IM) and in infertility due to a previous condition of cryptorchidism (CryM) or to Y chromosome long arm microdeletions (YM). DESIGN: Observational study without intervention(s). PATIENTS: One hundred and ten IM patients [90 idiopathic olizoospermic males (IOM) and 20 idiopathic azoospermic males (IAM)], 19 CryM male and 10 YM patients were included. Sixty-one age-matched healthy men who had fathered within 3 years were involved representing the control group (FM). RESULTS: AR-CAG repeats stretch was significantly longer in IOM (p<0.05), CryM (p<0.05) and YM (p<0.001) than FM. When the AR-CAG repeat tracts were subdivided in three subgroups according to the length of CAG repeats tract assessed in fertile subjects (the one with the middle (n 19-21) belonging to the 25 and 75 % inter-quartile, the ends belonging to the <25 % inter-quartile and >75 % inter-quartile, respectively), there was a statistically significant difference of distribution of AR-CAG tract length among fertile and different groups of infertile men (p=<0.0005; chi-square test). Moreover, the subgroup of AR-CAG repeat stretch with 22-28 triplets was associated with lower levels of InhB both in idiopathic oligozoospermic (Scheffe, Bonferroni and Dunett tests p=<0.01) and azoospermic men (Scheffe, Bonferroni and Dunett test p=<0.05), while, when FM and men with idiopathic infertility were gathered in a single group, both the subgroup of AR- CAG tract with 15-18 repeats and the one with 22-28 repeats are associated with lower testis volume, reduced sperm count and serum InhB levels. CONCLUSIONS: Our study showed that the outliers of AR-CAG repeat length seem to influence the function of AR, affecting testis volume and Sertoli cell function and consequently sperm production in both fertile and idiopathic infertile men.

Free triiodothyronine is associated with smoking habit, independently of obesity, body fat distribution, insulin, and metabolic parameters.

BACKGROUND: The aim of this study was to examine the relationship between thyroid hormones and smoking and several other parameters like age, gender, insulin, and anthropometric and metabolic parameters in subjects with a wide range of body mass index (BMI). PATIENTS AND METHODS: A total of 931 euthyroid normal weight (BMI<25.0 kg/m2), overweight and obese subjects (BMI ≥25.0 kg/m2), 663 women and 268 men, aged 18-68 yr, were investigated. Fasting TSH, free T3 (FT3), free T4 (FT4), insulin, glucose, and lipid serum levels were determined. Waist circumference was measured as an indirect parameter of central fat accumulation. RESULTS: Smokers were younger (p<0.001) and showed higher FT3 (p<0.01), and triglyceride (p<0.01) levels and lower glucose (p<0.01) and HDL (p<0.001) concentrations than non smoking subjects. FT3 levels were directly associated with BMI (p<0.001), waist circumference (p<0.001), insulin (p<0.001), and triglyceride (p<0.01) levels and negatively correlated with age (p<0.001) and HDL-cholesterol levels (p<0.001). When a multiple regression analysis was performed with FT3 levels as the dependent variable, and smoking, age, gender, and TSH, insulin, triglyceride, and HDL-cholesterol serum concentrations as independent variables, FT3 levels maintained an independent positive association with smoking (p<0.05), age (p<0.001), male sex (p<0.001), waist circumference (p<0.05), and insulin levels (p<0.001). CONCLUSIONS: Smoking increases FT3 levels independently of age, gender, obesity, body fat distribution and metabolic parameters.

Abdominal fat accumulation, and not insulin resistance, is associated to oligomenorrhea in non-hyperandrogenic overweight/obese women.

BACKGROUND: There is a very high prevalence of obese women in the infertile population and many studies have highlighted the link between obesity and infertility. The aim of this study was to evaluate the prevalence of oligomenorrhea in uncomplicated obesity, and to examine whether this menstrual alteration is associated with anthropometric, hormonal, and metabolic parameters. PATIENTS AND METHODS: This is a cross-sectional study of 266 overweight and obese body mass index (BMI) > or =25.0 kg x m(-2)] women, all having apparent normal fertility. Measurements included BMI, central fat accumulation (evaluated by waist circumference), blood pressure levels, and fasting insulin, glucose, and lipid (triglycerides, total and HDL-cholesterol) serum concentrations, and insulin resistance [estimated by (homeostasis model assessment) HOMAIR] during the early follicular phase (days 2-5 of the menstrual cycle). RESULTS: One hundred and seventy-one (64.3%) of 266 women had normal menstrual cycles, 57 (21.4%) had oligomenorrhea, and 38 (14.3%) had hypermenorrhea and/or polimenorrhea. Women with oligomenorrhea had higher waist circumference, BMI, HOMAIR, and insulin levels than women with normal menstrual cycles. When association among oligomenorrhea and other variables (waist circumference, BMI, insulin and HOMAIR) was evaluated by logistic regression, and odds ratio was calculated per unit of SD increase, only waist circumference maintained a significant relationship with oligomenorrhea. CONCLUSIONS: This study shows that more than 20% of women with simple obesity have oligomenorrhea, and suggests that central fat accumulation seems to have a possible direct role in this menstrual alteration, independently of hyperinsulinemia and/or insulin resistance.

Relation between adiponectin and bone mineral density in elderly post-menopausal women: role of body composition, leptin, insulin resistance, and dehydroepiandrosterone sulfate.

INTRODUCTION: Adipocytokines have been proposed as new mediators of the protective effects of fat mass on the skeleton. The aim of this study was to test the relationship between adiponectin, leptin, and bone mineral density (BMD), independently of body composition, insulin resistance, and other factors known to affect bone metabolism. METHODS: Thirty-six post-menopausal non-diabetic elderly women, with ages ranging from 66 to 77 yr took part in the study. In all subjects we evaluated body weight, height, body mass index (BMI), waist circumference, adiponectin, leptin, insulin, DHEAS, and homeostasis model assessment of insulin resistance (HOMA), as well as yr since menopause. Total body fat mass (FM) and BMD at whole body and femoral level were measured with Dual energy X-ray Absorptiometry (DXA). Volumetric BMD was defined as the ratio between total body BMD and height. RESULTS: Leptin was positively and adiponectin negatively related with whole body and femoral BMD. Positive associations between insulin, HOMA, DHEAS, and BMD measures were also found. After adjusting for FM, only adiponectin maintained a significant relation with whole body and femoral BMD; the strength of this association was reduced after adjustment for insulin resistance, estimated by HOMA. In stepwise multiple linear regression analyses adiponectin explained 11.7% of total BMD variance, 17.4% of femoral neck BMD variance, and 30.7% of volumetric BMD variance, independently of BMI, FM, leptin, HOMA, and DHEAS. CONCLUSIONS: The present study may suggest possible involvement of adiponectin in bone metabolism, independently of FM and insulin resistance even in elderly post-menopausal women.

sP-selectin plasma levels in obesity: association with insulin resistance and related metabolic and prothrombotic factors.

BACKGROUND AND AIM: Soluble P-selectin (sP-sel) represents a marker of platelet activation. This study was addressed to investigate the associations of sP-sel plasma levels with anthropometric parameters, insulin resistance, and related metabolic and prothrombotic factors. METHODS AND RESULTS: 50 non-diabetic women, 17 with normal weight and 33 overweight and obese, aged 18-55 years, were examined. Measurements included body mass index (BMI), central fat accumulation (evaluated by waist circumference), systolic and diastolic blood pressure levels, fasting plasma concentrations of sP-sel, glucose, lipids (triglycerides, total cholesterol and HDL-cholesterol), insulin, and prothrombotic factors (plasminogen activator inhibitor-1, von Willebrand factor, fibrinogen), and insulin resistance (estimated by the homeostasis model assessment: HOMA(IR)). Overweight and obese women had higher fasting plasma sP-sel concentrations compared to normal-weight controls (P<0.05). sP-sel concentrations were positively correlated with BMI, HOMA(IR), systolic and diastolic blood pressure, fasting insulin, triglyceride and PAI-1 plasma levels (P<0.05 for all the correlations). When a multiple regression analysis was performed, with P-sel as dependent variable and all the other parameters as independent variables, P-sel did not maintain a significant relationship with any of these variables. CONCLUSIONS: s-P-selectin plasma concentrations are higher in overweight and obese insulin resistant subjects, thus possibly contributing to the cardiovascular risk of these patients. However, body fatness and insulin resistance are not independent determinants of fasting plasma sP-sel concentrations.

Haptoglobin serum levels are independently associated with insulinemia in overweight and obese women.

BACKGROUND: Obesity is associated with a chronic low-grade inflammatory condition. Haptoglobin is a glycoprotein involved in the acute-phase response to inflammation, and it is increased in obese subjects. The possibility that hyperinsulinemia and/or insulin resistance may directly increase haptoglobin levels has never been tested. The aim of this study was to investigate the associations of haptoglobin serum levels with anthropometric parameters, insulin levels, insulin resistance and related metabolic variables in overweight and obese women. PATIENTS AND METHODS: This is a cross-sectional study of 194 non-diabetic overweight and obese subjects, aged 18-68 yr. Measurements included body mass index (BMI), central fat accumulation [evaluated by waist circumference (WC)], systolic and diastolic blood pressure, and fasting concentrations of haptoglobin, insulin, glucose, lipids (triglycerides, total cholesterol, and HDL-cholesterol), and insulin resistance as estimated by the homeostasis model assessment (HOMAIR). RESULTS: Haptoglobin serum levels showed a positive association with BMI (p<0.001), WC (p<0.001), HOMAIR (p<0.001), and fasting insulin (p<0.001), triglyceride (p<0.001) and glucose (p<0.05) blood levels. However, only insulin maintained a significant independent association with haptoglobin (p<0.001) when a multiple regression analysis was performed and age, BMI (or WC), blood pressure levels, HOMAIR, and fasting insulin, glucose, and lipid blood concentrations were entered as independent variables. CONCLUSIONS: Higher haptoglobin serum levels seem to be a strong marker of hyperinsulinemia, independently of BMI, body fat distribution, insulin resistance and related parameters.

Free triiodothyronine and thyroid stimulating hormone are directly associated with waist circumference, independently of insulin resistance, metabolic parameters and blood pressure in overweight and obese women.

OBJECTIVE: To examine whether obesity, body fat distribution and insulin resistance have an independent effect on serum TSH and free thyroid hormones (FT3 and FT4) in a cohort of euthyroid women, represented by overweight and obese patients. DESIGN AND PATIENTS: A total of 201 women, aged 18-68 years, with body mass index (BMI) > or = 25.0 kg/m(2) and TSH levels < 4.0 mU/l were investigated. MEASUREMENTS: Fasting TSH, FT3, FT4, insulin, glucose, and serum lipid concentrations, and the level of insulin resistance, estimated by the homeostasis model assessment for insulin resistance (HOMA-IR). Waist circumference was measured as an indirect parameter of central fat accumulation. RESULTS: FT3 was directly associated with BMI (P < 0.01) and waist circumference (P < 0.01), and negatively correlated with age (P < 0.001). FT4 was negatively associated with HOMA-IR (P < 0.05) and fasting insulin levels (P < 0.05). TSH was positively correlated with waist circumference (P < 0.05) and negatively associated with age (P < 0.05). When multiple regression analysis was performed with FT3 as the dependent variable, and waist circumference, HOMA-IR, blood pressure levels and serum lipid concentrations as independent variables, FT3 maintained an independent association only with waist circumference (positive, P < 0.05) and age (negative, P < 0.001). When multiple regression analysis was performed with TSH as the dependent variable, and the above parameters as independent variables, TSH maintained an independent association only with waist circumference (positive, P < 0.05) and age (negative, P < 0.05). By contrast, when multiple regression analysis was performed with FT4 as the dependent variable, FT4 did not maintain an independent association with any of the independent parameters. CONCLUSIONS: Progressive central fat accumulation is associated with an increase in both FT3 and TSH serum levels, independently of insulin sensitivity, metabolic parameters and blood pressure. These results suggest that (1) progressive central fat accumulation is associated with a parallel increase in FT3 levels, possibly as an adaptive thermogenic phenomenon, and (2) the control of TSH secretion by free thyroid hormones is possibly impaired in obesity.

WNT10B mutations in human obesity.

AIMS/HYPOTHESIS: Recent studies suggest that wingless-type MMTV integration site family, member 10B (WNT10B) may play a role in the negative regulation of adipocyte differentiation in vitro and in vivo. In order to determine whether mutations in WNT10B contribute to human obesity, we screened two independent populations of obese subjects for mutations in this gene. SUBJECTS AND METHODS: We studied 96 subjects with severe obesity of early onset (less than 10 years of age) from the UK Genetics of Obesity Study and 115 obese Italian subjects of European origin. RESULTS: One proband with early-onset obesity was found to be heterozygous for a C256Y mutation, which abrogated the ability of WNT10B to activate canonical WNT signalling and block adipogenesis and was not found in 600 control alleles. All relatives of the proband who carried this allele were either overweight or obese. Three other rare missense variants were found in obese probands, but these did not clearly cosegregate with obesity in family studies and one (P301S), which was found in three unrelated subjects with early-onset obesity, had normal functional properties. CONCLUSIONS/INTERPRETATION: These mutations represent the first naturally occurring missense variants of WNT10B. While the pedigree analysis in the case of C256Y WNT10B does not provide definitive proof of a causal link of this variant with obesity, the finding of a non-functioning WNT10B allele in a human family affected by obesity should encourage further study of this gene in other obese populations.

Influence of subclinical hypothyroidism and T4 treatment on the prevalence and severity of obstructive sleep apnoea syndrome (OSAS).

BACKGROUND: Obstructive sleep apnoea (OSA) and subclinical hypothyroidism are relatively frequent disorders that may be causally linked. However, discordant results exist on the prevalence and severity of OSA in subclinical hypothyroidism. The aim of this study was to compare the prevalence and severity of sleep-disordered breathing in individuals with or without subclinical hypothyroidism, and to investigate the possible effect of levothyroxine treatment on these patients. PATIENTS AND METHODS: One hundred and eight subjects were consecutively enrolled and divided in 3 groups, according to the TSH levels and levothyroxine therapy. The first group (Group A) was represented by 63 subjects with normal TSH and thyroid function. The other two groups included patients affected by subclinical hypothyroidism; one group (Group B) treated with levothyroxine, while the other group (Group C) was never treated with levothyroxine. Anthropometric, respiratory and polysomnographic data were evaluated in all individuals. RESULTS: The percentage of OSA, neck circumference, and body mass index (BMI) were not statistically different among the 3 groups. Respiratory disturbance index (RDI) as well as the percentage of the total number of events (apnoea-hypopnoea) by total sleep time (TST) with <90% oxyhemoglobin saturation (TSTSaO2 <90%) were not different among the groups. When we observed OSA patients, the only significant difference between groups B and C was represented by the Epworth Sleepiness Scale (ESS) (p=0.005). CONCLUSION: This study shows that subclinical hypothyroidism and treatment with levothyroxine do not influence the prevalence and severity of OSA, while sleep propensity is increased by untreated subclinical hypothyroidism.

High prevalence of previously unknown subclinical hypothyroidism in obese patients referred to a sleep clinic for sleep disordered breathing.

BACKGROUND AND AIM: To evaluate the prevalence of previously unknown hypothyroidism in adult male and female patients with a wide range of body mass index (BMI) values, referred to a Sleep Clinic because of sleep disordered breathing (SDB). METHODS AND RESULTS: Serum concentrations of thyroid stimulating hormone (TSH) and free thyroxin (fT4), as well as forced vital capacity (FVC), PaO2, PaCO2, the Epworth sleepiness scale (ESS), respiratory disturbance index (RDI), loud snoring, and the percentage of total sleep time (TST) with <90% oxyhemoglobin saturation (TST(saO2<90%)) were measured in 78 overweight and obese adult subjects with no previous diagnosis of hypothyroidism (age: 18-72 years). The prevalence of previously undiagnosed subclinical hypothyroidism in the population as a whole was 11.5%. BMI, TSH and ESS were significantly higher in the hypothyroid than the euthyroid subjects, but there was no significant between-group difference in RDI, TST(saO2<90%) or the other investigated variables, including the prevalence of obstructive sleep apnea (OSA). Among the hypothyroid individuals, BMI, neck circumference, ESS, RDI and TST(Sao2<90%) were significantly higher in those with than in those without OSA. Furthermore, there was a clear trend towards a lower FVC% and higher snoring score in the OSA patients. CONCLUSIONS: Our results demonstrate a higher prevalence of hypothyroidism than that commonly reported in overweight and obese individuals referred to a Sleep Clinic for polysomnography because of SDB, thus suggesting that thyroid function should be evaluated in all obese patients suffering from SDB despite economic concerns.

Prevalence of obstructive sleep apnoea in a sample of obese women: effect of menopause.

BACKGROUND: Obesity is a well known risk factor for obstructive sleep apnoea (OSA). Previous studies have investigated the prevalence of OSA among obese people, but a sample of women was rarely studied. OBJECTIVE: To describe the anthropometric and polysomnographic characteristics of a sample of obese women and investigate the effect of menopause on the prevalence of OSA. MATERIALS AND METHODS: Using a full-night polysomnography we studied a sample of 133 obese women with a body mass index (BMI) > or = 30 kg/m2. RESULTS: About 44% of our sample had a respiratory disturbance index (RDI) > or = 10. Neck circumference, BMI and age resulted the strongest predictors of RDI value. We also found that the prevalence of OSA was higher among post-menopausal women (67%) in comparison with pre-menopausal women (31%). Moreover, post-menopausal women had larger neck circumference and higher waist-to-hip circumference ratio (WHR). CONCLUSIONS: Among post-menopausal obese women the prevalence of OSA increases. We suggest that menopause could cause a different body fat distribution with an increase of fat in upper parts of the body and, consequently, with an increase of neck circumference.

Gender, age and menopause effects on the prevalence and the characteristics of obstructive sleep apnea in obesity.

BACKGROUND: In the 1970s and 80s it was believed that obstructive sleep apnea (OSA) was primarily a disease of men. The present study was addressed to evaluate the effect of gender and menopause on the prevalence and the characteristics of OSA and on anthropometric, clinical, respiratory and polysomnographic data in a population of obese individuals. PATIENTS AND METHODS: A total of 230 obese subjects (BMI >/= 30 kg m-2), 148 women and 82 men, aged 16-75 years, were recruited and evaluated for general and anthropometric parameters, respiratory function, sleep-related symptoms and sleep disorders of breathing. RESULTS: Respiratory disturbance index (RDI) and the prevalence of OSA were lower in women than in men (P < 0.001 and P < 0.001, respectively). Among subjects < 55 years, neck circumference, percentage of predicted normal neck circumference (PPNC), waist-to-hip ratio (WHR), PaCO2, RDI and the prevalence of OSA were lower in female subjects (P = 0.05, P < 0.05, P < 0.001, P < 0.01 and P < 0.01, respectively). BMI, neck circumference, PPNC, WHR, RDI and the prevalence of OSA were higher in postmenopausal compared with premenopausal women (P < 0.01, P < 0.01, P < 0.01, P < 0.01 and P < 0.01, respectively). CONCLUSIONS: Our study demonstrates that (i) the male dominance regarding the prevalence and the severity of OSA disappears in men older than 55 years, and (ii) menopause seems to play a pivotal role in modulating both the presence and the degree of sleep disorder.