Paradoxical effect of dopamine-agonists on IGF-1 in patients with prolactinoma: the role of weight.

PURPOSE: An increase of IGF-1 has been reported during therapy with dopamine agonists (DA) for prolactinomas; in such cases a correct diagnosis is pivotal to avoid an unnecessary reduction or withdrawal of DA, which are needed to maintain normal prolactin levels. This study was aimed to measure IGF-1 levels, at baseline and during follow-up, in a cohort of patients with prolactinoma, treated with cabergoline, stratified by body mass index. METHODS: We retrospectively enrolled 35 patients (15 F/20 M; age m ± SD, years: 43.4 ± 13.7) with prolactinoma (21 microadenomas and 14 macroadenomas) who were followed-up at the Endocrinology Unit, in Siena, and with available pituitary hormone assessment at baseline and during follow-up (m ± SD, years: 2.74 ± 0.55). RESULTS: IGF-1 increased in the whole cohort, but remaining within normal range, except two patients, in whom acromegaly was ruled out with oral glucose tolerance test. After dividing patients by weight, this trend was confirmed only in subjects with overweight and obesity (OV/OB) (p = 0.04). Interestingly, the reduction of prolactin levels was significantly greater in the OV/OB compared to normal-weight patients (median decrease of 97.5% versus 88.2%, p = 0.04). CONCLUSIONS: Since DA and normalization of prolactin are known to improve insulin sensitivity, we speculated they have favored the increase of IGF-1 in OV/OB. Our results should be confirmed and the hypothesis proven by further studies.

Traffic-related air pollution associations with cytokeratin-18, a marker of hepatocellular apoptosis, in an overweight and obese paediatric population.

INTRODUCTION: Traffic-related air pollution causes fatty liver, inflammation and fibrosis in animal models, but there have been few studies in humans. OBJECTIVES: To test the hypothesis that traffic-related air pollution causes non-alcoholic fatty liver disease (NAFLD) and increased markers for non-alcoholic steatohepatitis (NASH); and that NAFLD increases liver susceptibility to increased NASH risk. METHODS: Data collected prospectively from 74 overweight or obese children were obtained from the Yale Pediatric Obesity Clinic. Traffic-related air pollution was characterized as vehicle traffic volume on major roads within a 1 km residential buffer, and as residential nitrogen dioxide (NO2 ) exposure. Outcomes were hepatic fat fraction (HFF) measured by magnetic resonance imaging, liver enzymes using standard assays and plasma cytokeratin-18 (CK-18) by immunosorbent assays. RESULTS: Significant non-linear relationships with air pollution and CK-18 were found. Plasma CK-18 at follow-up increased from approximately 150 U/L to almost 200 U/L as residential traffic volume increased from 220 000 vehicle-km to 330 000 vehicle-km, after adjustment for baseline CK-18, age and gender. Among patients with NAFLD at baseline, CK-18 increased from 140 U/L to 200 U/L (a 1.5 standard deviation increase in CK-18) as NO2 increased from 8 to 10 ppb. CONCLUSIONS: Traffic-related air pollution was associated with CK-18. Effects were larger in children with pre-existing NAFLD at study entry.

Psychosocial predictors and moderators of weight management programme outcomes in ethnically diverse obese youth.

BACKGROUND: An important area of research in childhood obesity is the identification of factors that predict or moderate the responses to obesity intervention programmes, yet few studies have examined the impact of self-esteem and family functioning on obesity treatment outcomes. OBJECTIVES: We sought to determine whether baseline self-esteem and family functioning predicted or moderated childhood obesity intervention outcomes at 6 months. METHODS: From 2009 to 2011, seventy-five 10-16 year old, racially/ethnically diverse obese youths with abnormal glucose tolerance were randomized to 6 months of an intensive family-based obesity lifestyle intervention (Bright Bodies) or routine outpatient Clinic Care. We examined youth self-concept, parent-rated family functioning and 6-month outcomes (youths' glucose tolerance, weight, body mass index and percent fat). We set the significance threshold as P ≤ 0.05 for moderator and predictor analyzes. RESULTS: Having poor family functioning and self-concept scores indicating high anxiety and low self-esteem at baseline predicted poor 6-month outcomes overall (Bright Bodies and Clinic Care groups combined). Additionally, baseline self-esteem and family functioning moderated treatment effects such that Bright Bodies outperformed Clinic Care in youths with low self-esteem and poorly functioning families, whereas youths with high self-esteem and high-functioning families did similarly well with either intervention. DISCUSSION: Our findings suggest intensive family-based lifestyle programmes are particularly beneficial for youth with low self-esteem and poorly functioning families.

Islet function in obese adolescents.

Concurrent with the epidemic of childhood obesity, an unprecedented increase in the prevalence of several adiposity-related complications in this age group has emerged. In particular, type 2 diabetes (T2D), once considered an illness restricted to adulthood, is progressively affecting more and more adolescents, and represents now roughly 20-45% of new-onset cases in this age group. To unravel the pathogenesis of diabetes development during adolescence, many studies have focused on defining early defects in both insulin sensitivity and secretion that might be implicated in the natural history of the disease. Although a lot still need to be clarified, studies have shown that the progression from normal glucose tolerance to T2D involves intermediate stages of impaired fasting glucose and/or impaired glucose tolerance, also known as prediabetes. Insulin resistance and ß-cell dysfunction represent the two major key pathogenetic defects underlying the progression to diabetes in obese youth. In this review, we have sought to mainly describe the role of ß-cell function in relation to the ambient insulin resistance in the development of T2D in obese adolescents.

1-Hour plasma glucose in obese youth.

Adults with normal glucose tolerance (NGT) but exaggerated plasma glucose excursion at 1 h (1HPG) following the oral glucose tolerance test (OGTT) have significantly higher risk of developing impaired glucose tolerance (IGT) or diabetes. Aim of the study will be to characterize the metabolic phenotype of NGT obese youth according to values of 1HPG. To accomplish this aim, obese patients (N = 1,454; 761 men; 79 IGT; BMI z-score 2.56 ± 0.16 SDS; age 11 ± 0.7 years) from two data sets were analyzed. In all patients, empirical parameters of insulin metabolism were calculated in fasting condition and following an OGTT (1.75 mg of glucose per kilogram/body weight). Receiver-operating characteristic (ROC) analysis was performed in the first group (training set, N = 920) to establish the cutoff value of 1HPG best identifying IGT. The second set (validation set, N = 534) served to verify the goodness of the model and the identified cutoff values. 1HPG ≥ 132.5 mg/dl identified IGT with 80.8% sensitivity and 74.3% specificity in the training set (AUC 0.855, 95% CI 0.808-0.902, p < 0.0001), and 70.3% sensitivity and 80% specificity in the validation set (AUC 0.81, 95% CI 0.713-0.907, p < 0.0001), respectively. NGT patients with 1HPG ≥ 132.5 mg/dl had a metabolic phenotype (triglycerides, insulin action, and secretion) that was in between those of NGT patients with 1HPG below the threshold and IGT patients (p < 0.0001 for all the comparisons). 1HPG ≥ 132.5 mg/dl seems to be associated with increased metabolic risk in obese youth, identifying patients with lower insulin sensitivity, early secretion, and higher total insulin secretion than in obese mates with lower 1HPG.

High prevalence of diabetes and pre-diabetes in adults with Williams syndrome.

A standard oral glucose tolerance test (OGTT) was administered to 28 adults with Williams syndrome (WS). Three quarters of the WS subjects showed abnormal glucose curves, meeting diagnostic criteria for either diabetes or the pre-diabetic state of impaired glucose tolerance. Fasting mean glucose and median insulin levels did not differ significantly in the total WS cohort versus age-gender-BMI matched controls, though the glucose area under the curve was greater in the WS subjects. HbA1c levels were not as reliable as the OGTT in diagnosing the presence of diabetes. Given the high prevalence of impaired glucose regulation, adults with WS should be screened for diabetes, and when present should be treated in accordance with standard medical practice. Hemizygosity for a gene mapping to the Williams syndrome chromosome region (WSCR) is likely the major factor responsible for the high frequency of diabetes in WS. Syntaxin-1A is a prime candidate gene based on its location in the WSCR, its role in insulin release, and the presence of abnormal glucose metabolism in mouse models with aberrantly expressed Stx-1a.

High normal fasting glucose level in obese youth: a marker for insulin resistance and beta cell dysregulation.

AIMS/HYPOTHESIS: A high but normal fasting plasma glucose level in adults is a risk factor for future development of type 2 diabetes mellitus and cardiovascular disease. We investigated whether normal fasting plasma glucose levels (<5.60 mmol/l) are associated with decreases in insulin sensitivity and beta cell function, as well as an adverse cardiovascular profile in obese youth. METHODS: We performed a cross-sectional analysis in a multiethnic sample of 1,020 obese youth (614 girls and 406 boys; mean age 12.9 years [CI 95% 12.7-13.1], BMI z score 2.34 [CI 95% 2.31-2.38]) with normal fasting plasma glucose. All participants had a standard OGTT, with calculation of indices of insulin sensitivity and beta cell function. For the analysis, prepubertal and pubertal participants were stratified into quartiles of normal fasting plasma glucose. RESULTS: We observed a significant increase in fasting insulin and AUC 2 h glucose across quartiles. Pronounced changes were observed in insulin sensitivity and secretion, particularly in the pubertal group. Moreover, the odds of presenting with impaired glucose tolerance increased by 4.5% with each 0.06 mmol/l increase in fasting plasma glucose. No significant differences in cardiovascular indices were seen across quartiles. CONCLUSIONS/INTERPRETATION: These data suggest that in obese youth, independent of age, BMI z score, sex, family history and ethnicity, insulin sensitivity and secretion decline when moving from low to high normal fasting plasma glucose. The simple measure of fasting plasma glucose could assist clinicians in identifying children for targeted diabetes screening and subsequent lifestyle management.

Change in leptin, body composition and other hormones around menarche--a visual representation.

AIM: To present a visual representation of changes in body composition, leptin, insulin, estradiol and follicular stimulating hormone (FSH) levels in relation to menarche in girls. METHODS: Participants were a subset of healthy girls (n = 108) enrolled in a longitudinal study of growth and development conducted at the General Clinical Research Center at the Massachusetts Institute of Technology (MIT). Participants were seen annually from before menarche until 4 years postmenarche for measures of body composition and serum levels of leptin, insulin, estradiol and FSH. Body composition was determined by bioelectrical impedance. Standardized body composition and hormone levels were smoothed and plotted relative to menarche to visualize patterns of change. RESULTS: At menarche, the mean percentage body fat (%BF) of girls was 24.6% (SD = 4.1%) after menarche %BF was approximately 27%. Leptin levels averaged 8.4 ng/mL (SD = 4.6) at menarche and were approximately 12 ng/mL after menarche. Changes in leptin levels closely paralleled changes in %BF. Insulin, estradiol and FSH levels followed expected patterns relative to menarche. Leptin began rising closer to menarche than did insulin or the other sex hormones. CONCLUSION: We provide a visual presentation of hormonal and body composition changes occurring throughout the pubertal period in girls which may be useful in generating new hypotheses related to the timing of menarche.

Development of type 2 diabetes in children and adolescents.

Altered glucose metabolism in obese youth is an emerging phenomenon of the last 2 decades, strongly associated with the increase in the prevalence of childhood obesity. Peripheral insulin resistance, tightly coupled with obesity in this age group, seems to be the major driving force of deteriorating glucose metabolism. Patterns of lipid partitioning, mainly an increased deposition of fat in the intramyocellular and visceral compartments are strongly associated with insulin resistance in this population. Impaired glucose tolerance in this age group is characterized by a decline in first phase sensitivity of the beta cell while a combined decline of first and second phase sensitivity is the hallmark of type 2 diabetes. The dynamics of impaired glucose metabolism in childhood seem to be faster than in adults, representing a limited window of opportunity for successful preventive intervention.

Autoantibodies from Sjögren's syndrome induce activation of both the intrinsic and extrinsic apoptotic pathways in human salivary gland cell line A-253.

Sjögren's syndrome (SS) is an autoimmune rheumatic disease that targets salivary and lachrymal glands, characterized by a high concentration of serum autoantibodies directed against nuclear and cytoplasmic antigens. It is known that autoantibodies can enter viable cells and this phenomenon has functional consequences including activation of apoptotic process. The objective of this work was to explore whether autoantibodies contained in IgG purified from Sjögren sera trigger apoptotic process in an experimental model represented by the human salivary gland cell line A-253. To define if the intrinsic or extrinsic pathways are activated, we examined which caspases are critical for inducing cell death. The results have demonstrated that morphological changes and DNA laddering, consistent with apoptotic cell death, occurred in A-253 cells treated with IgG from Sjögren sera. Sjögren IgG induced cleavage and activation of the effector caspase-3 and degradation of the caspase-3 substrate poly(ADP-ribose)polymerase. Both the intrinsic and extrinsic apoptotic pathways were activated, since both caspase-8 and caspase-9 cleavages occurred. In conclusion, autoantibodies contained in IgG purified from Sjögren sera mediate apoptosis of the A-253 cell line in a caspase-dependent manner.

Ethnic differences in beta cell adaptation to insulin resistance in obese children and adolescents.

AIMS/HYPOTHESIS: The prevalence of altered glucose metabolism in obese children and adolescents is growing at a significant rate, especially in ethnic minorities. It is not clear whether young people of different ethnic backgrounds differ in their adaptive mechanisms to obesity-related insulin resistance. The aim of this study was to evaluate the early insulin response and insulin clearance in response to an oral glucose load in obese children and adolescents. METHODS: Seven hundred and nine obese children and adolescents underwent an OGTT. Indices of the early insulin response and insulin clearance were compared in participants of White European, African American and Hispanic origin. RESULTS: Participants of the three ethnic groups demonstrated similar mechanisms of adaptation to increasing insulin resistance, but with different magnitudes. African American subjects had a greater early insulin response and decreased insulin clearance than their White European and Hispanic counterparts. This happened regardless of whether the cohort was divided by glucose tolerance level or by level of insulin sensitivity. IGT across ethnic groups was characterised by a marked decline in the acute insulin response in the context of severe insulin resistance and very low insulin clearance. CONCLUSIONS/INTERPRETATION: In obese children and adolescents, mechanisms of adaptation to obesity related to insulin resistance are similar across ethnic groups. The greater early insulin response needed to maintain glucose tolerance in young people of ethnic minorities may partially explain their greater tendency to develop type 2 diabetes.

Microalbuminuria in pediatric obesity: prevalence and relation to other cardiovascular risk factors.

BACKGROUND: Microalbuminuria (MA) has emerged as a strong predictor of cardiovascular (CV) events, even in nondiabetic adults. While the mechanisms behind this association remain to be established, most studies suggest that MA is the result of increased vascular leakage denoting endothelial dysfunction associated with early vasculopathy. OBJECTIVE: To examine if a urine albumin creatinine ratio (UACR) in the microalbuminuric range is related to metabolic markers of CV risk in obese and pre-diabetic youth recruited from an obesity clinic. METHODS: MA was defined as a UACR between 2.0 and 20 mg/mmol. Subjects with gross proteinuria (UACR>20 mg/mmol) were excluded from the study. Analyses were performed to assess the relationship of MA and markers of CV risk, including body mass index (BMI), % body fat, blood pressure (BP), lipid profile, inflammatory markers, insulin sensitivity indexes and degrees of oral glucose tolerance. MA was also correlated with risk factor constellations unique to the metabolic syndrome, a distinct CV risk entity. RESULTS: Postchallenge alterations in glucose metabolism and overall loss in insulin sensitivity were strongly and positively correlated with the presence of MA (P = 0.002 and 0.01, respectively). Neither the metabolic syndrome nor any of the individual CV risk factors examined were associated with MA. CONCLUSIONS: These data suggest that early glucose toxicity, as reflected by postchallenge elevations in plasma glucose even below the diagnostic cutoff for diabetes mellitus may contribute to the presence of MA. Whether MA is equally as predictive of CV disease in youth, as in adulthood, remains to be investigated.

[The strange case of a patient affected by acromegaly with osteoporomalacia without hypogonadism]. / Lo strano caso di un paziente affetto da acromegalia con osteoporomalacia senza ipogonadismo.

Acromegaly is a rare disease that, in the majority of cases, is due to the presence of a benign growth hormone (GH)-producing tumor of the pituitary. Growth hormone has profound effects on linear bone growth, bone metabolism, and bone mass. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. The Autors describe a case of patient affected by acromegaly without hypogonadism with serious osteoporosis and biological signs of osteomalacia.

[Prosthetic rehabilitation of edentulous patients after stroke]. / Riabilitazione protesica di pazienti edentuli con esiti di stroke.

AIM: Stroke is actually the 3rd cause of death in the world after cardiovascular diseases and cancer. In Italy, every year there are 100000 new cases; 2/3 of them die or become heavily disabled. The greatest part of patients which survive is old-aged and 70% of patients that survive is a removable denture wearer. METHODS: At the Neurological Clinic of the Polyclinic Hospital of Bari we have studied 14 removable denture wearers that had had a stroke. RESULTS: We observed that 85.7 % of removable dentures were inefficient, in 50% there will need a new removable prosthesis; 50% of persons had a bad dental hygiene; 93% of denture wearers with stroke didn't make an odontoiatric control after stroke. CONCLUSIONS: Although the analysis of the orodental status has been carried out on a limited number of patients, the need of a greater motivation and solicitation in dental check-up is underlined. The role of the dentist in oral rehabilitation and in rehabilitation of post stroke dysphagia in stroke survivors is also examined.

Importance of plasma leptin in predicting future weight gain in obese children: a two-and-a-half-year longitudinal study.

OBJECTIVE: To determine whether relatively low leptin levels predict changes in adiposity in prepubertal and pubertal obese children. RESEARCH METHODS AND PROCEDURES: In a biracial cohort of 68 obese children (33 male and 35 female; 46 Caucasians and 22 African-Americans, age range 7-18 y), we measured at baseline fasting insulin and leptin levels, height and weight and calculated body mass index (kg/m(2)) and expressed body mass index as (BMI) Z-score. After a 2.5-y follow-up, anthropometric measurements were repeated and changes in weight gain were calculated as changes in BMI Z-score. RESULTS: At baseline obese preadolescent boys and girls had similar age and BMI Z-score, fasting insulin and leptin levels. After an average follow-up of 2.5 y, mean weight change calculated by changes in BMI Z-score from baseline was similar in both groups. In obese adolescent boys and girls at baseline, no significant gender differences were observed for BMI Z-score and insulin levels. In contrast, plasma leptin levels were significantly higher in obese girls compared with obese adolescent boys. At follow-up, there was no significant difference in change in BMI Z-score between obese boys and girls. Multiple linear regression analysis revealed that high basal leptin levels were positively associated with greater changes in BMI Z-score only in girls (r(2)=0.18, P<0.02), after adjusting for basal BMI Z-score, Tanner stage, years of follow-up and basal insulin. High basal leptin levels in girls explained 18% of the weight gain. CONCLUSION: High leptin levels are associated with excessive future weight gain only in girls.

Temporal patterns of circulating leptin levels in lean and obese adolescents: relationships to insulin, growth hormone, and free fatty acids rhythmicity.

Alterations in nutritional status, such as obesity, markedly influence insulin, leptin, GH secretion, and free fatty acid (FFA) levels. We measured every hour for 24 h circulating leptin, insulin, GH, and FFA levels in lean and obese adolescents to determine: 1) the impact of adolescent obesity on the diurnal changes in leptin concentrations; and 2) the temporal relationships between the diurnal patterns of circulating leptin levels and insulin, GH, and FFA levels. During puberty, we found that the 24-h profile of circulating plasma leptin levels follows a bimodal pattern with minimal concentrations occurring early in the afternoon and a nocturnal elevation starting after midnight and culminating early morning. The time course of the diurnal variation in leptin levels in the obese adolescents was not different from that in lean controls. Of note, however, in obese girls leptin 24-h excursion and leptin night to day ratio were lower than those found in lean girls. In obese adolescents, mean GH levels varied significantly less during the day and night than lean controls. During the day, there were distinct preprandial increases and postprandial decreases in FFA levels, whereas after midnight FFA levels rose in both lean and obese adolescents. A significant positive correlation was found between mean plasma insulin levels between 0800 h and 2000 h and peak in leptin in lean and obese girls and boys (r = 0.63, P: < 0.001). Peak leptin was inversely correlated with the area under the nocturnal GH levels in all groups (r = -0.31, P: < 0.0003), whereas it was positively correlated with the nocturnal peak in FFA levels (r = 0.45, P: < 0.004). In summary, we report in obese adolescent girls a blunted relative diurnal excursion in leptin levels. This abnormal rhythmicity may, in part, explain their leptin resistance state. The nocturnal rise in leptin was paralleled by a nocturnal rise in GH and FFA levels. Additional studies are needed to test the potential link between the adipose-derived peptide and GH axis in humans.

Impaired in vivo stimulation of lipolysis in adipose tissue by selective beta2-adrenergic agonist in obese adolescent girls.

Studies performed in adults with long-standing obesity suggest a reduced lipolytic sensitivity to catecholamines in subcutaneous abdominal adipose tissue (AT). We used microdialysis to study the in situ lipolytic effects of dobutamine (selective beta1-agonist) and terbutaline (selective beta2-agonist) on glycerol release (lipolytic index) in abdominal subcutaneous AT in 10 obese girls aged 13-17 years, BMI 38 +/- 2.1 kg/m2, and in 7 lean girls aged 11-17 years, BMI 21 +/- 1.1 kg/m2, and compared them with 10 obese women aged 21-39 years, BMI 36 +/- 1.6 kg/m2, and 10 lean women aged 18-42 years, BMI 21 +/- 0.4 kg/m2. Terbutaline at 10(-6) mol/l stimulated glycerol release more efficiently in lean girls than in obese girls (peak response approximately 350 vs. 150% of control, P < 0.01). At the lower concentration of agonist, no significant difference was seen. In women, terbutaline was more effective in lean than in obese women in stimulating glycerol release at both 10(-8) mol/l (peak response lean approximately 175% vs. obese 125% of control) and 10(-6) mol/l (approximately 300 vs. 150% of control, P < 0.05). No significant difference in glycerol release between obese and lean girls or women was detected with selective beta1-stimulation. Our data demonstrate a specific impairment in the capacity of beta2-adrenergic agonists to promote lipolysis in subcutaneous abdominal adipose tissue of obese adolescent girls and women. Thus, decreased mobilization of fat during activation of the adrenergic system might be present early in the development of adolescent obesity.

Augmentation of alimentary insulin secretion despite similar gastric inhibitory peptide (GIP) responses in juvenile obesity.

Insulin secretion rates are greater after oral glucose than after parenteral administration of an equivalent glucose load. This augmented beta-cell secretory response to an oral glucose load results from the release of mainly two gut hormones: gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1, which potentiate glucose-induced insulin secretion. Because of their insulinotropic action, their abnormal secretion may be involved in the pathogenesis of the hyperinsulinemia of childhood obesity. In this study, we used the hyperglycemic clamp with a small oral glucose load to assess the effect of childhood obesity on GIP response in seven prepubertal lean and 11 prepubertal obese children and in 14 lean adolescents and 10 obese adolescents. Plasma glucose was acutely raised to 11 mM by infusing i.v. glucose and kept at this concentration for 180 min. Each subject ingested oral glucose (30 g) at 120 min, and the glucose infusion was adjusted to maintain the plasma glucose plateau. Basal insulin and C-peptide concentrations and insulin secretion rates (calculated by the deconvolution method) were significantly greater in obese children compared with lean children (p < 0.001). Similarly, during the first 120 min of the clamp, insulin secretion rates were higher in obese than lean children. After oral glucose, plasma insulin, C-peptide, and insulin secretion rates further increased in all four groups. This incretin effect was 2-fold greater in obese versus lean adolescents (p < 0.001). Circulating plasma GIP concentrations were similar at baseline in all four groups and remained unchanged during the first 120 min of the clamp. After oral glucose, plasma GIP concentrations rose sharply in all groups (p < 0.002). Of note, the rise in GIP was similar in both lean and obese children. In conclusion, under conditions of stable hyperglycemia, the ingestion of a small amount of glucose elicited equivalent GIP responses in both lean and obese children. However, despite similar GIP responses, insulin secretion was markedly augmented in obese adolescents. Thus, in juvenile obesity, excessive alimentary beta-cell stimulation may be independent of the increased release of GIP.