Relative Contributions of Lean and Fat Mass to Bone Mineral Density: Insight From Prader-Willi Syndrome

Context: Low bone mineral density (BMD) is the most important risk factor for fragility fracture. Body weight is a simple screening predictor of difference in BMD between individuals. However, it is not clear which component of body weight, lean (LM), or fat mass (FM), is associated with BMD. People with the genetic disorder of Prader-Willi syndrome (PWS) uniquely have a reduced LM despite increased FM.Objective: We sought to define the individual impact of LM and FM on BMD by investigating subjects with and without PWS.Design, Setting and Participants: This cross-sectional study was conducted at the Clinical Research Facility of the Garvan Institute of Medical Research, with PWS and control participants recruited from a specialized PWS clinic and from the general public by advertisement, respectively. The study involved 11 adults with PWS, who were age- and sex-matched with 12 obese individuals (Obese group) and 10 lean individuals (Lean group).Main Outcome Measures: Whole body BMD was measured by dual-energy X-ray absorptiometry. Total body FM and LM were derived from the whole body scan. Differences in BMD between groups were assessed by the analysis of covariance model, taking into account the effects of LM and FM.Results: The PWS group had significantly shorter height than the lean and obese groups. As expected, there was no significant difference in FM between the Obese and PWS group, and no significant difference in LM between the Lean and PWS group. However, obese individuals had greater LM than lean individuals. BMD in lean individuals was significantly lower than in PWS individuals (1.13 g/cm2 vs. 1.21 g/cm2, p < 0.05) and obese individuals (1.13 g/cm2 vs. 1.25 g/cm2, p < 0.05). After adjusting for both LM and FM, there was no significant difference in BMD between groups, and the only significant predictor of BMD was LM.Conclusions: These data from the human genetic model Prader-Willi syndrome suggest that LM is a stronger determinant of BMD than fat mass

The Association between Midnight Salivary Cortisol and Metabolic Syndrome in Korean Adults

BackgroundThe common characteristics of metabolic syndrome (MetS) and Cushing's syndrome suggest that excess cortisol may be involved in the pathogenesis of MetS. Salivary cortisol measurements are simple and can be surrogates for plasma free cortisol, which is the most biologically active form. We evaluated the association between levels of midnight salivary cortisol and MetS in Korean adults.MethodsA total of 46 subjects, aged 20 to 70 years, who visited the Health Care Center at Konkuk University Hospital from August 2008 to August 2009 were enrolled. We compared the levels of midnight salivary cortisol in subjects with MetS with those in subjects without MetS. We analyzed the associations between midnight salivary cortisol levels and components of MetS.ResultsMidnight salivary cortisol levels were higher in the MetS group (70±42.4 ng/dL, n=12) than that in the group without MetS (48.1±36.8 ng/dL, n=34) (P=0.001). Positive correlations were observed between midnight salivary cortisol levels and waist circumference, fasting blood glucose, and homeostasis model assessment of insulin resistance. The risk for MetS was significantly higher in subjects with midnight salivary cortisol levels ≥100 ng/dL than in those with levels <50 ng/dL (odds ratio, 5.9; 95% confidence interval, 2.35 to 36.4).ConclusionThe results showed a positive correlation between midnight salivary cortisol levels and MetS, suggesting that hypercortisolism may be related to MetS

The Neurotensin Receptor-1 Pathway Contributes to Human Ductal Breast Cancer Progression

BACKGROUND: The neurotensin (NTS) and its specific high affinity G protein coupled receptor, the NT1 receptor (NTSR1), are considered to be a good candidate for one of the factors implicated in neoplastic progression. In breast cancer cells, functionally expressed NT1 receptor coordinates a series of transforming functions including cellular migration and invasion. METHODS AND RESULTS: we investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal breast carcinomas (IDCs) by immunohistochemistry and RT-PCR. NTS is expressed and up-regulated by estrogen in normal epithelial breast cells. NTS is also found expressed in the ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade, the size of the tumor, and the number of metastatic lymph nodes. Furthermore, the NTSR1 high expression is an independent factor of prognosis associated with the death of patients. CONCLUSION: these data support the activation of neurotensinergic deleterious pathways in breast cancer progression

The role of insulin, peptide YY and the immune system in the pathogenesis of type 2 diabetes

Obesity and type 2 diabetes (T2D) are associated with insulin resistance and increased levels of inflammation markers, suggesting activation of the immune system. However, the link between this so called &#145;low-grade inflammation&#146; and insulin resistance is poorly understood. In this thesis we aimed to investigate the direct effects of insulin on immune cells, and if these effects are changed in the setting of insulin resistance. We showed that insulin has anti-inflammatory effects by shifting T cell differentiation into a T helper type 2 phenotype. This effect was lost in insulin resistant subjects, which resulted in a more pro-inflammatory T helper type 1 cell hyperpolarisation. We also demonstrated that the Th1/2 balance is related to the degree of insulin resistance, and varies accordingly in clinical models of increasing or decreasing insulin resistance. Furthermore, we demonstrated that in a very early stage of pre-diabetes, where normal glucose tolerance and insulin sensitivity are still preserved, we cannot detect any immune activation, but we see a blunted food response of the appetite suppressant hormone PYY. Whilst this could put subjects at risk for further weight gain and development of obesity and T2D, we also demonstrated for the first time that PYY itself has strong anti-inflammatory properties, and that a deficiency in PYY could result in promoting a pro-inflammatory environment. In summary, we could demonstrate strong evidence that both, insulin and PYY are potent anti-inflammatory hormones which modulate immune function, and the observed deficiency in these hormones could contribute to further increase in inflammation and disease progression. Further work is indicated in this area to better understand the sequence and mechanism of immune activation, which may open up new therapeutic avenues for prevention and treatment of T2D

Effects of a single dose of exenatide on appetite, gut hormones, and glucose homeostasis in adults with Prader-Willi syndrome

Context: Prader-Willi syndrome (PWS) is associated with hyperphagia and obesity, without effective pharmacological treatment. Exenatide, recently developed for treatment of type 2 diabetes, induces appetite suppression and weight loss with common side effects. Objective: The objective of the study was to investigate the initial safety and effectiveness of exenatide in adult PWS subjects compared with obese controls (OBESE). Design, Setting, Patients, and Intervention: Eight PWS and 11 OBESE patients underwent standardized meal studies after a single sc injection of 10 g exenatide or placebo in a single-blinded, crossover design. Main Outcome Measures: Glucose, insulin, C-peptide, glucagon, peptide YY (PYY; total)/PYY (3- 36), glucagon-like peptide-1, and ghrelin (total) were measured fasting and postprandially. Appetite and satiety were assessed by visual analog scales. Energy expenditure (EE) was measured by indirect calorimetry. Side effects were screened during and for 24 h after the meal. Results:PWSand OBESE patients were matched for gender, age, body mass index, and central/total body fat. In both groups, exenatide increased satiety and lowered glucose and insulin levels but increased insulin secretion rate. Side effects were absent in PWS but common in OBESE patients. During the meal, PYY (total) and ghrelin were elevated in PWS patients. Exenatide decreased PYY (total) and glucagon-like peptide-1, whereas ghrelin remained unchanged. Energy expenditure was unchanged by exenatide. Conclusions: Our pilot study demonstrates that exenatide is well tolerated in PWS patients. It increases satiety independently of measured appetite hormones, exerting glucose lowering, and insulinotropic effects similarly in PWS and OBESE patients. Larger prospective studies should investigate whether chronic exenatide administration will reduce hyperphagia and overweight in PWS patients without side effects

Reproducibility of nighttime salivary cortisol and its use in the diagnosis of hypercortisolism compared with urinary free cortisol and overnight dexamethasone suppression test

BACKGROUND/METHODS: Nighttime salivary cortisol (NSC) has been suggested to be a useful diagnostic test for Cushing`s syndrome (CS). In the absence of published data on its day-to-day variability, we assessed the reproducibility of NSC by repeated measurements in healthy volunteers. Its diagnostic performance was compared with 24-h urinary free cortisol (UFC) and 1 mg overnight dexamethasone suppression test in 12 patients with CS, 20 healthy volunteers, 14 referred patients in which CS was excluded or not firmly established, 16 obese patients, and 20 women in late pregnancy. RESULTS: NSC showed a superior reproducibility in healthy volunteers with a low day-to-day variability as reflected by an intraclass correlation coefficient of 0.78. The receiver operating characteristic curve-estimated cutoff of 6.1 nmol/liter (0.22 microg/dl) demonstrated a sensitivity and specificity of 100% (area under the receiver operating characteristic curve, 1.0; 95% confidence interval, 0.94-1.0) in the diagnosis of CS. NSC, 24-h UFC [after adjusting the local laboratory cutoff to 504 nmol/d (183 microg/d)], and the urinary cortisol/creatinine ratio showed a tendency to be superior to 1 mg dexamethasone suppression test in correctly identifying CS. In late pregnancy, the preserved diurnal variation at a higher level of salivary cortisol reduced the specificity of NSC to 75%. CONCLUSION: Based on its remarkable reproducibility, easy noninvasive nature, and at least similar diagnostic performance, NSC appears to be a preferable alternative to 24-h UFC as a first-line screening test for CS. The cutoff values of NSC, 24-h UFC, and urinary cortisol/creatinine ratio have to be carefully adjusted using assay and center-specific reference ranges of sufficiently large populations