Search

Context: Cholesteryl ester transfer protein (CETP) regulates high-density lipoprotein (HDL) cholesterol levels and interaction between glucose, and HDL metabolism is central in the development of diabetes., Objective: We hypothesized that CETP levels would be regulated in diabetic pregnancies. We tested the hypothesis by evaluating CETP activity measured multiple times during pregnancy and at 5 years' follow-up in a prospective cohort (STORK) and investigated its association with gestational diabetes mellitus (GDM) during pregnancy or development of prediabetes 5 years after pregnancy. We also evaluated the strongest correlation of CETP activity among measures of adipocity and glucose metabolism, lipoproteins, adipokines, and monocyte/macrophage activation markers., Design: A population-based longitudinal cohort study was conducted from 2001 to 2013., Setting: The study setting was Oslo University Hospital., Patients or Other Participants: A total of 300 women during pregnancy and at 5 years postpartum participated in this study., Main Outcome Measures: CETP activity was measured at 14 to 16, 22 to 24, 30 to 32, and 36 to 38 weeks' gestation, and at 5 years' follow-up., Results: We found higher CETP activity in pregnancy in women developing prediabetes but no association with GDM. CETP activity decreased throughout pregnancy and remained low at follow-up. High CETP activity was associated with sCD14 levels, in particular in women who developed prediabetes. These data show that enhanced CETP activity during pregnancy is associated with systemic indices of monocyte/macrophage activation, in particular in women who develop prediabetes later in life., Conclusions: CETP activity during pregnancy identifies women at risk for later diabetes development., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Fetuses exposed to an obese intrauterine environment are more likely to be born large-for-gestational age (LGA) and are at increased risk of obesity in childhood and cardiovascular disease and/or type 2 diabetes mellitus as adults, but which factors that influence the intrauterine environment is less clear., Objective: To investigate the association between circulating levels of leptin and adiponectin, measured multiple times during pregnancy, and birth weight and prevalence of LGA or small-for-gestational-age infants. The association between birth weight and messenger RNA (mRNA) expression of adiponectin receptors and genes involved in nutrient transport in the placenta was also investigated., Design: Population-based prospective cohort [substudy of the STORK study (STORe barn og Komplikasjoner, translated as Large Babies and Complications)] from 2001 to 2008., Setting: University hospital. Patients or other participants: 300 women., Main Outcome Measures: Oral glucose tolerance test was performed twice along with adiponectin and leptin levels measured four times during pregnancy., Results: Circulating adiponectin was lower in mothers who gave birth to LGA offspring or had fetuses with high intrauterine abdominal circumference late in pregnancy. Adiponectin decreased most from early to late pregnancy in mothers who gave birth to LGA offspring, and the decrease was an independent predictor of birth weight. Adiponectin receptor 2 and system A amino acid transporter mRNA expression in placentas was negatively correlated with birth weight and was lower in placentas from LGA infants., Conclusions: Our findings suggest that maternal adiponectin may be an important predictor of fetal growth and birth weight, independent of body mass index and insulin resistance., (Copyright © 2017 by the Endocrine Society)

Context: Growth hormone (GH) substitution of adult-onset growth hormone deficiency (aoGHD) patients partially reverses unfavorable body composition profile. Wnt signaling pathway has being acknowledged as an important modulator of bone mass and of energy metabolism in adipose tissue and in β-cells., Objective: To assess the role of selected Wnt antagonists in bone and glucose metabolism before and after GH replacement in aoGHD., Patients and Methods: Patients from two randomized placebo-controlled studies of GH replacement in aoGHD were used. In study 1, 39 patients received GH or placebo for 9 months with 4 months wash-out. In study 2, iliac bone biopsies were obtained before and after GH or placebo (n = 10 each) for 12 months. Body composition and serum (study 1) and bone matrix (study 2) levels of Wnt antagonists (DKK-1, sFRP-3, WIF-1, and SOST) were quantified before and after GH. In vitro effect of GH and IGF-1 on DKK-1 secretion and expression of Wnt signaling modulators was assessed in human osteoblasts and mature adipocytes., Results: GH replacement increased circulating and bone matrix levels of DKK-1, but not sFRP-3, WIF-1, and SOST. Furthermore, DKK-1 secretion increased in human osteoblasts stimulated by GH in vitro, with no effects on other cells. At baseline and after treatment, circulating DKK-1 was negatively associated with bone mass, but not fat mass or measures of insulin resistance, in aoGHD patients., Conclusions: An increase in DKK-1 may limit the effects of GH on bone mass, but does not seem to impact the increase in insulin resistance following GH substitution.

Context: Reduced expression of somatostatin receptors (SSTRs) in somatotroph adenomas and their potential down-regulation after medical treatment may explain the unsatisfactory response to octreotide in particular acromegalic patients. The expression of SSTRs other than SSTR2a has not been studied in large, unselected cohorts using novel rabbit monoclonal antibodies., Objective: We aimed to determine the expression of SSTRs 1, 2a, 3, and 5 in somatotroph adenomas, to correlate expression with clinical characteristics and the response to octreotide, and to ascertain whether preoperative octreotide treatment affected SSTR expression., Design, Setting, Patients: The study included 78 adenomas from patients operated on consecutively during 2000 to 2010. After exclusion of 13 patients, immunohistochemical analysis with rabbit monoclonal antibodies against SSTRs 1, 2a, 3, and 5 (clones UMB-7, -1, -5, and -4) was performed on 65 adenomas., Intervention: Twenty-eight patients received preoperative octreotide, and 37 patients were operated on without pretreatment. Twenty-six patients were randomized to direct surgery (n = 13) or to octreotide pretreatment (n = 13)., Main Outcome Measure: SSTR expression was evaluated using a 12-grade scoring system. The responses to the octreotide test dose (GH reduction) and to 6 months of octreotide (IGF-I reduction) were measured., Results: The majority of adenomas showed membranous expression of SSTRs 2a and 5. SSTR2a expression was reduced in the pretreated group and correlated with the acute octreotide test results and the effect of octreotide treatment. In a linear regression model with SSTR2a expression as the determinant, the correlation with the acute test response improved after adjustment for medical pretreatment., Conclusion: Rabbit monoclonal antibodies are reliable markers of SSTRs in somatotroph adenomas. SSTR2a expression correlated with the response to octreotide and was reduced after octreotide treatment, indicating the need for adjustment when SSTR2a expression is correlated with baseline characteristics. Evaluation of SSTR subtypes may be an important aspect of improving the medical treatment for acromegaly.

Context: The epithelial marker E-cadherin plays a crucial role in epithelial-mesenchymal transition (EMT). Decreased protein content in somatotroph adenomas has been associated with increased tumor size, invasion, and poor response to somatostatin analog (SA) treatment, but the potential mechanisms of EMT progression in these adenomas are lacking., Objective: We hypothesized that characterization of EMT-related transcripts in somatotroph adenomas could identify novel therapeutic targets in individuals with poor response to SA treatment and provide more knowledge of the mechanism of EMT progression., Patients: Fifty-three patients with acromegaly participated in the study., Research Design and Methods: We performed microarray analysis of 16 adenomas, eight with high expression and eight with low expression of E-cadherin, in order to identify EMT-related transcripts. Candidate transcripts were further explored in vivo in 53 adenomas and in vitro in a rat pituitary GH-producing cell (GH3) after exploring three models for reducing E-cadherin and inducing a mesenchymal phenotype., Results: In vivo E-cadherin mRNA expression in tumor tissue is associated negatively with tumor size and invasiveness and positively with GH and IGF-I levels in serum and response to SA treatment. Microarray and subsequent PCR analysis identify several EMT-related genes associated with E-cadherin expression. In vitro, few of these EMT-related genes were regulated by silencing E-cadherin or by TGF-β1 treatment in GH3 cells. In contrast, silencing Esrp1 in GH3 cells regulated many of the EMT-related transcripts., Conclusion: These results indicate that ESRP1 could be a master regulator of the EMT process in pituitary adenomas causing acromegaly.

Background: Nicotinamide phosphoribosyltransferase (NAMPT)/visfatin is a widely expressed protein with various effects on glucose and lipid metabolism, cell survival, and inflammation., Aim: We hypothesized that NAMPT was related to metabolic disturbances in active acromegaly., Methods: Body composition, glucose metabolism, and NAMPT levels were measured in 47 patients with active, untreated acromegaly and 24 age-, sex-, and body mass index-matched controls. The in vitro effects of GH/IGF-I on NAMPT expression in human sc adipocytes (SCA), visceral adipocytes, osteoblasts, and hepatocytes were studied. The effects of overnight incubation with the highly specific NAMPT inhibitor FK866 on the GH-stimulated monocyte chemotactic protein-1 and IL-6 expression in mature SCA were evaluated., Results: NAMPT was increased in active acromegaly (P = 0.004) and correlated negatively with limb (arms + legs) fat percentage (% fat, r = -0.32; P = 0.032). After adjusting for age, gender, leptin, and GH, the circulating NAMPT correlated negatively with limb and total body fat percentage (% fat limbs, r = -0.43, P = 0.006; % fat total body, r = -0.36, P = 0.022) and correlated positively with limb and total body lean percentage (% lean limbs, r = 0.31, P = 0.047; % lean total body, r = 0.33, P = 0.034). No correlation between NAMPT and glucose metabolic parameters was found. In vitro studies revealed that GH increased NAMPT expression in adipocytes. The inhibition of NAMPT enzymatic activity attenuated GH-induced monocyte chemotactic protein-1 expression in SCA., Conclusions: NAMPT is increased in active acromegaly and may be an inflammatory mediator that causes monocyte infiltration in adipose tissue.

Context: Appropriate cell-to-cell adhesion is fundamental for the epithelial phenotype of pituitary cells. Loss of the adhesion protein E-cadherin has been associated with invasiveness, metastasis, and poor prognosis in cancers of epithelial origin. In somatotroph adenomas, a variable and reduced expression of E-cadherin has been demonstrated. In addition, nuclear translocation of E-cadherin was found to correlate with pituitary tumor invasion., Objective: The objective was to examine the protein expression of E-cadherin in somatotroph pituitary adenomas in relation to adenoma size, invasiveness, and somatostatin analog (SMS) efficacy., Patients and Methods: Eighty-three patients were included, and 29 were treated preoperatively with SMS. Adenoma E-cadherin protein expression was analyzed by Western blot (61 patients) and immunohistochemistry (IHC) (80 patients) with antibodies directed against both extracellular and intracellular domains (IHC). The acute (direct surgery group) and long-term (preoperatively treated group) SMS responses were evaluated. Baseline tumor volume and invasiveness were measured on magnetic resonance imaging scans., Results: Membranous E-cadherin was lost in several adenomas. Nine of these were nuclear E-cadherin positive. The E-cadherin protein expression correlated negatively to tumor size and positively to acute SMS response. Low E-cadherin levels (preoperatively treated group only) and loss of membranous E-cadherin correlated to tumor invasiveness. The E-cadherin level correlated positively to tumor reduction after SMS treatment, and adenomas with nuclear E-cadherin staining had lower IGF-I reduction and tumor shrinkage. Preoperatively treated adenomas had reduced E-cadherin protein levels, but the IHC expression was unaltered., Conclusion: Reduced E-cadherin expression may correlate to a dedifferentiated phenotype in the somatotroph pituitary adenomas.

Context: Glucocorticoid-induced bone loss is a serious complication in patients with endogenous Cushing's syndrome. However, the mechanism(s) by which excess glucocorticoids influence bone metabolism is not completely understood., Objective: The aim of the study was to investigate the functional role of glucocorticoid-induced leucine zipper (GILZ) in bone remodeling with special focus on glucocorticoid-induced osteoporosis (GIO)., Patients: Nine patients with endogenous Cushing's syndrome participated in the study., Research Design and Methods: We analyzed bone biopsies from Cushing's patients before and after treatment to screen for expressional candidate genes with putative roles in GIO. Microarray analysis combined with real-time RT-PCR revealed that the gene encoding GILZ ranked among the topmost regulated genes and was selected for functional characterization in vitro., Results: GILZ mRNA was expressed by human fetal osteoblasts (hFOB), human mesenchymal stem cells (hMSC), osteoblasts differentiated from hMSC, and osteoclasts. GILZ was increased by dexamethasone in a time- and dose-dependent manner in hFOB. Inhibition of GILZ in hFOB cells by small interfering RNA decreased typical osteoblast-related genes, suggesting a physiological role in promoting osteoblast maturation. Our data further support a functional role for GILZ in normal bone remodeling by modulating expression of TNF-(ligand) receptor superfamily/osteoprotegerin in favor of increased ratio in hFOB. Finally, osteoclasts exposed to conditioned media from GILZ-silenced hFOB indicated effects on osteoclast activity., Conclusion: Taken together, these results implicate the transcription factor GILZ in the pathophysiology of GIO by regulating osteoblast maturation and bone turnover.

Objective: Patients with active acromegaly display a range of abnormalities in glucose metabolism. To elucidate interactions between bone and energy homeostasis in relation to excess GH, we sought to determine whether these patients were characterized by alterations in circulating levels of adipokines and cytokines and potential interactions with osteocalcin (OCN) and insulin resistance., Methods: Forty-seven patients with active acromegaly: 26 women and 21 men (49 +/- 11, mean +/- sd) were evaluated and compared with age-, sex-, and body mass index-matched controls by x-ray absorptiometry, biochemical analysis [GH, IGF-I, OCN, leptin, adiponectin, retinol binding protein 4, IL-6, IL-1beta, and IL-1 receptor antagonist (IL-1Ra)], and glucose metabolism (homeostasis model assessment). In vitro effects of GH/IGF-I on IL-1beta/IL-1Ra in THP-1 macrophages and human white adipocytes as well as effects of GH/IGF-I in combination with carboxylated and undercarboxylated OCN on glucose-stimulated insulin release in human pancreatic islets were also investigated., Results: Patients with acromegaly were characterized by markedly decreased serum levels of IL-1Ra and increased IL-1beta and IL-1beta to IL-1Ra ratio, suggesting enhanced IL-1 activity. The decreased IL-1Ra was strongly associated with increased OCN levels in multivariate models and was significantly correlated with decreased total body fat mass. In macrophages, IGF-I/GH significantly decreased the release of IL-1Ra and increased IL-1beta, suggesting that the decreased circulating IL-1Ra levels in acromegaly could reflect both direct and indirect mechanisms. Finally, circulating OCN was the main determinant of insulin resistance and beta-cell function in acromegaly and in vitro, a blunted insulin response was observed in the presence of OCN and GH/IGF-I., Conclusion: These data confirm and establish novel and complex interactions between bone, energy metabolism, and adipose tissue and suggest an unfavorable effect of OCN and GH/IGF-I in combination on insulin metabolism in active acromegaly.