Octreotide remains 40 years after its development a drug, which is commonly used in the treatment of acromegaly and GEP-NETs. Very little innovation that competes with this drug occurred over this period. This review discusses several aspects of 40 years of clinical use of octreotide, including the application of radiolabeled forms of the peptide.
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Steven W J Lamberts and Leo J Hofland
Ida Kim Wium-Andersen, Merete Osler, Martin Balslev Jørgensen, Jørgen Rungby and Marie Kim Wium-Andersen
Diabetes is a risk factor for dementia, but whether antidiabetic medication decreases the risk is unclear. We examined the association between antidiabetic medication and dementia.
We performed a nested case–control study within a cohort of all 176 250 patients registered with type 2 diabetes in the Danish National Diabetes Register between 1995 and 2012. This population was followed for dementia diagnosis or anti-dementia medication use until May 2018. Using risk-set sampling, each dementia case (n = 11 619) was matched on follow-up time and calender year of dementia with four controls randomly selected among cohort members without dementia (n = 46 476). Ever use and mean daily defined dose of antidiabetic medication was categorized in types (insulin, metformin, sulfonylurea and glinides combined, glitazone, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP1) analogs, sodium-glucose transport protein 2 (SGLT2) inhibitors and acarbose).
Conditional logistic regression models were fitted to calculate odds ratios (ORs) for dementia associated with antidiabetic medication use, adjusting for potential confounders.
Use of metformin, DPP4 inhibitors, GLP1 analogs, and SGLT2 inhibitors were associated with lower odds of dementia after multible adjustments (ORs of 0.94 (95% confidence interval (CI): 0.89–0.99), 0.80 (95% CI 0.74–0.88), 0.58 (95% CI: 0.50–0.67), and 0.58 (95% CI: 0.42–0.81), respectively), with a gradual decrease in odds of dementia for each increase in daily defined dose. Analyses of the most frequent treatment regimes did not show any synergistic effects of combined treatment.
Use of metformin, DPP4 inhibitors, GLP1 analogs and SGLT2 inhibitors was associated with lower risk of dementia in patients with diabetes.
Oliveira Flávia R, Marcelo Mamede, Mariana F Bizzi, Rocha Ana Luiza L, Cláudia N Ferreira, Karina B Gomes, Ana L Cândido and Fernando M Reis
To evaluate whether brown adipose tissue (BAT) activity is altered in women with polycystic ovary syndrome (PCOS), and whether BAT activity correlates with plasma levels of irisin, a myokine that can induce BAT formation.
We performed a cross-sectional study including women with PCOS (n = 45) and a healthy control group (n = 25) matched by age and body mass index (BMI).
BAT activity was measured using 18F-FDG positron emission tomography-computed tomography (PET-CT) and plasma irisin levels were measured by a validated enzyme immunoassay.
Total BAT activity was significantly reduced in women with PCOS (maximal standardized uptake value (SUVmax): median 7.4 g/mL, interquartile range 0.9–15.4) compared to controls (median 13.0 g/mL, interquartile range 4.7–18.4, P = 0.047). However, this difference was no longer significant after adjustment for waist circumference, a surrogate marker of central adiposity. In the PCOS group, BAT activity correlated negatively with BMI (Spearman’s r = −0.630, P = 0.000) and waist circumference (r = −0.592, P = 0.000) but not with plasma irisin levels.
BAT activity was reduced in women with PCOS possibly due to increased central adiposity. In PCOS women, BAT activity did not correlate with plasma irisin levels.
Ute I Scholl
Germline mutations in the chloride channel gene CLCN2 have been described as cause of familial hyperaldosteronism type II. In this issue, Dutta and colleagues in a groundbreaking study identify a somatic (tumor-specific) CLCN2 mutation in an aldosterone-producing adenoma, expanding the disease spectrum associated with CLCN2 mutations.
Phillip J Monaghan and Peter J Trainer
Julia Vergier, Frederic Castinetti, Alexandru Saveanu, Nadine Girard, Thierry Brue and Rachel Reynaud
Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. This syndrome is an antenatal developmental defect belonging to the holoprosencephaly phenotype spectrum. It is heterogeneous regarding clinical, biological and radiological presentation and is characterized by the following triad: thin (<1 mm) or interrupted pituitary stalk connecting the hypothalamus to the pituitary gland, no eutopic posterior lobe, and hypoplasia or aplasia of the anterior lobe. This review reports current knowledge about the composite pathogenesis, for which underlying mechanisms remain unclear. Current data suggest genetic origins involving early developmental gene mutations with complex inheritance patterns and environmental influence, placing PSIS at the crossroads between Mendelian and multifactorial diseases. The phenotype associated with PSIS is highly heterogeneous with a high incidence of various combinations of hormonal deficiencies, sometimes associated with extra-pituitary birth defects. The age at onset is variable, but typical presentation is evolutive combined anterior pituitary hormone deficiencies at pediatric age, which progress even during adulthood to panhypopituitarism. Therefore, patients’ follow-up throughout life is essential for adequate management.
Haixia Guan, Nathalie Silva de Morais, Jessica Stuart, Sara Ahmadi, Ellen Marqusee, Mathew I Kim and Erik K. Alexander
To investigate the concordance of serologic and sonographic evidence of Hashimoto’s thyroiditis with its gold standard histopathologic identification.
We performed a retrospective analysis on a cohort of 825 consecutive patients in whom TPOAb and thyroid ultrasound were performed, and in whom thyroid nodule evaluation led to surgical and histopathologic analysis. The presence or absence of Hashimoto’s thyroiditis on histopathology was correlated with serologic and sonographic markers. We further assessed the impact of low versus high titers of TPOAb upon this concordance.
Of 825 patients, 277 (33.5%) had histologic confirmation of Hashimoto’s thyroiditis, 235 patients (28.4%) had elevated serum levels of TPOAb, and 197 (23.8%) had sonographic evidence of diffuse heterogeneity. Of those with histopathologic evidence, only 64% had elevated TPOAb (sensitivity: 63.9%; specificity: 89.4%), while only 49% were sonographically diffusely heterogeneous (sensitivity: 49.1%; specificity: 88.9%). A subset of only 102 of 277 (37%) with histologically proven Hashimoto’s thyroiditis was positive for both TPOAb and diffusely heterogeneous. Concordance analysis demonstrated that TPOAb and histopathology had higher agreement (κ = 0.55) than did ultrasound and histopathology (κ = 0.40) for the diagnosis of Hashimoto’s thyroiditis. Higher titers of TPOAb correlated with a higher likelihood of Hashimoto’s thyroiditis, with a best cutoff of 2.11-fold the upper normal level of TPOAb.
Only moderate concordance exists between serological evidence of Hashimoto’s thyroiditis and histopathologic findings, though it increases with higher TPOAb concentration. Diffuse heterogeneity on ultrasound is a less-sensitive diagnostic tool than elevated TPOAb.
Liron Yoffe, Avital Polsky, Avital Gilam, Chen Raff, Federico Mecacci, Agostino Ognibene, Fatima Crispi, Eduard Gratacós, Hannah Kanety, Shali Mazaki-Tovi, Noam Shomron and Moshe Hod
Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and its prevalence is constantly rising worldwide. Diagnosis is commonly in the late second or early third trimester of pregnancy, though the development of GDM starts early; hence, first-trimester diagnosis is feasible.
Our objective was to identify microRNAs that best distinguish GDM samples from those of healthy pregnant women and to evaluate the predictive value of microRNAs for GDM detection in the first trimester.
We investigated the abundance of circulating microRNAs in the plasma of pregnant women in their first trimester. Two populations were included in the study to enable population-specific as well as cross-population inspection of expression profiles. Each microRNA was tested for differential expression in GDM vs control samples, and their efficiency for GDM detection was evaluated using machine-learning models.
Two upregulated microRNAs (miR-223 and miR-23a) were identified in GDM vs the control set, and validated on a new cohort of women. Using both microRNAs in a logistic-regression model, we achieved an AUC value of 0.91. We further demonstrated the overall predictive value of microRNAs using several types of multivariable machine-learning models that included the entire set of expressed microRNAs. All models achieved high accuracy when applied on the dataset (mean AUC = 0.77). The significance of the classification results was established via permutation tests.
Our findings suggest that circulating microRNAs are potential biomarkers for GDM in the first trimester. This warrants further examination and lays the foundation for producing a novel early non-invasive diagnostic tool for GDM.
Urszula Razny, Anna Polus, Joanna Goralska, Anna Zdzienicka, Anna Gruca, Maria Kapusta, Maria Biela, Aldona Dembinska-Kiec, Bogdan Solnica and Malgorzata Malczewska-Malec
To evaluate the effect of insulin resistance in obesity on the expression in whole blood of mRNA and miRNA affecting bone homeostasis as well as to estimate the influence of oral glucose load (OGTT) on serum osteocalcin concentration in obese individuals with and without insulin resistance.
Carboxylated (cOC), undercarboxylated (ucOC) and total osteocalcin were measured by ELISA in the serum of obese subjects with insulin resistance (n = 41) and obese subjects without insulin resistance (n = 41) (control group) during OGTT. Analysis of gene expression (microarray) and miRNAs (real-time PCR) was performed in venous blood (representating samples) collected before OGTT from obese with insulin resistance and controls.
Obese subjects with insulin resistance (higher HOMA-IR and lower oral glucose insulin sensitivity index) presented significantly increased expression of WNT signalling inhibitors (DKK1, DKK2, SOST, SFRP1) and downregulation of the key factor in WNT signalling – β catenin participating in osteoblasts differentiation. Expression of miRNA involved in osteoblastogenesis was also inhibited (miR-29b, miR-181a, miR-210, miR-324-3p). During OGTT, contrary to the control group, subjects with insulin resistance presented suppression of cOC and total OC decrease after 1 and 2 h of oral glucose load.
Obese subjects with insulin resistance may have defects in osteoblastogenesis that was demonstrated via key signalling molecules mRNA downregulation, and increased expression of WNT antagonists as well as inhibition of expression of miRNA participating in the regulation of osteoblast differentiation. Disturbed osteoblastogenesis in insulin-resistant subjects results in the suppression of blood carboxylated and total osteocalcin decrease during OGTT.
Günter Stalla, Christina Dimopoulou, Caroline Jung-Sievers, Eduardo Arzt, Marcelo Paez Pereda, Marily Theodoropoulou, Denis Ciato and Ulrich Renner
Although effective treatment regimens (surgical resection, drug treatment with dopamine agonists or somatostatin analogues, radiotherapy) have been established for the therapy of most pituitary tumours, a considerable proportion of affected patients cannot completely cured due to incomplete resection or drug resistance. Moreover, even if hormone levels have been normalized, patients with hormone secreting tumours still show persistent pathophysiological alterations in metabolic, cardiovascular or neuropsychiatric parameters and have an impaired quality of life. In this review reasons for the discrepancy between biochemical cure and incomplete recovery from tumour-associated comorbidities are discussed and the clinical management is delineated exemplary for patients with acromegaly and Cushing’s disease. In view of the development of additional treatment concepts for the treatment of pituitary adenomas we speculate about the relevance of RSUME as a potential target for the development of an anti-angiogenic therapy. Moreover, the role of BMP-4 which stimulates prolactinoma development through the Smad signalling cascade is described and its role as putative drug target for the treatment of prolactinomas is discussed. Regarding the well-known resistance of a part of somatotropinomas to somatostatin analogue treatment, recently identified mechanisms responsible for the drug resistance are summarized and ways to overcome them in future treatment concepts are presented. Concerning novel therapeutic options for patients with Cushing’s disease the impact of retinoic acid, which is currently tested in clinical studies, is shown, and the action and putative therapeutic impact of silibinin to resolve glucocorticoid resistance in these patients is critically discussed.