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Fulltext Orbital Signaling in Graves' Orbitopathy

Draman MS, Zhang L, Dayan C, Ludgate M

Front Endocrinol (Lausanne), 2021;12:739994.
PMID: 34899596 DOI: 10.3389/fendo.2021.739994

Graves' orbitopathy (GO) is a complex and poorly understood disease in which extensive remodeling of orbital tissue is dominated by adipogenesis and hyaluronan production. The resulting proptosis is disfiguring and underpins the majority of GO signs and symptoms. While there is strong evidence for the thyrotropin receptor (TSHR) being a thyroid/orbit shared autoantigen, the insulin-like growth factor 1 receptor (IGF1R) is also likely to play a key role in the disease. The pathogenesis of GO has been investigated extensively in the last decade with further understanding of some aspects of the disease. This is mainly derived by using in vitro and ex vivo analysis of the orbital tissues. Here, we have summarized the features of GO pathogenesis involving target autoantigens and their signaling pathways.
Prostaglandin F2-Alpha Eye Drops (Bimatoprost) in Graves' Orbitopathy: A Randomized Controlled Double-Masked Crossover Trial (BIMA Trial)

Draman MS, Morris DS, Evans S, Haridas A, Pell J, Greenwood R, et al.

Thyroid, 2019 04;29(4):563-572.
PMID: 30880626 DOI: 10.1089/thy.2018.0506

BACKGROUND: Previous in vitro experiments have demonstrated that prostaglandin F2-alpha (PF2α) reduced proliferation and adipogenesis in a murine cell line and human orbital fibroblasts derived from subjects with inactive Graves' orbitopathy (GO). The objective of this study was to determine if the PGF2α analogue bimatoprost is effective at reducing proptosis in this population.
METHODS: A randomized controlled double-masked crossover trial was conducted in a single tertiary care academic medical center. Patients with long-standing, inactive GO but persistent proptosis (>20 mm in at least one eye) were recruited. Allowing for a 15% dropout rate, 31 patients (26 females) were randomized in order to identify a treatment effect of 2.0 mm (p = 0.05; power 0.88). Following informed consent, participants were randomized to receive bimatoprost or placebo for three months, after which they underwent a two-month washout before switching to the opposite treatment. The primary outcome was the change in exophthalmometry readings over the two three-month treatment periods.
RESULTS: The mean exophthalmometer at baseline was 23.6 mm (range 20.0-30.5 mm), and the mean age of the patients was 55 years (range 28-74 years). The median duration of GO was 7.6 years (interquartile range 3.6-12.3 years). The majority were still suffering from diplopia (61.3%) with bilateral involvement (61.3%). Using multi-level modeling adjusted for baseline, period, and carry-over, bimatoprost resulted in a -0.17 mm (reduction) exophthalmometry change ([confidence interval -0.67 to +0.32]; p = 0.490). There was a mean change in intraocular pressure of -2.7 mmHg ([confidence interval -4.0 to -1.4]; p = 0.0070). One patient showed periorbital fat atrophy on treatment, which resolved on stopping treatment. Independent analysis of proptosis by photographic images (all subjects) and subgroup analysis on monocular disease (n = 12) did not show any apparent benefit.
CONCLUSIONS: In inactive GO, bimatoprost treatment over a three-month period does not result in an improvement in proptosis.
Fulltext Expression of Endogenous Putative TSH Binding Protein in Orbit

Draman MS, Grennan-Jones F, Taylor P, Muller I, Evans S, Haridas A, et al.

Curr Issues Mol Biol, 2021 Oct 27;43(3):1794-1804.
PMID: 34889904 DOI: 10.3390/cimb43030126

Thyroid stimulating antibodies (TSAB) cause Graves' disease and contribute to Graves' Orbitopathy (GO) pathogenesis. We hypothesise that the presence of TSH binding proteins (truncated TSHR variants (TSHRv)) and/or nonclassical ligands such as thyrostimulin (α2β5) might provide a mechanism to protect against or exacerbate GO. We analysed primary human orbital preadipocyte-fibroblasts (OF) from GO patients and people free of GO (non-GO). Transcript (QPCR) and protein (western blot) expression levels of TSHRv were measured through an adipogenesis differentiation process. Cyclic-AMP production by TSHR activation was studied using luciferase-reporter and RIA assays. After differentiation, TSHRv levels in OF from GO were significantly higher than non-GO (p = 0.039), and confirmed in ex vivo analysis of orbital adipose samples. TSHRv western blot revealed a positive signal at 46 kDa in cell lysates and culture media (CM) from non-GO and GO-OF. Cyclic-AMP decreased from basal levels when OF were stimulated with TSH or Monoclonal TSAB (M22) before differentiation protocol, but increased in differentiated cells, and was inversely correlated with the TSHRv:TSHR ratio (Spearman correlation: TSH r = -0.55, p = 0.23, M22 r = 0.87, p = 0.03). In the bioassay, TSH/M22 induced luciferase-light was lower in CM from differentiated GO-OF than non-GO, suggesting that secreted TSHRv had neutralised their effects. α2 transcripts were present but reduced during adipogenesis (p < 0.005) with no difference observed between non-GO and GO. β5 transcripts were at the limit of detection. Our work demonstrated that TSHRv transcripts are expressed as protein, are more abundant in GO than non-GO OF and have the capacity to regulate signalling via the TSHR.
CATS II Long-term Anthropometric and Metabolic Effects of Maternal Sub-optimal Thyroid Function in Offspring and Mothers

Muller I, Taylor PN, Daniel RM, Hales C, Scholz A, Candler T, et al.

J Clin Endocrinol Metab, 2020 07 01;105(7).
PMID: 32396189 DOI: 10.1210/clinem/dgaa129

CONTEXT AND OBJECTIVES: The Controlled Antenatal Thyroid Screening Study I (CATS-I) was a randomized controlled trial investigating the effects of levothyroxine therapy for suboptimal gestational thyroid function (SGTF), comparing outcomes in children of treated (SGTF-T) with untreated (SGTF-U) women during pregnancy. This follow-up study, CATS-II, reports the long-term effects on anthropometric, bone, and cardiometabolic outcomes in mothers and offspring and includes a group with normal gestational thyroid function (NGTF).
DESIGN & PARTICIPANTS: 332 mothers (197 NGTF, 56 SGTF-U, 79 SGTF-T) aged 41.2±5.3 years (mean±SD) and 326 paired children assessed 9.3±1.0 years after birth for (i) body mass index (BMI); (ii) lean, fat, and bone mass by dual-energy X-ray absorptiometry; (iii) blood pressure, augmentation index, and aortic pulse-wave-velocity; and (iv) thyroid function, lipids, insulin, and adiponectin. The difference between group means was compared using linear regression.
RESULTS: Offspring's measurements were similar between groups. Although maternal BMI was similar between groups at CATS-I, after 9 years (at CATS-II) SGTF-U mothers showed higher BMI (median [interquartile ratio] 28.3 [24.6-32.6] kg/m2) compared with NGTF (25.8 [22.9-30.0] kg/m2; P = 0.029), driven by fat mass increase. At CATS-II SGTF-U mothers also had higher thyroid-stimulating hormone (TSH) values (2.45 [1.43-3.50] mU/L) than NGTF (1.54 [1.12-2.07] mU/L; P = 0.015), since 64% had never received levothyroxine. At CATS-II, SGTF-T mothers had BMI (25.8 [23.1-29.8] kg/m2, P = 0.672) and TSH (1.68 [0.89-2.96] mU/L; P = 0.474) values similar to NGTF mothers.
CONCLUSIONS: Levothyroxine supplementation of women with SGTF did not affect long-term offspring anthropometric, bone, and cardiometabolic measurements. However, absence of treatment was associated with sustained long-term increase in BMI and fat mass in women with SGTF.
Fulltext Molecular, Metabolic, and Nutritional Changes after Metabolic Surgery in Obese Diabetic Patients (MoMen): A Protocol for a Multicenter Prospective Cohort Study

Fazliana M, Nor Hanipah Z, Mohd Yusof BN, Zainal Abidin NA, Tan YZ, Mohkiar FH, et al.

Metabolites, 2023 Mar 10;13(3).
PMID: 36984853 DOI: 10.3390/metabo13030413

Metabolic surgery is an essential option in the treatment of obese patients with type 2 diabetes (T2D). Despite its known advantages, this surgery still needs to be introduced in Malaysia. In this prospective study, the pathophysiological mechanisms at the molecular level will be studied and the metabolomics pathways of diabetes remission will be explored. The present study aims to evaluate the changes in the anthropometric measurements, body composition, phase angle, diet intake, biochemistry parameters, adipokines, microRNA, and metabolomics, both pre- and post-surgery, among obese diabetic patients in Malaysia. This is a multicenter prospective cohort study that will involve obese patients (n = 102) with a body mass index (BMI) of ≥25 kg/m2 (Asian BMI categories: WHO/IASO/IOTF, 2000) who will undergo metabolic surgery. They will be categorized into three groups: non-diabetes, prediabetes, and diabetes. Their body composition will be measured using a bioimpedance analyzer (BIA). The phase angle (PhA) data will be analyzed. Venous blood will be collected from each patient for glycated hemoglobin (HbA1c), lipids, liver, renal profile, hormones, adipokines, and molecular and metabolomics analyses. The serum microRNA will be measured. A gene expression study of the adipose tissue of different groups will be conducted to compare the groups. The relationship between the 1HNMR-metabolic fingerprint and the patients' lifestyles and dietary practices will be determined. The factors responsible for the excellent remission of T2D will be explored in this study.
Fulltext Gut Microbiome Associated With Graves Disease and Graves Orbitopathy: The INDIGO Multicenter European Study

Biscarini F, Masetti G, Muller I, Verhasselt HL, Covelli D, Colucci G, et al.

J Clin Endocrinol Metab, 2023 Jul 14;108(8):2065-2077.
PMID: 36683389 DOI: 10.1210/clinem/dgad030

CONTEXT: Gut bacteria can influence host immune responses but little is known about their role in tolerance-loss mechanisms in Graves disease (GD; hyperthyroidism caused by autoantibodies, TRAb, to the thyrotropin receptor, TSHR) and its progression to Graves orbitopathy (GO).
OBJECTIVE: This work aimed to compare the fecal microbiota in GD patients, with GO of varying severity, and healthy controls (HCs).
METHODS: Patients were recruited from 4 European countries (105 GD patients, 41 HCs) for an observational study with cross-sectional and longitudinal components.
RESULTS: At recruitment, when patients were hyperthyroid and TRAb positive, Actinobacteria were significantly increased and Bacteroidetes significantly decreased in GD/GO compared with HCs. The Firmicutes to Bacteroidetes (F:B) ratio was significantly higher in GD/GO than in HCs. Differential abundance of 15 genera was observed in patients, being most skewed in mild GO. Bacteroides displayed positive and negative correlations with TSH and free thyroxine, respectively, and was also significantly associated with smoking in GO; smoking is a risk factor for GO but not GD. Longitudinal analyses revealed that the presence of certain bacteria (Clostridiales) at diagnosis correlated with the persistence of TRAb more than 200 days after commencing antithyroid drug treatment.
CONCLUSION: The increased F:B ratio observed in GD/GO mirrors our finding in a murine model comparing TSHR-immunized with control mice. We defined a microbiome signature and identified changes associated with autoimmunity as distinct from those due to hyperthyroidism. Persistence of TRAb is predictive of relapse; identification of these patients at diagnosis, via their microbiome, could improve management with potential to eradicate Clostridiales.