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Open access

Panisa Hantrakun, Rattanaporn Sekararithi, Thidarat Jaiwongkam, Sirinart Kumfu, Chatree Chai-adisaksopha, Nipon Chattipakorn, Theera Tongsong, and Phudit Jatavan

Objectives

To evaluate the effect of metformin in improving platelet dysfunction in women with gestational diabetes mellitus (GDM).

Patients and methods

A randomized controlled trial was conducted on pregnant women diagnosed with GDM. Singleton low-risk pregnancies meeting the inclusion criteria were randomly allocated at 27–31 weeks to receive metformin and placebo through the rest of pregnancy. Thirty-seven and 39 cases were recruited into the metformin group and the placebo group, respectively. MPVs, P-selectin, and 8-isoprostane levels were determined at the time of allocation and 6 weeks after treatment. Obstetric and neonatal outcomes were also assessed.

Results

Most baseline characteristics of the two groups were comparable. The levels of P-selectin after 6 weeks of treatment were significantly higher in the metformin group (68.9 ± 14.4 vs 60.6 ± 11.3; P-value = 0.006), indicating more platelet activation. All of the obstetric and neonatal outcomes were comparable except that birth weight was significantly lower in the metformin group (3018 ± 364 g vs 3204 ± 393 g; P-value = 0.037).

Conclusion

Metformin, in addition to diet and lifestyle modifications, does not improve or worsen oxidative stress and platelet dysfunction in women with GDM. Nevertheless, metformin significantly reduces fetal weight in women with GDM, theoretically preventing macrosomia.

Open access

Katrine M Lauritsen, Jens Hohwü Voigt, Steen Bønløkke Pedersen, Troels K Hansen, Niels Møller, Niels Jessen, Lars C Gormsen, and Esben Søndergaard

SGLT2 inhibition induces an insulin-independent reduction in plasma glucose causing increased lipolysis and subsequent lipid oxidation by energy-consuming tissues. However, it is unknown whether SGLT2 inhibition also affects lipid storage in adipose tissue. Therefore, we aimed to determine the effects of SGLT2 inhibition on lipid storage and lipolysis in adipose tissue. We performed a randomized, double-blinded, placebo-controlled crossover design of 4 weeks of empagliflozin 25 mg and placebo once-daily in 13 individuals with type 2 diabetes treated with metformin. Adipose tissue fatty acid uptake, lipolysis rate and clearance were measured by 11C-palmitate PET/CT. Adipose tissue glucose uptake was measured by 18F-FDG PET/CT. Protein and gene expression of pathways involved in lipid storage and lipolysis were measured in biopsies of abdominal s.c. adipose tissue. Subjects were weight stable, which allowed us to quantify the weight loss-independent effects of SGLT2 inhibition. We found that SGLT2 inhibition did not affect free fatty acids (FFA) uptake in abdominal s.c. adipose tissue but increased FFA uptake in visceral adipose tissue by 27% (P  < 0.05). In addition, SGLT2 inhibition reduced GLUT4 protein (P  = 0.03) and mRNA content (P  = 0.01) in abdominal s.c. adipose tissue but without affecting glucose uptake. In addition, SGLT2 inhibition decreased the expression of genes involved in insulin signaling in adipose tissue. We conclude that SGLT2 inhibition reduces GLUT4 gene and protein expression in abdominal s.c. adipose tissue, which could indicate a rebalancing of substrate utilization away from glucose oxidation and lipid storage capacity through reduced glycerol formation.

Open access

Vita Birzniece, Teresa Lam, Mark McLean, Navneeta Reddy, Haleh Shahidipour, Amy Hayden, Howard Gurney, Glenn Stone, Rikke Hjortebjerg, and Jan Frystyk

Objective

Androgen deprivation therapy (ADT), a principal therapy in patients with prostate cancer, is associated with the development of obesity, insulin resistance, and hyperinsulinemia. Recent evidence indicates that metformin may slow cancer progression and improves survival in prostate cancer patients, but the mechanism is not well understood. Circulating insulin-like growth factors (IGFs) are bound to high-affinity binding proteins, which not only modulate the bioavailability and signalling of IGFs but also have independent actions on cell growth and survival. The aim of this study was to investigate whether metformin modulates IGFs, IGF-binding proteins (IGFBPs), and the pregnancy-associated plasma protein A (PAPP-A) – stanniocalcin 2 (STC2) axis.

Design and methods

In a blinded, randomised, cross-over design, 15 patients with prostate cancer on stable ADT received metformin and placebo treatment for 6 weeks each. Glucose metabolism along with circulating IGFs and IGFBPs was assessed.

Results

Metformin significantly reduced the homeostasis model assessment as an index of insulin resistance (HOMA IR) and hepatic insulin resistance. Metformin also reduced circulating IGF-2 (P  < 0.05) and IGFBP-3 (P  < 0.01) but increased IGF bioactivity (P  < 0.05). At baseline, IGF-2 correlated significantly with the hepatic insulin resistance (r2= 0.28, P  < 0.05). PAPP-A remained unchanged but STC2 declined significantly (P  < 0.05) following metformin administration. During metformin treatment, change in HOMA IR correlated with the change in STC2 (r2= 0.35, P  < 0.05).

Conclusion

Metformin administration alters many components of the circulating IGF system, either directly or indirectly via improved insulin sensitivity. Reduction in IGF-2 and STC2 may provide a novel mechanism for a potential metformin-induced antineoplastic effect.

Open access

Lian Duan, Han-Yu Zhang, Min Lv, Han Zhang, Yao Chen, Ting Wang, Yan Li, Yan Wu, Junfeng Li, and Kefeng Li

Background and objective: Radioiodine therapy (RAI) is one of the most common treatment solutions for Graves' disease (GD). However, many patients will develop hypothyroidism as early as 6 months after RAI. This study aimed to implement machine learning (ML) algorithms for early prediction of post-RAI hypothyroidism.

Methods: 471 GD patients who underwent RAI between January 2016 and June 2019 were retrospectively recruited and randomly split into the training set (310 patients) and the validation set (161 patients). These patients were followed for 6 months after RAI. A set of 138 clinical and lab test features from the electronic medical record (EMR) were extracted, and multiple ML algorithms were conducted to identify the features associated with the occurrence of hypothyroidism at 6 months after RAI.

Results: An integrated multivariate model containing patients’ age, thyroid mass, 24 h radioactive iodine uptake, serum concentrations of aspartate aminotransferase (AST), thyrotropin-receptor antibodies (TRAb), thyroid microsomal antibodies (TMA), and blood neutrophil count demonstrated an area under the ROC (AUROC) of 0.72 (95% CI: 0.61 - 0.85), an F1 score of 0.74, and an MCC score of 0.63 in the training set. The model also performed well in the validation set with an AUROC of 0.74 (95% CI: 0.65 - 0.83), an F1 score of 0.74, and a MCC of 0.63. A user-friendly nomogram was then established to facilitate the clinical utility.

Conclusion: The developed multivariate model based on EMR data could be a valuable tool for predicting post-RAI hypothyroidism, allowing them to be treated differently before the therapy. Further study is needed to validate the developed prognostic model at independent sites.

Open access

Carole Morin, Keo-Morakort Benedetto, Agathe Deville, Laurent Milot, Aurélie Theillaumas, Valerie Hervieu, Mathieu Pioche, Gilles Poncet, Julien Forestier, Laurent François, Francoise Borson-Chazot, Mustapha Adham, Catherine Lombard-Bohas, and Thomas Walter

Purpose: To improve neuroendocrine neoplasm (NEN) management, the European Neuroendocrine Tumor Society (ENETS) recognised 62 Centers of Excellence (CoE). This retrospective study compares conformity of patients’ initial management within vs outside an ENETS CoE with clinical practice guidelines (CPGs).

Methods: Patients diagnosed with a NEN between August 2018 and July 2020 and presented in the Lyon-CoE Multidisciplinary Tumour Board (MDT) were included. Factors potentially associated with conformity of initial management (work-up and first treatment) to CPG underwent univariate and multivariate analyses.

Results: Among the 615 included patients, 170 (27.6%) were initially managed in the CoE and 445 (72.4%) were only presented at the CoE-MDT. Patients in the CoE group more often had intestinal or pancreatic primaries, metastatic disease (61.8% vs 33%), hereditary syndrome and a functioning tumour. Work-up conformity was 37.1% in the CoE (vs 29.9%, p=0.09); this was 95.8% for the first treatment (vs 88.7%, p=0.01). After multivariate analysis, CPG conformity was significantly higher for patients managed in the CoE, for younger patients, for those having a grade 1-2 tumour, and a genetic syndrome. Pancreatic and small intestinal (SI) NET surgeries performed in the CoE had higher splenic preservation rate during left pancreatectomy, better detection of multiple tumours in SI surgeries, and higher number of resected lymph nodes.

Conclusions: Given the widespread observance of CPG, not all patients require management in the CoE. Referral should be considered for more complex cases such as metastatic diseases, G2 tumours or carcinoid syndromes. Finally, we should encourage centralization of NET surgery.

Open access

Panagiotis Anagnostis, Irene Lambrinoudaki, John C Stevenson, and Dimitrios G Goulis

Cardiovascular disease (CVD) is of major concern in women entering menopause. The changing hormonal milieu predisposes them to increased CVD risk, due to a constellation of risk factors, such as visceral obesity, atherogenic dyslipidemia, dysregulation in glucose homeostasis, non-alcoholic fatty liver disease and arterial hypertension. However, an independent association of menopause per se with increased risk of CVD events has only been proven for early menopause (<45 years). Menopausal hormone therapy (MHT) ameliorates most of the CVD risk factors mentioned above. Transdermal estrogens are the preferable regimen, since they do not increase triglyceride concentrations and they are not associated with increased risk of venous thromboembolic events (VTE). Although administration of MHT should be considered on an individual basis, MHT may reduce CVD morbidity and mortality, if commenced during the early postmenopausal period (<60 years or within ten years since the last menstrual period). In women with premature ovarian insufficiency (POI), MHT should be administered at least until the average age of menopause (50–52 years). MHT is contraindicated in women with a history of VTE and is not currently recommended for the sole purpose of CVD prevention. The risk of breast cancer associated with MHT is generally low and is mainly conferred by the progestogen. Micronized progesterone and dydrogesterone are associated with lower risk compared to other progestogens.

Open access

Alexander A L Jorge, Thomas Edouard, Mohamad Maghnie, Alberto Pietropoli, Nicky Kelepouris, Alicia Romano, Martin Zenker, and Reiko Horikawa

Introduction

Mutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating short stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated.

Methods

This analysis included pooled data from the observational American Norditropin Studies: Web-Enabled Research Program (NCT01009905) and the randomized, double-blinded GHLIQUID-4020 clinical trial (NCT01927861). Pediatric patients with clinically diagnosed NS and confirmed PTPN11mutation status were eligible for inclusion. The effectiveness analysis included patients who were GHT-naïve and pre-pubertal at GHT start. Growth outcomes and safety were assessed over 4 years of GHT (Norditropin®, Novo Nordisk A/S).

Results

A total of 69 patients were included in the effectiveness analysis (71% PTPN11 positive). The proportion of females was 32.7 and 30.0% in PTPN11-positive and negative patients, respectively, and mean age at GHT start was 6.4 years in both groups. Using general population reference data, after 4 years of GHT, the mean (s.d.) height SD score (HSDS) was −1.9 (1.1) and −1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference observed between groups. The mean (s.d.) change in HSDS at 4 years was +1.3 (0.8) in PTPN11-positive patients and +1.5 (0.7) in PTPN11-negative patients (no significant differences between groups). Safety findings were consistent with previous analyses.

Conclusions

GHT resulted in improved growth outcomes over 4 years in GHT-naïve, pre-pubertal NS patients, irrespective of PTPN11 mutation status.

Open access

Luca Giovanella, Maria Luisa Garo, Domenico Albano, Rainer Görges, and Luca Ceriani

Objective

In patients with differentiated thyroid cancer (DTC), recurrences may occur in up to 20% and may have a fatal outcome in 10% of cases. Thyroglobulin doubling time (Tg-DT) values may contribute to predict response to treatment and disease recurrence in DTC patients. This study aimed to address the following questions: (1) Are Tg-DT values indicative of response to treatments in patients with DTC (i.e. ’treatment monitoring’)?; (2) Is Tg-DT predictive of 2-[18F]fluoro-2-deoxy-d-glucose (2-[18F]FDG) PET/CT in patients with DTC?; (3) Are Tg-DT values predictive of DTC prognosis (i.e. ‘prediction’)?

Design

Systematic review and meta-analysis.

Methods

Methodology was registered in the PROSPERO database (CRD42021257947). A systematic search was carried out in PubMed, Web Of Science, and Scopus from June to August 2021 without time and language restrictions.

Results

Eleven studies were included for a total of 1421 patients. Positive association between Tg-DT < 1 year and recurrence or disease progression was observed. Tg-DT was found to be related with (2-[18F]FDG) PET/CT results in patients with DTC. The area under the curve was 0.86 (95% CI: 0.83–0.89), sensitivity was 0.84 (0.64;0.94), specificity was 0.71 (0.35; 0.92), DOR was 13.1 (3.1; 55.0), LR+ was 2.9 (1.0; 8.1), LR− was 0.22 (0.1; 0.5). For patients with Tg-DT < 1 year (n  = 247), the survival risk ratio was 2.09 (95% CI: 1.49; 2.94).

Conclusions

Tg-DT values are valuable in predicting response to treatment and disease recurrence in patients with DTC, as well as their overall survival. In addition, Tg-DT significantly increases the detection rate of 2-[18F]-FDG PET/CT.

Open access

Yanfei Chen, Mei Li, Binrong Liao, Jingzi Zhong, and Dan Lan

Objective

The objective of this study is to investigate the role of serum irisin level in diagnosis of central precocious puberty (CPP) in girls and its major determinants.

Methods

This study was conducted in 67 girls with CPP, 19 girls with premature thelarche (PT) and 59 normal controls. The major determinants of irisin were assessed by multivariate linear regression (MLR) analysis. Propensity score matching (PSM) analysis was performed to minimize the bias that can result from BMI. A receiver operating characteristic curve was used to obtain the optimal threshold value of irisin.

Results

The girls with CPP and PT had higher irisin levels than controls (P  < 0.05). The optimal cutoff value of irisin levels for predicting CPP was 91.88 ng/mL, with a sensitivity of 70.1% and a specificity of 72.9%. MLR analysis showed that BMI was a predictor of irisin (P  < 0.05). Serum irisin levels remained higher in the CPP girls than the controls with adjustment for BMI (P  < 0.05).

Conclusions

Increased serum irisin levels with CPP suggest that irisin is involved in puberty. However, due to low sensitivity and specificity, irisin level can only be used as an auxiliary indicator rather than a single diagnostic indicator of CPP.

Open access

Jiaxi Li, Pu Huang, Jing Xiong, Xinyue Liang, Mei Li, Hao Ke, Chunli Chen, Yang Han, Yanhong Huang, Yan Zhou, Ziqiang Luo, Dandan Feng, and Chen Chen

Objective: Ghrelin regulates body weight, food intake and blood glucose. It also regulates insulin secretion from pancreatic islet cells. LEAP2 is a newly discovered endogenous ligand of growth hormone secretagogue’s receptor (GHSR). It not only antagonizes the stimulation of GHSR by ghrelin but also inhibits constitutive activation of GHSR as an inverse agonist. Type 2 diabetes (T2D) patients have endocrine disorders with metabolic imbalance. Plasma levels of ghrelin and LEAP2 may be changed in obese and T2D patients. However, there is no report yet on circulating LEAP2 levels or ghrelin/LEAP2 ratio in T2D patients. In this study, fasting serum ghrelin and LEAP2 levels in healthy adults and T2D patients were assessed to clarify the association of two hormones with different clinical anthropometric and metabolic parameters.

Design: A total of 16 females and 40 males, ages 23-68 years old normal (n = 27) and T2D patients (n = 29) were enrolled as a cross-sectional cohort.

Results: Serum levels of ghrelin were lower but serum levels of LEAP2 were higher in T2D patients. Ghrelin levels were positively correlated with fasting serum insulin levels and HOMA-IR in healthy adults. LEAP2 levels were positively correlated with age and HbA1c in all tested samples. Ghrelin/LEAP2 ratio was negatively correlated with age, fasting blood glucose and HbA1c.

Conclusions: This study demonstrated a decrease in serum ghrelin levels and an increase in serum LEAP2 levels in T2D patients. LEAP2 levels were positively correlated with HbA1c, suggesting that LEAP2 was associated with T2D development. The ghrelin/LEAP2 ratio was closely associated with glycemic control in T2D patients showing negative correlation with glucose and HbA1c.