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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

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

Zhandong Lei, Yunfei Chen, Jin Wang, Yan Zhang, Wenjuan Shi, Xuejiao Wang, Dehai Xing, Dongxue Li, and Xiangying Jiao

Elucidating the mechanisms of regulation of β-cell proliferation is key to understanding the pathogenesis of diabetes mellitus. Txnip is a tumor suppressor that is upregulated in diabetes and plays an important role in the regulation of insulin sensitivity; however, its potential effect on pancreatic β-cell proliferation remains unclear. Here, we evaluated the role of Txnip in pancreatic β-cell compensatory proliferation by subjecting WT and Txnip knockout (KO) mice to a high-fat diet (HFD). Our results demonstrate that Txnip deficiency improves glucose tolerance and increases insulin sensitivity in HFD-induced obesity. The antidiabetogenic effect of Txnip deficiency was accompanied by increased β-cell proliferation and enhanced β-cell mass expansion. Furthermore, Txnip deficiency modulated the expression of a set of transcription factors with key roles in β-cell proliferation and cell cycle regulation. Txnip KO in HFD mice also led to activated levels of p-PI3K, p-AKT, p-mTOR and p-GSK3β, suggesting that Txnip may act via PI3K/AKT signaling to suppress β-cell proliferation. Thus, our work provides a theoretical basis for Txnip as a new therapeutic target for the treatment of diabetes mellitus.

Open access

Ning Yuan, Jianbin Sun, Xin Zhao, Jing Du, Min Nan, Qiaoling Zhang, and Xiaomei Zhang

Background

Numerous studies have found that subclinical hypothyroidism (SCH) may increase adverse pregnancy outcomes; however, the benefit of levothyroxine (LT4) treatment remains controversial. The 2017 guidelines of the American Thyroid Association weakly recommended LT4 therapy for serum antithyroid peroxidase antibody (TPOAb)-negative women with thyroid-stimulating hormone (TSH) concentrations greater than the pregnancy-specific reference range and below 10.0 mU/L. Therefore, the primary goal of this study was to investigate the correlation between thyroid autoantibody-negative SCH with or without LT4 treatment and adverse pregnancy outcomes.

Methods

We prospectively enrolled 1868 consecutive pregnant women. Finally, 1344 women were involved in the study according to the inclusion and exclusion criteria. Assays for TSH, free thyroxine (FT4), TPOAb, anti-thyroglobulin antibody, and laboratory indicators were performed. The participants were divided into the euthyroid (ET) group (n  = 1250) and the SCH group(n  = 94). The SCH group was further divided into LT4 group (n  = 40) and non-LT4 group(n  = 54). The laboratory indicators and pregnancy outcomes were evaluated during follow-ups.

Results

Maternal age, BMI, parity, and the history of spontaneous abortion did not differ significantly between the ET group and the different SCH groups. There were no significant differences in lipid profile and homocysteine levels between ET and SCH group in the first and third trimester of pregnancy. After adjusting the confounding factors, the non-LT4 group was a risk factor for spontaneous abortion (odds ratio: 3.141, 95% CI: 1.060–9.302). Survival analysis showed that the time of abortion was different between the ET group and SCH group (log-rank P= 0.042). The spontaneous abortion in SCH, especially in non-LT4, group mainly occurred in the first trimester of pregnancy.

Conclusions

Thyroid autoantibody negative-SCH seems to be associated with increased risk of spontaneous abortions during the first trimester of pregnancy. LT4 therapy in this patient population might be beneficial to reduce adverse pregnancy outcomes.

Open access

Johanna Öberg, Rolf Jorde, Yngve Figenschau, Per Medbøe Thorsby, Sandra Rinne Dahl, Anne Winther, and Guri Grimnes

Objective

Combined hormonal contraceptive (CHC) use has been associated with higher total 25-hydroxyvitamin D (25(OH)D) levels. Here, we investigate the relation between CHC use and vitamin D metabolism to elucidate its clinical interpretation.

Methods

The cross-sectional Fit Futures 1 included 1038 adolescents. Here, a subgroup of 182 girls with available 25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)2D), 24,25-dihydroxyvitamin D (24,25(OH)2D), vitamin D-binding protein (DBP) and measured free 25(OH)D levels, in addition to parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), was investigated. Vitamin D metabolites were compared between girls using (CHC+) and not using CHC (CHC−). Further, the predictability of CHC on 25(OH)D levels was assessed in a multiple regression model including lifestyle factors. The ratios 1,25(OH)2D/25(OH)D and 24,25(OH)2D/25(OH)D (vitamin D metabolite ratio (VMR)) in relation to 25(OH)D were presented in scatterplots.

Results

CHC+ (n  = 64; 35% of the girls) had higher 25(OH)D levels (mean ± s.d., 60.3 ± 22.2) nmol/L) than CHC- (n  = 118; 41.8 ± 19.3 nmol/L), P -values <0.01. The differences in 25(OH)D levels between CHC+ and CHC− were attenuated but remained significant after the adjustment of lifestyle factors. CHC+ also had higher levels of 1,25(OH)2D, 24,25(OH)2D, DBP and calcium than CHC−, whereas 1,25(OH)2D/25(OH)D, PTH, FGF23 and albumin were significantly lower. Free 25(OH)D and VMR did not statistically differ, and both ratios appeared similar in relation to 25(OH)D, irrespective of CHC status.

Conclusion

This confirms a clinical impact of CHC on vitamin D levels in adolescents. Our observations are likely due to an increased DBP-concentration, whereas the free 25(OH)D appears unaltered.