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Open access

Esben S Lauritzen, Thomas Voss, Ulla Kampmann, Annette Mengel, Mikkel H Vendelbo, Jens O L Jørgensen, Niels Møller and Esben T Vestergaard

Objective

Ghrelin has glucoregulatory and orexigenic actions, but its role in acute hypoglycemia remains uncertain. We aimed to investigate circulating levels of acylghrelin (AG) and unacylated ghrelin (UAG) in response to hyperinsulinemia and to hypoglycemia.

Design

A randomized, single-blind, placebo-controlled crossover study including 3 study days was performed at a university hospital clinical research center.

Methods

Nine healthy men completed 3 study days: i) saline control (CTR), ii) hyperinsulinemic euglycemia (HE) (bolus insulin 0.1 IE/kg i.v. and glucose 20% i.v. for 105 min, plasma glucose ≈5 mmol/l), and iii) hyperinsulinemic hypoglycemia (HH) (bolus insulin 0.1 IE/kg i.v.).

Results

HH and HE suppressed AG concentrations at t=45–60 min as compared with CTR (P<0.05). At t=90 min, a rebound increase in AG was observed in response to HH as compared with both HE and CTR (P<0.05). UAG also decreased during HH and HE at t=45 min (P<0.05), whereas the AG-to-UAG ratio remained unaffected.

Conclusions

This study demonstrates that AG and UAG are directly suppressed by hyperinsulinemia and that AG concentrations increase after a latency of ≈1 h in response to hypoglycemia, suggesting a potential counterregulatory role of AG.

Open access

Xiaomei Liu, Wei Qiang, Xingjun Liu, Lianye Liu, Shu Liu, Aibo Gao, Shan Gao and Bingyin Shi

Objective

There are scarce reports regarding the prognosis of a second course of antithyroid drug (ATD) therapy on recurrent Graves' disease (GD). The aim of this study was to assess the long-term remission rate after a second ATD therapy and verify significant clinical predictors of a remission.

Design

A prospective randomized clinical trial with long-term follow-up was conducted to evaluate the effects of a second course of ATD therapy.

Methods

A total of 128 recurrent GD patients who had finished a first regular ATD therapy were enrolled in this study, and prescribed methimazole (MMI) treatment with titration regimen. The patients were randomly assigned to two groups when the drug doses were reduced to 2.5 mg daily (qd). Group 1 was discontinued with 2.5 mg qd after about 5 months. Group 2 was continuously reduced to 2.5 mg every other day (qod) after 5 months and then discontinued with 2.5 mg qod after about a further 5 months. The patients were followed for 48 months after drug withdrawal.

Results

Of the total number of patients, 97 cases (75.78%) achieved permanent remission at the end of follow-up, with the recurrence of 31 cases (24.22%). The remission rate of group 2 (84.62%) was significantly higher than that of group 1 (66.67%) (P=0.024). Cox regression showed that the hazard ratio for recurrence decreased under a high or high normal TSH level at drug withdrawal.

Conclusion

A second course of ATD therapy can bring about a satisfying long-term remission on recurrent GD. The drug dose of 2.5 mg qod and a high or high normal TSH level at drug withdrawal may increase the likelihood of permanent remission.

Open access

Viveca Åberg, Sophie Norenstedt, Jan Zedenius, Maria Sääf, Jörgen Nordenström, Ylva Pernow and Inga-Lena Nilsson

Objective

Vitamin D insufficiency is common in primary hyperparathyroidism (pHPT). Patients with pHPT frequently have a reduced health-related quality of life (HRQoL). Our objectives were to evaluate whether HRQoL in pHPT is associated with vitamin D insufficiency and whether vitamin D supplementation after parathyroidectomy (PTX) could improve HRQoL.

Design

A randomized, double-blind study (ClinicalTrials.gov identifier: NCT00982722).

Methods

The study included 150 pHPT patients randomized, 6 weeks after PTX, to daily treatment with either cholecalciferol 1600 IU and calcium carbonate 1000 mg (D+) or calcium carbonate alone (D−). HRQoL was estimated with SF-36 before and after PTX and after 12 months of study medication.

Results

Three-quarters (77%) of the pHPT patients had vitamin D insufficiency, defined as 25OHD <50 nmol/l. The pHPT patients scored lower than a reference population in all domains of SF-36. A total of 135 patients completed the entire study period. Improvements in nearly all domains were registered at the follow-up 6 weeks after PTX. At the end of the study medication period, the D+ group had a significantly higher median serum (s-) 25OHD concentration (76 (65; 93) (lower; upper interquartile ranges) vs 48 (40; 62) nmol/l, P<0.001) and a lower plasma (p-) parathyroid hormone concentration (40 (34; 52) vs 49 (38; 66) ng/l, P=0.01) than the D− group. The improvements in HRQoL remained unchanged at the follow-up 1 year after PTX. Postoperative vitamin D supplementation had no obvious effect on HRQoL.

Conclusion

PTX resulted in significant improvements in HRQoL. Despite a high prevalence of vitamin D insufficiency, 1 year of postoperative vitamin D supplementation had no obvious beneficial effect on HRQoL.

Open access

Bahareh Rasouli, Tomas Andersson, Per-Ola Carlsson, Mozhgan Dorkhan, Valdemar Grill, Leif Groop, Mats Martinell, Tiinamaja Tuomi and Sofia Carlsson

Objective

Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes. Our aim was to investigate whether alcohol consumption is associated with the risk of latent autoimmune diabetes in adults (LADA), an autoimmune form of diabetes with features of type 2 diabetes.

Design

A population-based case–control study was carried out to investigate the association of alcohol consumption and the risk of LADA.

Methods

We used data from the ESTRID case–control study carried out between 2010 and 2013, including 250 incident cases of LADA (glutamic acid decarboxylase antibodies (GADAs) positive) and 764 cases of type 2 diabetes (GADA negative), and 1012 randomly selected controls aged ≥35. Logistic regression was used to estimate the odds ratios (ORs) of diabetes in relation to alcohol intake, adjusted for age, sex, BMI, family history of diabetes, smoking, and education.

Results

Alcohol consumption was inversely associated with the risk of type 2 diabetes (OR 0.95, 95% CI 0.92–0.99 for every 5-g increment in daily intake). Similar results were observed for LADA, but stratification by median GADA levels revealed that the results only pertained to LADA with low GADA levels (OR 0.85, 95% CI 0.76–0.94/5 g alcohol per day), whereas no association was observed with LADA having high GADA levels (OR 1.00, 95% CI 0.94–1.06/5 g per day). Every 5-g increment of daily alcohol intake was associated with a 10% increase in GADA levels (P=0.0312), and a 10% reduction in homeostasis model assessment of insulin resistance (P=0.0418).

Conclusions

Our findings indicate that alcohol intake may reduce the risk of type 2 diabetes and type 2-like LADA, but has no beneficial effects on diabetes-related autoimmunity.

Open access

A G Nilsson, C Marelli, D Fitts, R Bergthorsdottir, P Burman, P Dahlqvist, B Ekman, B Edén Engström, T Olsson, O Ragnarsson, M Ryberg, J Wahlberg, H Lennernäs, S Skrtic and G Johannsson

Objective

The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI).

Design

Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden.

Methods

Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20–40 mg once daily and hydrocortisone 20–40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness).

Results

In stage 1, patients had a median 1.5 (range, 1–9) intercurrent illness events with DR-HC and 1.0 (1–8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1–3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure.

Conclusions

This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

Open access

Luca Giovanella, Penelope M Clark, Luca Chiovato, Leonidas Duntas, Rossella Elisei, Ulla Feldt-Rasmussen, Laurence Leenhardt, Markus Luster, Camilla Schalin-Jäntti, Matthias Schott, Ettore Seregni, Herald Rimmele, Jan Smit and Frederik A Verburg

Differentiated thyroid cancer (DTC) is the most common endocrine cancer and its incidence has increased in recent decades. Initial treatment usually consists of total thyroidectomy followed by ablation of thyroid remnants by iodine-131. As thyroid cells are assumed to be the only source of thyroglobulin (Tg) in the human body, circulating Tg serves as a biochemical marker of persistent or recurrent disease in DTC follow-up. Currently, standard follow-up for DTC comprises Tg measurement and neck ultrasound combined, when indicated, with an additional radioiodine scan. Measurement of Tg after stimulation by endogenous or exogenous TSH is recommended by current clinical guidelines to detect occult disease with a maximum sensitivity due to the suboptimal sensitivity of older Tg assays. However, the development of new highly sensitive Tg assays with improved analytical sensitivity and precision at low concentrations now allows detection of very low Tg concentrations reflecting minimal amounts of thyroid tissue without the need for TSH stimulation. Use of these highly sensitive Tg assays has not yet been incorporated into clinical guidelines but they will, we believe, be used by physicians caring for patients with DTC. The aim of this clinical position paper is, therefore, to offer advice on the various aspects and implications of using these highly sensitive Tg assays in the clinical care of patients with DTC.

Open access

Ilaria Messuti, Stefania Corvisieri, Francesca Bardesono, Ida Rapa, Jessica Giorcelli, Riccardo Pellerito, Marco Volante and Fabio Orlandi

Objective

Differentiated thyroid cancer (DTC) commonly occurs in women of child-bearing age and represents the second most frequent tumor diagnosed during pregnancy only behind breast cancer. It is possible that associated physiological changes could favor tumor development and growth. However, few data are available about the outcome of DTC related to pregnancy, leading to conflicting results.

Methods

Among the study population, 340 patients with DTC <45 years old were retrospectively studied. Patients were divided into three groups according to the time of tumor diagnosis in respect of pregnancy. Group 1, diagnosis of DTC at least 2 years after delivery; group 2, diagnosis during pregnancy or within the second year after delivery; and group 3, nulliparous patients at the time of diagnosis. We evaluated clinical outcome and immunohistochemical expression of estrogen receptor α (ERα), ERβ, progesterone receptor, and aromatase. We also analyzed the gene expression of NIS (SLC5A5) and the prevalence of BRAF V600E mutations.

Results

Persistence/recurrence of disease was significantly higher in group 2 patients than control groups (P=0.023). No significant differences were observed in other clinical parameters. Furthermore, no differences among the groups were recorded about ER pattern, NIS expression, and BRAF mutations.

Conclusions

Persistence/recurrence of DTC is significantly higher in pregnant patients, suggesting that pregnancy could really exert a negative prognostic role in patients with DTC. The underlying mechanisms are not yet clarified and further studies are required. Our results suggest that a more careful follow-up is needed when diagnosis of DTC occurs during pregnancy or shortly after.

Open access

Mojca Jensterle Sever, Tomaz Kocjan, Marija Pfeifer, Nika Aleksandra Kravos and Andrej Janez

Objective

The effect of metformin on weight reduction in polycystic ovary syndrome (PCOS) is often unsatisfactory. In this study, we investigated the potential add-on effect of treatment with the glucagon-like peptide-1 receptor agonist liraglutide on weight loss in obese nondiabetic women with PCOS who had lost <5% body weight during pretreatment with metformin.

Methods

A total of 40 obese women with PCOS, who had been pretreated with metformin for at least 6 months, participated in a 12-week open-label, prospective study. They were randomized to one of three treatment arms: metformin (MET) arm 1000 mg BID, liraglutide (LIRA) arm 1.2 mg QD s.c., or combined MET 1000 mg BID and LIRA (COMBI) 1.2 mg QD s.c. Lifestyle intervention was not actively promoted. The primary outcome was change in body weight.

Results

Thirty six patients (aged 31.3±7.1 years, BMI 37.1±4.6 kg/m2) completed the study: 14 on MET, 11 on LIRA, and 11 on combined treatment. COMBI therapy was superior to LIRA and MET monotherapy in reducing weight, BMI, and waist circumference. Subjects treated with COMBI lost on average 6.5±2.8 kg compared with a 3.8±3.7 kg loss in the LIRA group and a 1.2±1.4 kg loss in the MET group (P<0.001). The extent of weight loss was stratified: a total of 38% of subjects were high responders who lost ≥5% body weight, 22% of them in the COMBI arm compared with 16 and 0% in the LIRA and MET arm respectively. BMI decreased by 2.4±1.0 in the COMBI arm compared with 1.3±1.3 in LIRA and 0.5±0.5 in the MET arm (P<0.001). Waist circumference also decreased by 5.5±3.8 cm in the COMBI arm compared with 3.2±2.9 cm in LIRA and 1.6±2.9 cm in the MET arm (P=0.029). Subjects treated with liraglutide experienced more nausea than those treated with metformin, but severity of nausea decreased over time and did not correlate with weight loss.

Conclusions

Short-term combined treatment with liraglutide and metformin was associated with significant weight loss and decrease in waist circumference in obese women with PCOS who had previously been poor responders regarding weight reduction on metformin monotherapy.

Open access

Bing-Li Liu, Shao-Ying Yang, Wei Liu, Li-Qiong Xue, Xia Chen, Chun-Ming Pan, Zhao-Hui Gu, Ming Zhan, Xiao-Mei Zhang, Jun Liang, Guan-Qi Gao, Wen-Hua Du, Guo-Yue Yuan, Ru Ying, Shuang-Xia Zhao and Huai-Dong Song

Background

Convincing evidence has demonstrated the association of TSH receptor (TSHR) with Graves' disease (GD) in the Chinese Han population.

Objective

The aim of this study was to identify the causal variants for GD in the region encompassing TSHR by a refining association study.

Design and methods

GD patients (1536) and 1516 sex-matched controls were recruited in the first stage, and an additional 3832 GD patients and 3426 sex-matched controls were recruited in the replication stage. Genotyping was performed using Illumina Human660-Quad BeadChips or TaqMan single nucleotide polymorphism (SNP) Genotyping Assays and the Fluidigm EP1 platform.

Results

When the results of regression analysis for 74 genotyped SNPs and 922 imputed SNPs in the first-stage cohort were combined, rs179243 and rs3783949 were the probable susceptibility SNPs associated with GD in TSHR. Eleven SNPs, including rs179243 and rs3783949, were selected to further refine the association in the replication study. Finally, rs12101261 and rs179243 were confirmed as independent GD susceptibility variants in the replication and combined populations. Further, we also found that the rate of persistent TSHR autoantibody positivity (pTRAb+) was significantly higher in the GD patients with the susceptible genotypes rs12101261 or rs179243 than in the GD patients carrying the protective genotypes, after the GD patients had been treated for more than 1 year.

Conclusions

These findings indicate that rs12101261 and rs179243 are the possible causal SNPs for GD susceptibility in the TSHR gene and could serve as genetic markers to predict the outcome of pTRAb+ in GD patients.