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Open access

Selina Mäkinen, Neeta Datta, Yen H Nguyen, Petro Kyrylenko, Markku Laakso, and Heikki A Koistinen

Objectives

Simvastatin use is associated with muscular side effects, and increased risk for type 2 diabetes (T2D). In clinical use, simvastatin is administered in inactive lipophilic lactone-form, which is then converted to active acid-form in the body. Here, we have investigated if lactone- and acid-form simvastatin differentially affect glucose metabolism and mitochondrial respiration in primary human skeletal muscle cells.

Methods

Muscle cells were exposed separately to lactone- and acid-form simvastatin for 48 h. After pre-exposure, glucose uptake and glycogen synthesis were measured using radioactive tracers; insulin signalling was detected with Western blotting; and glycolysis, mitochondrial oxygen consumption and ATP production were measured with Seahorse XFe96 analyzer.

Results

Lactone-form simvastatin increased glucose uptake and glycogen synthesis, whereas acid-form simvastatin did not affect glucose uptake and decreased glycogen synthesis. Phosphorylation of insulin signalling targets Akt substrate 160 kDa (AS160) and glycogen synthase kinase 3β (GSK3β) was upregulated with lactone-, but not with acid-form simvastatin. Exposure to both forms of simvastatin led to a decrease in glycolysis and glycolytic capacity, as well as to a decrease in mitochondrial respiration and ATP production.

Conclusions

These data suggest that lactone- and acid-forms of simvastatin exhibit differential effects on non-oxidative glucose metabolism as lactone-form increases and acid-form impairs glucose storage into glycogen, suggesting impaired insulin sensitivity in response to acid-form simvastatin. Both forms profoundly impair oxidative glucose metabolism and energy production in human skeletal muscle cells. These effects may contribute to muscular side effects and risk for T2D observed with simvastatin use.

Open access

Hei Yi Vivian Pak, Andrew Lansdown, Peter Taylor, Dafydd Aled Rees, John Stephen Davies, and Caroline Hayhurst

Objective

Acromegaly is a rare condition and there is often a long path to diagnosis for many patients. We sought to explore patient’s perceptions and understanding of acromegaly, to examine the quality of communication and find gaps in the information provided at diagnosis.

Design

A prospective study using qualitative research methodology and grounded theory. A semi-structured interview was conducted with 18 patients treated for acromegaly in a single tertiary centre and verbatim transcripts were thematically analysed for overarching themes.

Results

Eighteen patients with acromegaly were interviewed. The mean age of participants was 52 (range 30–72). Four overarching themes emerged; (1) Patients rely on online resources to understand acromegaly in the time between diagnosis and tertiary care clinic; (2) There is not enough support available for patients; (3) Patients have a basic understanding of acromegaly and associated conditions, but the long-term impact is underestimated; and (4) Patients initially felt intimidated by the multidisciplinary team panel, but overall found it useful.

Conclusion

Acromegalic patients have a strong need for information at the point of initial diagnosis, in particular online resources and interaction with other experienced patients. Wider dissemination of patient educational resources into primary and secondary care settings may improve overall patient satisfaction, treatment adherence and subsequent health care provider–patient relationships.

Open access

Xiaojie Wang, Zhiyuan Chen, Ziyi Li, Bo Chen, Yong Qi, Guowei Li, and Jonathan D Adachi

Background

Several epidemiological studies have demonstrated the risk factors for fall, while few studies investigated the association between frailty and risk of fall in diabetic patients aged ≥45 years.

Methods

In this multicity observational study, participants with type 2 diabetes aged ≥45 years were enrolled. Frailty status was measured by a frailty index (FI) of deficit accumulation. We used multivariable regression models to examine the relationship between frailty and fall in diabetic patients, and further investigated the associations between frailty and fall in varied subgroups.

Results

A total of 2049 participants with type 2 diabetes were identified in our study. Our results showed a per-s.d. and a per-0.01 increment of FI were associated with an increased risk of fall, with a fully adjusted OR of 1.89 (95% CI: 1.50, 2.38), 1.06 (95% CI: 1.04, 1.09), respectively. The effects were magnified when frailty was considered as dichotomous, with an OR of 3.08 (95% CI: 2.18, 4.34). In further subgroup analyses, we found that the females, the older, rural residents, individuals with no sitting toilet, people with poor balance performance and those in poor health status were susceptible to fall. Especially, for the risk of fall in the older, a per-s.d. increase of FI corresponded to an OR of 2.46 (95% CI: 1.68, 3.62). When frailty was regarded as a binary variable, the effect increased to 4.62 (95% CI: 2.54, 8.38) in the older subgroup.

Conclusion

Frailty was associated with a higher risk of fall in people with type 2 diabetes, and the effects were higher in vulnerable groups. This evidence suggested that more attention should be paid to vulnerable groups for fall prevention.

Open access

Pan Chen, Liqin Pan, Wensi Huang, Huijuan Feng, Wei Ouyang, Juqing Wu, Jing Wang, Yuying Deng, Jiaxin Luo, and Yanying Chen

Objective

To evaluate the relationship between the BRAF V600E mutation in lymph node metastasis (LNM) and its invasive characteristics in papillary thyroid cancer (PTC).

Material and methods

A total of 373 PTC patients were enrolled in this study conducted at Zhujiang Hospital of Southern Medical University between January 2017 and December 2018. PTCs with cervical lymph node metastases were verified pathohistologically, and primary tumors and LNM were examined for the BRAF V600E mutation. Patients were excluded from the study if the BRAF V600E mutation was examined only in primary tumors or only in LNM.

Results

Of the 373 patients examined, BRAF V600E mutation frequency in primary tumors was slightly higher than in LNM (81.5% vs 78.0%, P = 0.000), the intra-class correlation coefficient (ICC) was 0.865 (95% CI 0.835–0.890). The BRAF V600E mutation in both primary tumor and LNM negatively correlated with the size of the largest metastatic focus of LNM (Odds ratio, OR = 0.297, 95% CI 0.143–0.616, P = 0.001; OR = 0.242, 95% CI 0.119–0.492, P = 0.000, respectively). There was no relationship between BRAF V600E mutation in LNM and the number, extranodal extension or stage of LNM (P > 0.05).

Conclusion

The BRAF V600E mutation in LNM may not be related to the invasive characteristics of LNM in PTC.

Open access

Guido Zavatta and Bart L Clarke

The first adjunctive hormone therapy for chronic hypoparathyroidism, recombinant human parathyroid hormone (1–84) (rhPTH(1–84)) was approved by the FDA in January 2015. Since the approval of rhPTH(1–84), growing interest has developed in other agents to treat this disorder in both the scientific community and among pharmaceutical companies. For several reasons, conventional therapy with calcium and activated vitamin D supplementation, magnesium supplementation as needed, and occasionally thiazide-type diuretic therapy remains the mainstay of treatment, while endocrinologists and patients are constantly challenged by limitations of conventional treatment. Serum calcium fluctuations, increased urinary calcium, hyperphosphatemia, and a constellation of symptoms that limit mental and physical functioning are frequently associated with conventional therapy. Understanding how conventional treatment and hormone therapy work in terms of pharmacokinetics and pharmacodynamics is key to effectively managing chronic hypoparathyroidism. Multiple questions remain regarding the effectiveness of PTH adjunctive therapy in preventing or slowing the onset and progression of the classical complications of hypoparathyroidism, such as chronic kidney disease, calcium-containing kidney stones, cataracts, or basal ganglia calcification. Several studies point toward an improvement in the quality of life during replacement therapy. This review will discuss current clinical and research challenges posed by treatment of chronic hypoparathyroidism.

Key points:

  • Conventional therapy with calcium and activated forms of vitamin D are currently the mainstays of treatment for most patients with chronic hypoparathyroidism.
  • Hormone therapy can be administered through FDA-approved once-daily rhPTH(1–84), or off-label multiple-daily injections of teriparatide. The former is the only FDA-approved drug, with safety and efficacy supported by a randomized placebo-controlled trial and open-label long-term extension trial data.
  • Twice-daily teriparatide has been used in children safely for up to 10 years.
  • New pharmacological options that replace the deficient hormone wi ll likely be available within the next few years.
Open access

Raja Padidela, Moira S Cheung, Vrinda Saraff, and Poonam Dharmaraj

X-linked hypophosphataemia (XLH) is caused by a pathogenic variant in the PHEX gene, which leads to elevated circulating FGF23. High FGF23 causes hypophosphataemia, reduced active vitamin D concentration and clinically manifests as rickets in children and osteomalacia in children and adults. Conventional therapy for XLH includes oral phosphate and active vitamin D analogues but does not specifically treat the underlying pathophysiology of elevated FGF23-induced hypophosphataemia. In addition, adherence to conventional therapy is limited by frequent daily dosing and side effects such as gastrointestinal symptoms, secondary hyperparathyroidism and nephrocalcinosis. Burosumab, a recombinant human IgG1 MAB that binds to and inhibits the activity of FGF23, is administered subcutaneously every 2 weeks. In clinical trials (phase 2 and 3) burosumab was shown to improve phosphate homeostasis that consequently resolves the skeletal/non-skeletal manifestations of XLH. Burosumab was licensed in Europe (February 2018) with the National Institute for Health and Care Excellence, UK approving use within its marketing authorisation in October 2018. In this publication, the British Paediatric and Adolescent Bone Group (BPABG) reviewed current evidence and provide expert recommendations for care pathway and management of XLH with burosumab.

Open access

Anna Eremkina, Julia Krupinova, Ekaterina Dobreva, Anna Gorbacheva, Ekaterina Bibik, Margarita Samsonova, Alina Ajnetdinova, and Natalya Mokrysheva

Hypercalcemic crisis is a severe but rare complication of primary hyperparathyroidism (PHPT), and data on denosumab treatment of patients with this disease is still very limited. The aim of this paper is to investigate the hypocalcemic effect of denosumab in PHPT patients with severe hypercalcemia when surgery should be delayed or is impossible for some reasons. We performed a retrospective study of 10 patients. The analysis included the use of biochemical markers of calcium-phosphorus metabolism, which were followed after the administration of 60 mg of denosumab. The trend to calcium reduction was already determined on the 3rd day after denosumab administration. In most cases the decrease in serum calcium level to the range of 2.8 mmol/L on average or lower was observed on the 7th day (P = 0.002). In addition to a significant increase in calcium levels we confirmed a significant increase in the estimated glomerular filtration rate on 7th day (P = 0.012). After that, seven patients underwent successful parathyroidectomy and achieved eucalcemia or hypocalcemia, one patient developed the recurrence of parathyroid cancer after initial surgery, while two patients with severe cardiovascular pathology refused surgery. Our study shows that denosumab is a useful tool in PHPT-associated hypercalcemia before surgery or if surgery is contraindicated.

Open access

Grethe Å Ueland, Thea Grinde, Paal Methlie, Oskar Kelp, Kristian Løvås, and Eystein S Husebye

Objective:

Autonomous cortisol secretion (ACS) is a condition with ACTH-independent cortisol overproduction from adrenal incidentalomas (AI) or adrenal hyperplasia. The hypercortisolism is often mild, and most patients lack typical clinical features of overt Cushing’s syndrome (CS). ACS is not well defined and diagnostic tests lack validation.

Methods:

Retrospective study of 165 patients with AI evaluated clinically and by assay of morning plasma ACTH, late-night saliva cortisol, serum DHEA sulphate (DHEAS), 24-h urine-free cortisol, and cortisol after dexamethasone suppression.

Results:

Patients with AI (n = 165) were diagnosed as non-functioning incidentalomas (NFI) (n = 82) or ACS (n = 83) according to current European guidelines. Late-night saliva cortisol discriminated poorly between NFI and ACS, showing a high rate of false-positive (23/63) and false-negative (38/69) results. The conventional low-dose dexamethasone suppression test (LDDST) did not improve the diagnostic specificity, compared with the 1 mg overnight DST. Receiver operating characteristic curve analysis of DHEAS in the two cohorts demonstrated an area under the curve of 0.76 (P < 0.01) with a sensitivity for ACS of 58% and a specificity of 80% using the recommended cutoff at 1.04 µmol/L (40 µg/dL).

Conclusion:

We here demonstrate in a large retrospective cohort of incidentaloma patients, that neither DHEAS, late-night saliva cortisol nor 24-h urine free cortisol are useful to discriminate between non-functioning adrenal incidentalomas and ACS. The conventional LDDST do not add further information compared with the 1 mg overnight DST. Alternative biomarkers are needed to improve the diagnostic workup of ACS.

Open access

Lina S Silva-Bermudez, Freddy J K Toloza, Maria C Perez-Matos, Russell J de Souza, Laura Banfield, Andrea Vargas-Villanueva, and Carlos O Mendivil

Objective

To estimate the effect of oral contraceptives (OC) containing different progestins on parameters of lipid and carbohydrate metabolism through a systematic review and meta-analysis.

Patients and methods

Premenopausal women aged 18 or older, who received oral contraceptives containing chlormadinone, cyproterone, drospirenone, levonorgestrel, desogestrel, dienogest, gestodene or norgestimate, for at least 3 months. Outcome variables were changes in plasma lipids, BMI, insulin resistance and plasma glucose. We searched MEDLINE and EMBASE for randomized trials and estimated the pooled within-group change in each outcome variable using a random-effects model. We performed subgroup analyses by study duration (<12 months vs ≥12 months) and polycystic ovary syndrome (PCOS) status.

Results

Eighty-two clinical trials fulfilled the inclusion criteria. All progestins (except dienogest) increased plasma TG, ranging from 12.1 mg/dL for levonorgestrel (P < 0.001) to 35.1 mg/dL for chlormadinone (P < 0.001). Most progestins also increased HDLc, with the largest effect observed for chlormadinone (+9.6 mg/dL, P < 0.001) and drospirenone (+7.4 mg/dL, P < 0.001). Meanwhile, levonorgestrel decreased HDLc by 4.4 mg/dL (P < 0.001). Levonorgestrel (+6.8 mg/dL, P < 0.001) and norgestimate (+11.5 mg/dL, P = 0.003) increased LDLc, while dienogest decreased it (–7.7 mg/dL, P = 0.04). Cyproterone slightly reduced plasma glucose. None of the progestins affected BMI or HOMA-IR. Similar results were observed in subgroups defined by PCOS or study duration.

Conclusion

Most progestins increase both TG and HDLc, their effect on LDLc varies widely. OC have minor or no effects on BMI, HOMA-IR and glycemia. The antiandrogen progestins dienogest and cyproterone displayed the most favorable metabolic profile, while levonorgestrel displayed the least favorable.

Open access

Marra Jai Aghajani, Tao Yang, Ulf Schmitz, Alexander James, Charles Eugenio McCafferty, Paul de Souza, Navin Niles, and Tara L Roberts

Programmed cell death-ligand 1 (PD-L1) has recently been shown to play a role in the regulation of epithelial-to-mesenchymal transition (EMT); however, the relationship between PD-L1 expression, EMT and the inflammatory tumour microenvironment has yet to be investigated in thyroid cancer. To address this issue, we examined the expression of CD8, PD-L1 and the EMT markers E-cadherin and vimentin in a cohort of 74 papillary thyroid cancer (PTC) patients and investigated the association of these with clinicopathologic characteristics and disease-free survival (DFS). The relationship between PD-L1 and EMT was further examined in three thyroid cancer cell lines via Western blot and live cell imaging. In order to expand our in vitro findings, the normalised gene expression profiles of 516 thyroid cancer patients were retrieved and analysed from The Cancer Genome Atlas (TCGA). PD-L1 positivity was significantly higher in PTC patients exhibiting a mesenchymal phenotype (P = 0.012). Kaplan–Meier analysis revealed that PD-L1 (P = 0.045), CD8 (P = 0.038) and EMT status (P = 0.038) were all significant predictors for DFS. Sub-analysis confirmed that the poorest DFS was evident in PD-L1 positive patients with EMT features and negative CD8 expression (P < 0.0001). IFN-γ treatment induced upregulation of PD-L1 and significantly promoted an EMT phenotype in two thyroid cancer cell lines. Our findings suggest that PD-L1 signalling may play a role in stimulating EMT in thyroid cancer. EMT, CD8 and PD-L1 expression may serve as valuable predictive biomarkers in patients with PTC.