Violeta Iotova, Jerome Bertherat, George Mastorakos, Olaf Hiort, and Alberto M Pereira
Hui-qing Yuan, Jia-xi Miao, Jia-ping Xu, Su-xiang Zhu, Feng Xu, Xiao-hua Wang, Chun-hua Wang, Chao Yu, Xue-qin Wang, Jian-bin Su, and Dong-mei Zhang
Increased serum cystatin C (CysC) can predict the onset of type 2 diabetes (T2D). Meanwhile, impaired pancreatic α- and β-cell functions get involved in the pathophysiological processes of T2D. So this study was to explore the relationships between serum CysC levels and pancreatic α- and β-cell functions in T2D.
In this cross-sectional observational study, a total of 2634 patients with T2D were consecutively recruited. Each recruited patient received a serum CysC test and oral glucose tolerance test for synchronous detection of serum C-peptide and plasma glucagon. As components of pancreatic β-cell function, insulin secretion and sensitivity indices were evaluated by C-peptide area under the curve (AUC-CP) and C-peptide-substituted Matsuda’s index (Matsuda-CP), respectively. Fasting glucagon (F-GLA) and post-challenge glucagon calculated by glucagon area under the curve (AUC-GLA) were used to assess pancreatic α-cell function. These skewed indices and were further natural log-transformed (ln).
With quartiles of serum CysC levels ascending, AUC-CP, F-GLA and AUC-GLA were increased, while Matsuda-CP was decreased (P for trend <0.001). Moreover, serum CysC levels were positively related to lnAUC-CP, lnF-GLA and lnAUC-GLA (r= 0.241, 0.131 and 0.208, respectively, P < 0.001), and inversely related to lnMatsuda-CP (r= –0.195, P < 0.001). Furthermore, after controlling for other relevant variables via multivariable linear regression analysis, serum CysC levels were identified to account for lnAUC-CP (β= 0.178, t= 10.518, P < 0.001), lnMatsuda-CP (β= –0.137, t= –7.118, P < 0.001), lnF-GLA (β= 0.049, t= 2.263, P = 0.024) and lnAUC-GLA (β= 0.121, t= 5.730, P < 0.001).
Increased serum CysC levels may be partly responsible for increased insulin secretion from β-cells, decreased systemic insulin sensitivity, and elevated fasting and postprandial glucagon secretion from α-cells in T2D.
Xiaohui Qi, Ping He, Huayan Yao, Huanhuan Sun, Jiying Qi, Min Cao, Bin Cui, and Guang Ning
The association between insulin therapy and the risk of biliary tract cancer (BTC) is uncertain. We aimed to assess this risk in type 2 diabetic patients.
Using electronic medical data from the Shanghai Hospital Link database, 202,557 patients with type 2 diabetes (164,997 insulin never-users and 37,560 insulin ever-users) were identified in this study between January 1, 2013, and December 31, 2016, with follow-up until December 31, 2019. By propensity score matching, an ever-user was matched with a never-user. Cox proportional hazards regression analysis was used to estimate risk ratios (HRs) and 95% CIs for three subtypes of BTC (intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC)).
At a mean follow-up of 5.33 years, 143 cases of BTC were observed. The crude incidence rates (per 100,000 person-years) of ECC, ICC, and GBC in ever-users:never-users were 10.22:3.63, 2.04:2.04, and 8.17:6.01, respectively. Insulin therapy was associated with an increased risk of ECC (HR, 4.10; 95% CI, 1.54–10.92; P = 0.005) compared to patients who never used insulin. No statistically significant results were observed for insulin and ICC/GBC. Consistent results were also found in the original cohort.
The relationship between insulin therapy and BTC is type-specific. Further studies are warranted to provide evidence on the identification of ECC risk groups among type 2 diabetic patients.
Jiaxin Luo, Weili Yin, Qiuxia Lin, Juqing Wu, Pan Chen, Yuanna Ling, Jing Wang, Zhen Li, Liqin Pan, Yanying Chen, Wei Ouyang, and Huijuan Feng
To evaluate the locoregional progression-free survival (LPFS) of bone metastatic lesions from differentiated thyroid cancer (DTC) after radioiodine therapy (RAIT) and to define its influencing factors, we performed a retrospective cohort analysis of 89 patients with bone metastases from DTC who received RAIT in our department over a 17-year period. The median follow-up time was calculated using the reverse Kaplan–Meier method. The log-rank test and a multivariate Cox proportional hazards regression model were performed in the analysis of prognostic indicators for LPFS. In this research, the median follow-up time for all patients was 47 (95% CI, 35.752–58.248) months, and that for patients with no progression was 42 months. The longest follow-up time was 109 months. The median LPFS time was 58 (95% CI, 32.602–83.398) months, and the 3- and 5-year LPFS probabilities were 57.8 and 45.1%, respectively. Multivariate analysis revealed bone structural changes as an independent risk factor for LPFS (P= 0.004; hazard ratio, 49.216; 95% CI, 3.558–680.704). Furthermore, the non–total-lesion uptake subgroup presented a worse LPFS than the total-lesion uptake subgroup in patients with structural bone lesions (P = 0.027). RAIT can improve the LPFS of radioiodine-avid bone metastases from DTC, especially those without bone structural changes.
Anne-Sophie C A M Koning, Philippe C Habets, Marit Bogaards, Jan Kroon, Hanneke M van Santen, Judith M de Bont, and Onno C Meijer
Synthetic glucocorticoids like dexamethasone can cause severe neuropsychiatric effects. They preferentially bind to the glucocorticoid receptor (GR) over the mineralocorticoid receptor (MR). High dosages result in strong GR activation but likely also result in lower MR activation based on GR-mediated negative feedback on cortisol levels. Therefore, reduced MR activity may contribute to dexamethasone-induced neuropsychiatric symptoms.
In this single case study, we evaluate whether dexamethasone leads to reduced MR activation in the human brain. Brain tissue of an 8-year-old brain tumor patient was used, who suffered chronically from dexamethasone-induced neuropsychiatric symptoms and deceased only hours after a high dose of dexamethasone.
Main outcome measures
The efficacy of dexamethasone to induce MR activity was determined in HEK293T cells using a reporter construct. Subcellular localization of GR and MR was assessed in paraffin-embedded hippocampal tissue from the patient and two controls. In hippocampal tissue from the patient and eight controls, mRNA of MR/GR target genes was measured.
In vitro, dexamethasone stimulated MR with low efficacy and low potency. Immunofluorescence showed the presence of both GR and MR in the hippocampal cell nuclei after dexamethasone exposure. The putative MR target gene JDP2 was consistently expressed at relatively low levels in the dexamethasone-treated brain samples. Gene expression showed substantial variation in MR/GR target gene expression in two different hippocampus tissue blocks from the same patient.
Dexamethasone may induce MR nuclear translocation in the human brain. Conclusions on in vivo effects on gene expression in the brain await the availability of more tissue of dexamethasone-treated patients.
Kazhan Mollazadegan, Britt Skogseid, Johan Botling, Tobias Åkerström, Barbro Eriksson, Staffan Welin, Anders Sundin, and Joakim Crona
Longitudinal changes in pancreatic neuroendocrine tumor (panNET) cell proliferation correlate with fast disease progression and poor prognosis. The optimal treatment strategy for secondary panNET grade (G)3 that has progressed from a previous low- or intermediate-grade to high-grade panNET G3 is currently unknown. This was a single-center retrospective cohort study aimed to characterize treatment patterns and outcomes among patients with secondary panNET-G3. Radiological responses were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. A total of 22 patients were included and received a median of 2 (range, 1–4) treatment lines in 14 different combinations. Median overall survival (OS) was 9 months (interquartile range (IQR): 4.25–17.5). For the 15 patients who received platinum–etoposide chemotherapy, median OS was 7.5 months (IQR: 3.75–10) and median progression-free survival (PFS) was 4 months (IQR: 2.5–5.5). The 15 patients who received conventional panNET therapies achieved a median OS of 8 months (IQR: 5–16.75) and median PFS was 5.5 months (IQR: 2.75–8.25). We observed one partial response on 177Lu DOTA-TATE therapy. In conclusion, this hypothesis-generating study failed to identify any promising treatment alternatives for patients with secondary panNET-G3. This demonstrates the need for both improved biological understanding of this particular NET entity and for designing prospective studies to further assess its treatment in larger patient cohorts.
Line Tang Møllehave, Marie Holm Eliasen, Ieva Strēle, Allan Linneberg, Rodrigo Moreno-Reyes, Ludmila B Ivanova, Zvonko Kusić, Iris Erlund, Till Ittermann, Endre V Nagy, Ingibjorg Gunnarsdottir, Jonathan Eli Arbelle, Aaron Milton Troen, Valdis Pīrāgs, Lisbeth Dahl, Alicja Hubalewska-Dydejczyk, Malgorzata Trofimiuk-Müldner, João Jacome de Castro, Mafalda Marcelino, Simona Gaberšček, Katja Zaltel, Manuel Puig-Domingo, Lluis Vila, Sofia Manousou, Helena Filipsson Nyström, Michael Bruce Zimmermann, Karen R Mullan, Jayne Valerie Woodside, Henry Völzke, and Betina Heinsbæk Thuesen
Registers of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs.
Register-based cross-sectional study.
National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates were calculated.
Register data on ≥1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroid surgery for benign disease and lower rates of thyroid hormone therapy were found for countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs.
The collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availability and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated. This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes across Europe.
Anna Gorbacheva, Anna Eremkina, Daria Goliusova, Julia Krupinova, and Natalia Mokrysheva
Multiple endocrine neoplasia type 1 (MEN1) is the most common cause of hereditary primary hyperparathyroidism (PHPT). Bone disorders are considered one of the key symptoms in PHPT present with the significant reduction in bone mineral density and low-energy fractures. Previously, these bone disorders were believed to be caused solely by the increase in the level of parathyroid hormone and its subsequent effect on bone resorption. The current paradigm, however, states that the mutations in the menin gene, which cause the development of MEN1, can also affect the metabolism of the cells of the osteoid lineage. This review analyzes both the proven and the potential intracellular mechanisms through which menin can affect bone metabolism.
Yi Chen, Wen Zhang, Chi Chen, Yuying Wang, Ningjian Wang, and Yingli Lu
We aimed to evaluate whether thyroid hormones, autoimmune and thyroid homeostasis status were related to bone turnover in type 2 diabetes.
The data were obtained from a cross-sectional study, the METAL study. In this study, 4209 participants (2059 men and 2150 postmenopausal women) with type 2 diabetes were enrolled. Thyroid function, thyroid antibodies and three bone turnover markers (BTMs), including a large N-mid fragment of osteocalcin (N-MID osteocalcin), β-C-terminal cross-linked telopeptides of type I collagen (β-CTX) and procollagen type I N-terminal propeptide (P1NP), were measured. Thyroid homeostasis parameters, including the sum activity of step-up deiodinases (SPINA-GD), thyroid secretory capacity (SPINA-GT), Jostel’s TSH index (TSHI) and the thyrotroph thyroid hormone resistance index (TTSI), were calculated. The associations of thyroid parameters with BTMs were analyzed using linear regression.
Free and total triiodothyronine were positively associated with N-MID osteocalcin and P1NP in both sexes and positively associated with β-CTX in postmenopausal women. Thyroid-stimulating hormone was negatively associated with β-CTX in postmenopausal women, and free thyroxine was negatively associated with N-MID osteocalcin and P1NP in men. SPINA-GD was positively associated with N-MID osteocalcin and P1NP in both sexes. There was a positive relationship of SPINA-GT with β-CTX, a negative relationship of TTSI with β-CTX, and a negative relationship of TSHI with β-CTX and P1NP in postmenopausal women.
Among men and postmenopausal women with type 2 diabetes, significant associations were observed between N-MID osteocalcin, β-CTX and P1NP with thyroid function and thyroid homeostasis. Further prospective studies are warranted to understand the causal relationship and underlying mechanism.
Ewa Stogowska, Karol Adam Kamiński, Bartosz Ziółko, and Irina Kowalska
The subject of vocal changes accompanying pathological conditions, although still not well explored, seems to be promising. The discovery of laryngeal receptors for sex hormones and thyroid hormones can strongly support the hypothesis of changes in voice due to various endocrinopathies. On the other hand, the impairment of the proper function of the vocal apparatus can also be caused in the process of the microvasculature complications of diabetes mellitus. This review was a comprehensive summary of the accessible literature concerning the influence of selected endocrinopathies on subjective and objective voice parameters. We analysed a total number of 16 English-language research papers from the PubMed database, released between 2008 and 2021, describing vocal changes in reproductive disorders such as polycystic ovary syndrome and congenital adrenal hyperplasia, thyroid disorders in shape of hypo- or hyperthyroidism and type 2 diabetes mellitus. The vast majority of the analysed articles proved some changes in voice in all mentioned conditions, although the detailed affected vocal parameters frequently differed between research. We assume that the main cause of the observed conflicting results might stem from non-homogeneous methodology designs of the analysed studies.