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Department of Endocrinology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Objective
Lipotoxicity-induced pancreatic β cell-dysfunction results in decreased insulin secretion in response to multiple stimulus. In this study, we investigated the reversible effects of palmitate (PA) or oleate (OA) on insulin secretion and the relationship with pancreatic β-cell ATP-sensitive potassium (KATP) channels.
Methods
MIN6 cells were treated with PA and OA for 48 h and then washed out for 24 h to determine the changes in expression and endocytosis of the KATP channels and glucose-stimulated insulin secretion (GSIS) and sulfonylurea-stimulated insulin secretion (SU-SIS).
Results
MIN6 cells exposed to PA or OA showed both impaired GSIS and SU-SIS; the former was not restorable, while the latter was reversible with washout of PA or OA. Decreased expressions of both total and surface Kir6.2 and SUR1 and endocytosis of KATP channels were observed, which were also recoverable after washout. When MIN6 cells exposed to free fatty acids (FFAs) were cotreated with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or dynasore, we found that endocytosis of KATP channels did not change significantly by AICAR but was almost completely blocked by dynasore. Meanwhile, the inhibition of endocytosis of KATP channels after washout could be activated by PIP2. The recovery of SU-SIS after washout was significantly weakened by PIP2, but the decrease of SU-SIS induced by FFAs was not alleviated by dynasore.
Conclusions
FFAs can cause reversible impairment of SU-SIS on pancreatic β cells. The reversibility of the effects is partial because of the changes of expression and endocytosis of Kir6.2 and SUR1 which was mediated by dynamin.
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Objective
The most common coexisting organ-specific autoimmune disease in patients with type 1 diabetes mellitus (T1DM) is autoimmune thyroid disease (AITD). However, there have been few clinical reports based on a large population about the prevalence of zinc transporter 8 autoantibody (ZnT8A) and other islet autoantibodies in AITD patients. We aimed to explore the presence of islet autoantibodies, ZnT8A, glutamic acid decarboxylase autoantibodies (GADA) and insulinoma-associated antigen 2 autoantibodies (IA-2A) compared with thyroid autoantibodies, thyroid peroxidase autoantibodies (TPOAb) and thyroglobulin autoantibodies (TGAb) and thyrotropin receptor autoantibodies (TRAb) in patients with Graves’ disease (GD), Hashimoto’s thyroiditis (HT) and T1DM patients with AITD.
Methods
Totally, 389 patients with GD, 334 patients with HT, 108 T1DM patients with AITD and 115 healthy controls (HC) were recruited in the study. Islet autoantibodies (ZnT8A, GADA and IA-2A) were detected by radioligand binding assay. Thyroid autoantibodies, TPOAb and TGAb were detected by chemiluminescence assay, and TRAb was detected by RIA.
Results
The prevalence of ZnT8A, GADA and IA-2A was higher in GD and HT patients than that of HC (ZnT8A: GD 8.48%, HT 10.8% vs HC 1.74%; GADA: GD 7.46%, HT 7.74% vs HC 0.870%; IA-2A: GD 4.88%, HT 3.59% vs HC 0%; All P < 0.05) but lower than that of T1DM subjects with AITD (ZnT8A: 42.6%; IA-2A: 44.4%; GADA: 74.1%; all P < 0.0001).
Conclusions
An increased prevalence of ZnT8A as well as GADA and IA-2A was found in both GD and HT patients, indicating that there is a potential link between thyroid autoimmunity and islet autoimmunity.
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Introduction
Tertiary hyperparathyroidism (THPT) and vitamin D deficiency are commonly seen in kidney transplant recipients, which may result in persistently elevated fibroblast growth factor 23 (FGF23) level after transplantation and decreased graft survival. The aim of this study is to evaluate the effect of vitamin D supplementation on THPT, FGF23-alpha Klotho (KLA) axis and cardiovascular complications after transplantation.
Materials and methods
Two hundred nine kidney transplant recipients were included and further divided into treated and untreated groups depending on whether they received vitamin D supplementation. We tracked the state of THPT, bone metabolism and FGF23–KLA axis within 12 months posttransplant and explored the predictors and risk factors for intact FGF23 levels, KLA levels, THPT and cardiovascular complications in recipients.
Results
Vitamin D supplementation significantly improved FGF23 resistance, THPT and high bone turnover status, preserved better graft function and prevented coronary calcification in the treated group compared to the untreated group at month 12. The absence of vitamin D supplementation was an independent risk factor for THPT and a predictor for intact FGF23 and KLA levels at month 12. Age and vitamin D deficiency were independent risk factors for coronary calcification in recipients at month 12.
Conclusion
Vitamin D supplementation effectively improved THPT, FGF23 resistance and bone metabolism, preserved graft function and prevented coronary calcification after transplantation.
Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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We assessed the prevalence of two novel islet autoantibodies, those targeting ubiquitin-conjugating enzyme 2L3 (UBE2L3) and eukaryote translation elongation factor 1 α1 (eEF1A1), in type 1 diabetes mellitus (T1DM) to evaluate their utility in T1DM diagnosis with comparison to other islet autoantibodies. We also aimed to determine whether age and ethnicity impacted their diagnostic value. Electrochemiluminescence assay was used to detect UBE2L3-Ab and eEF1A1-Ab in 193 Chinese Han and 570 American Caucasian subjects with T1DM, and 282 Chinese Han and 199 American Caucasian controls. In Chinese and American cohorts, the UBE2L3-Ab cut-off indices were 0.039 and 0.038, and the eEF1A1-Ab cut-off indices were 0.048 and 0.050, respectively. The prevalence of UBE2L3-Ab was significantly higher in the Chinese (9.33%) and American (3.86%) subjects with T1DM than in the controls (P < 0.05). The prevalence of UBE2L3-Ab in T1DM was significantly higher in Chinese than in American (P < 0.05). Albeit not statistically significant, the prevalence of UBE2L3-Ab in T1DM was slightly higher in children than in adults of both ethnicities. The differences in eEF1A1-Ab levels between subjects with T1DM and controls were not significant. Meanwhile, all American subjects with UBE2L3-Ab also harbored glutamic acid decarboxylase autoantibody (GADA) or insulin autoantibody (IAA). In contrast, 2.07% of the Chinese subjects with UBE2L3-Ab positive were previously classified as autoantibody-negative based on GADA and IAA. So the prevalence of UBE2L3-Ab in T1DM patients was significantly higher than in controls and was variable according to ethnicity as well as tended to be higher in children than adults. However, UBE2L3-Ab and eEF1A1-Ab may not be reliable diagnostic biomarkers forT1DM.
Institution of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Institution of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Institution of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Institution of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Institution of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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To explore the relationship between soluble ST2 (sST2) and metabolic syndrome (MetS) and determine whether sST2 levels can predict the presence and severity of MetS. We evaluated 550 consecutive subjects (58.91 ± 9.69 years, 50% male) with or without MetS from the Department of Vascular & Cardiology, Shanghai Jiao Tong University-Affiliated Ruijin Hospital. Serum sST2 concentrations were measured. The participants were divided into three groups according to the sST2 tertiles. Univariate and multivariable logistic regression models were used to evaluate the association between serum sST2 concentrations and the presence of MetS. Serum sST2 concentrations were significantly higher in the MetS group than in those in the no MetS group (14.80 ± 7.01 vs 11.58 ± 6.41 ng/mL, P < 0.01). Subjects with more MetS components showed higher levels of sST2. sST2 was associated with the occurrence of MetS after multivariable adjustment as a continuous log-transformed variable (per 1 SD, odds ratio (OR): 1.42, 95% CI: 1.13–1.80, P < 0.01). Subgroup analysis showed that individuals with MetS have significantly higher levels of sST2 than those without MetS regardless of sex and age. High serum sST2 levels were significantly and independently associated with the presence and severity of MetS. Thus, sST2 levels may be a novel biomarker and clinical predictor of MetS.
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Aims
Previous studies showed that abnormal mitochondrial structure and function were involved in the pathological process of diabetic nephropathy (DN). The dynamic mitochondrial processes, including fusion and fission, maintain the mass and quantity of mitochondria. Podocyte injury is a critical factor in the development and progression of DN. The present study evaluated the mitochondrial fission of podocytes in patients with DN.
Methods
We recruited 31 patients with biopsy-confirmed DN. A quantitative analysis of the mitochondrial morphology was conducted with electron microscopy using a computer-assisted morphometric analysis application to calculate the aspect ratio values. Immunofluorescence assays were used to evaluate protein colocalization in the glomeruli of patients.
Results
The urine protein level was significantly increased in DN patients compared to non-DN patients (P < 0.001), and the mitochondria in the podocytes from DN patients were more fragmentated than those from patients without DN. The mitochondrial aspect ratio values were negatively correlated with the proteinuria levels (r = −0.574, P = 0.01), and multiple regression analysis verified that the mitochondrial aspect ratio was significantly and independently associated with the urine protein level (β = −0.519, P = 0.007). In addition, Drp1, a mitochondrial fission factor, preferentially combines with AKAP1, which is located in the mitochondrial membrane.
Conclusions
In the podocytes of DN patients, mitochondrial fragmentation was increased, and mitochondrial aspect ratio values were correlated with the proteinuria levels. The AKAP1-Drp1 pathway may contribute to mitochondrial fission in the pathogenesis of DN.
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Shanghai Pituitary Tumor Center, Shanghai, China
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Shanghai Pituitary Tumor Center, Shanghai, China
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Introduction
The purpose of the study was to describe lipid profile and explore pathogenetic role of LDL-c on hypertension in patients with Cushing’s disease (CD). Hypertension is a common feature in patients with CD. Previous study found low-density lipoprotein cholesterol (LDL-c) uptake in vascular cells might be involved in vascular remodeling in patients with CD. Therefore, we evaluated the relationship between lipid profile and the blood pressure in patients with CD.
Methods
This retrospective study included 84 patients referred to Huashan Hospital for the evaluation and diagnosis of CD from January 2012 to December 2013. All subjects had detailed clinical evaluation by the same group of endocrinology specialists to avoid subjective influences.
Results
We found that high LDL-c patients had significant higher body mass index (BMI), systolic blood pressure (SBP), cholesterol (CHO), triglyceride (TG), and apolipoproteinB (apoB) (P < 0.05). An association was detected between SBP values and lipids profile including CHO, TG, LDL-c, apolipoproteinA (apoA), apoB and lipoprotein(a) (LP(a)). After adjustment for all covariates, the LDL-c remained positively associated with SBP. In patients with or without taking statins, patients with LDL-c ≥3.37 mmol/L had higher SBP than patients with LDL-c <3.37 mmol/L. Then, LDL-c was coded using restricted cubic splines (RCS) function with three knots located at the 5th, 50th and 95th percentiles of the distribution of LDL-c. Compared to individuals with 3.215 mmol/L of LDL-c, individuals with 4.0, 4.5 and 5.0 mmol/L of LDL-c had differences of 3.86, 8.53 and 14.11 mmHg in SBP, respectively.
Conclusions
An independent association between LDL-c and SBP was found in patients with CD. We speculate that LDL-c may be a pathogenic factor for hypertension in those patients.
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Purpose
To evaluate the value of MRI-based texture analysis of extraocular muscle (EOM) and orbital fat (OF) in monitoring and predicting the response to glucocorticoid (GC) therapy in patients with thyroid-associated ophthalmopathy (TAO).
Methods
Thirty-seven active and moderate-to-severe TAO patients (responders, n = 23; unresponders, n = 14) were retrospectively enrolled. MRI-based texture parameters (entropy, uniformity, skewness and kurtosis) of EOM and OF were measured before and after GC therapy, and compared between groups. Correlations between the changes of clinical activity score (CAS) and imaging parameters before and after treatment were assessed. Receiver operating characteristic curves were used to evaluate the predictive value of identified variables.
Results
Responsive TAOs showed significantly decreased entropy and increased uniformity at EOM and OF after GC therapy (P < 0.01), while unresponders showed no significance. Changes of entropy and uniformity at EOM and OF were significantly correlated with changes of CAS before and after treatment (P < 0.05). Responders showed significantly lower entropy and higher uniformity at EOM than unresponders before treatment (P < 0.01). Entropy and uniformity of EOM and disease duration were identified as independent predictors for responsive TAOs. Combination of all three variables demonstrated optimal efficiency (area under curve, 0.802) and sensitivity (82.6%), and disease duration alone demonstrated optimal specificity (100%) for predicting responsive TAOs.
Conclusion
MRI-based texture analysis can reflect histopathological heterogeneity of orbital tissues. It could be useful for monitoring and predicting the response to GC in TAO patients.
School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
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Saint Vincent’s Clinical School, UNSW Sydney, Sydney, Australia
SydPath, Saint Vincent’s Hospital, Sydney, Australia
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Gene & Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, New South Wales, Australia
Faculty of Medicine & Health, The University of Sydney, Camperdown, New South Wales, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
School of Medicine, University of Wollongong, New South Wales, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
Department of Head & Neck Surgery, Liverpool Hospital, Liverpool, New South Wales, Australia
Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
South West Sydney Clinical School, UNSW Sydney, Sydney, Australia
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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.
School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
South West Sydney Clinical School, UNSW Sydney, Sydney, Australia
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Saint Vincent’s Clinical School, UNSW Sydney, Sydney, Australia
SydPath, Saint Vincent’s Hospital, Sydney, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
South West Sydney Clinical School, UNSW Sydney, Sydney, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
Department of Head & Neck Surgery, Liverpool Hospital, Liverpool, New South Wales, Australia
Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
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To date, no research evaluating the predictive capabilities of soluble programmed cell death-ligand 1 (sPD-L1) in thyroid cancer patients has been performed. We aimed to investigate the prognostic significance of sPD-L1 expression in papillary thyroid cancer (PTC) and to evaluate the association between sPD-L1 levels with tumoural PD-L1 expression and patient outcomes. Pre-treatment levels of serum and plasma sPD-L1 were measured by ELISA in 101 PTC patients. Tissue microarrays were stained with an anti-PD-L1 antibody, clone SP263 (Ventana). The median serum sPD-L1 concentration in PTC patients was significantly higher compared to healthy controls (P = 0.028). An increased incidence of extrathyroidal extension was significantly associated with an elevated serum sPD-L1 level (P = 0.015). Patients with high serum sPD-L1 levels had significantly shorter median disease-free survival (DFS) as compared to those with low sPD-L1 levels (P = 0.011). Following multivariate analysis, serum sPD-L1 was the only statistically significant predictor for DFS. Patients with both positive serum and tumoural PD-L1 expression had a significantly shorter DFS than those in any other subgroup (P = 0.007). Our study is the first to confirm that sPD-L1 concentration is significantly associated with patient outcome in PTC. Soluble PD-L1 may provide clinicians with a non-invasive biomarker that can lessen dependence on tissue biopsies and diagnose aggressive thyroid cancers at a more treatable stage.
