Endocrine最新文献

Purpose: Preculturing isolated islets with Mesenchymal Stromal Cells (MSCs) improves their functional survival in vitro and subsequent transplantation outcomes in vivo. The MSC secretory product Annexin A1 (ANXA1) is a key modulator of MSC-mediated improvements in islet function. The current study aims to determine the influence of MSCs and defined MSC secretory products, including ANXA1, on the inflammatory crosstalk between isolated islets and Endothelial Cells (ECs), using in vitro models of the clinically-preferred intraportal islet transplantation niche.

Methods: Islets were cultured alone, with MSCs, or with MSC secretory products and exposed to pro-inflammatory cytokines. Islet gene expression of C-C Motif Chemokine Ligand 2 (CCL2), C-X-C Motif Chemokine Ligand (CXCL)-10 (CXCL10) and CXCL1 were assessed by RT-qPCR. EC activation was induced with 100 U/ml TNF for 24 h. Islet-EC co-cultures were used to determine the influence of MSCs, or MSC secretory products on the inflammatory crosstalk between isolated islets and ECs. VCAM-1 and ICAM-1 expression were assessed at the mRNA and protein level in ECs, using RT-qPCR and immunofluorescence.

Results: MSCs reduce pro-inflammatory cytokine-induced islet CCL2, CXCL10, and CXCL1 gene expression, which is partially mimicked by ANXA1. MSCs and ANXA1 have a similar capacity to reduce TNF-induced EC activation. Isolated islets exacerbate TNF-induced EC activation. Preculturing islets with MSCs reduces islet-exacerbated EC activation. ANXA1 reduces islet-exacerbated EC activation, when present during the islet preculture and islet-EC co-culture period.

Conclusion: MSC-derived secretory factors, including ANXA1, may be used in islet transplantation protocols to target donor islet and host EC inflammation at the intraportal niche.

Purpose: Pituitary neuroendocrine tumors (PitNETs) with invasion of the cavernous sinus (CS) are particularly challenging to treat. Tumor associated fibroblasts (TAFs) are recognized for their pivotal role in reprogramming extracellular matrix (ECM). Herein, we aimed to explore the potential involvement of TAFs in ECM reprogramming and elucidate the underlying mechanism involved.

Methods: We applied dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to measure tumor vessel permeability and applied atomic force microscopy (AFM) to measure the matrix stiffness of PitNETs located in both CS and sella turcica (ST). Western blotting, immunofluorescence, immunohistochemistry, and quantitative RT-PCR were utilized to analyze the ECM components. Proteomic biochemical analysis was utilized to uncover potential mechanisms governing ECM dynamics.

Results: We found that PitNETs in the CS were stiffer than those in the ST. Increased ECM stiffness within the CS facilitated the acquisition of stem-like properties, enhanced proliferation, and induced epithelial-to-mesenchymal transition (EMT) of GH3 cells. Furthermore, the expression levels of lysyl oxidase (LOX), matrix metallopeptidase 2 (MMP2) and MMP9 in pituitary adenoma cells increased in the stiffer matrix. Proteomic analysis suggested TAFs were activated in the CS area and contributed enhanced matrix stiffness by secreting Col-1 and Col-3. Furthermore, mTOR pathway was activated under higher matrix stiffness and the migration and invasion of GH3 cells be repressed by mTOR inhibitor.

Conclusion: These findings demonstrated that activated TAFs contributed to stiffer matrix and increased ECM stiffness stimulating mTOR pathway in pituitary tumor cells. Our study indicated that mTOR inhibitor was a promising treatment strategy from the standpoint of PitNET biomechanical properties.

Purpose: This study aimed to assess subclinical peripheral diabetic neuropathy (PDN) in adolescents with type 1 diabetes mellitus (T1DM).

Methods: Subjects included 53 T1DM patients (age (mean ± SE): 15.8 ± 0.54 years, disease duration: 6.0 ± 0.51 years and HbA1c: 7.9 ± 0.19%), and 37 healthy gender matched controls (age: 15.6 ± 0.52 years). PDN was assessed by vibration perception threshold (VPT) and by quantitative sensory testing (QST). In controls, 95% confidence intervals were calculated.

Results: Among patients, VPT prevalence of abnormality ranged from 60-73.4% on different sites. Higher VPT was found in patients on all examined sites (p < 0.01). In controls, VPT correlated with height (r = 0.48, p = 0.05). Regarding QST prevalence of abnormality, cold detection threshold (CDT) ranged 7.3-39.0%, cold pain threshold (CPT) ranged 22.22-29.63%, hot detection threshold (HDT) ranged 34.14-63.41%, and hot pain threshold (HPT) ranged 15.79-36.84%. In patients, CPT correlated with BMI (r = 0.42, p = 0.05) and diabetes duration, (r = 0.40, p = 0.05), HPT correlated with age (r = 0.36, p = 0.05) and height (r = 0.35, p = 0.05), while in controls with BMI (r = 0.51, p = 0.05). No correlation of VPT or QST with HbA1c was observed.

Conclusion: Adolescents with T1DM in this study, although asymptomatic, showed a high prevalence of impaired indices of PDN, highlighting potential clinical implications of early identification of PDN.

Purpose: The evaluation of the effect of dulaglutide on glycated hemoglobin (HbA1c) and non-invasive indices of hepatic steatosis among different genotypes of the PNPLA3 I148M (rs738409) and CETP Taq1B (rs708272) polymorphisms in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD).

Methods: Relevant data from patients with inadequately controlled T2DM, also displaying NAFLD, administered 1.5 mg dulaglutide weekly for 6 months were retrospectively retrieved. The non-invasive indices, fatty liver index (FLI) and hepatic steatosis index (HSI), were calculated. Genotyping for rs738409 and rs708272 were performed with polymerase chain reaction.

Results: Data from 80 patients (39 females), aged 64.4 ± 9.5 years and displaying a baseline BMI of 34.5 ± 5.8 kg/m², were retrieved at baseline and after 6 months (endpoint) of dulaglutide treatment. Glycated hemoglobin (HbA1c; -0.72 ± 1.10%; p < 0.001), FLI (-5.8 ± 9.8; p < 0.001) and HSI (-1.18 ± 3.51; p = 0.004) significantly decreased after treatment. Lipid profile and liver function tests also improved after treatment. Overall, homozygotes for the reference rs738409 allele (CC) displayed a 2.4-fold decrease (p = 0.002) and heterozygotes (CG) an 1.6-fold decrease (p = 0.013) compared to GG homozygotes after treatment, but the effect was largely limited to female patients. No similar effect was observed in FLI, HSI and other relevant parameters. No association was observed between rs708272 and any of the parameters studied.

Conclusions: rs738409, but not rs708272, was associated with the effect of dulaglutide on HbA1c, but not on presumed hepatic steatosis or other relevant parameters. Sex-specific effects were also noticed.

Purpose: Aims of this study were to investigate the prevalence of TP53 and TERT mutations in Medullary Thyroid carcinoma (MTC) and their role in inducing aggressiveness in positive cases.

Methods: We performed a literature search in PubMed to identify studies investigating the prevalence of TERT and TP53 mutations in MTC. We also included data on MTC cases (n = 193) obtained at our center and unpublished. The in-silico pathogenicity of the TP53 mutations has been evaluated by predictor tools.

Results: We identified a total of 25 and 11 published papers: all together 1280 cases have been investigated for the presence of TP53 mutations and 974 for TERT promoter mutation. Twenty-five out of 1280 (2%) cases had a TP53 mutation while only 3/974 MTC cases (0.3%) have been found to be positive for TERT promoter mutations. Among all, we identified 19 different TP53 mutations that in 12 cases were demonstrated to have an in silico predicted high pathogenic role and a high impact on protein function. Three non-sense and 4 probably not damaging mutations were also reported. The pathogenic role of the TERT promoter mutations has been previously in vitro determined. No correlation between TP53 and/or TERT mutations and aggressiveness of MTC has been demonstrated.

Conclusion: The prevalence of TP53 and TERT promoter mutations is very low in MTC. The reported mutations are pathogenic in the majority of cases. Because of their rarity it is not possible to clarify if they play or not a role in the pathogenesis and/or aggressiveness of this specific thyroid tumor.

Purpose: Thyroidectomy is the treatment of choice for malignant thyroid diseases as well as for benign conditions who cannot be treated medically. The most common complication following thyroidectomy is hypocalcaemia and hypoparathyroidism that usually results from accidental damage or removal of one or more parathyroid glands. Parathyroid gland autotransplantation has been one of the most common intraoperative strategies applied to tackle this problem. The aim of this study is to assess whether parathyroid auto trasnplantation is associated with a decrease in postoperative hypoparathyroidism following thyroidectomy.

Methods: We conducted a thorough systematic review and meta-analysis of relevant studies published up to February 2024 in MEDLINE, Scopus, Embase and Cochrane Library databases. We compared the incidence of postoperative hypoparathyroidism between the group of patients who underwent autotransplantation and the patients were the parathyroid glands were preserved in situ. A trial sequential analysis was performed subsequently to confirm the findings.

Results: Eighteen studies fulfilled all the inclusion criteria and were ultimately included in our study. The total number of patients was 8,182 with 4,029 receiving parathyroid gland autotransplantation. Autotransplantation was associated with a higher incidence of immediate (within 24 h) and transient hypoparathyroidism (RR 1.58, 1.45-1.73, CI 95%, p < 0.00 and RR 1.60, 1.47-1.76, CI 95%, p < 0.001, respectively). However, it did not affect the rate of permanent postoperative hypoparathyroidism (RR 0.85, 0.51-1.41, CI 95%, p = 0.54). The subsequent trial sequential analysis confirmed these findings.

Conclusion: Parathyroid autotransplantation does not lead to a decrease in the rate of permanent post-thyroidectomy hypoparathyroidism. The most important factor to decrease its incidence remains the accurate identification and preservation of the parathyroid glands intraoperatively.

Objectives: With the prolongation of life expectancy in patients with myasthenia gravis, the number of comorbidities is increasing. Diabetes mellitus is one of the main comorbidities faced by patients with myasthenia gravis. However, there is not enough epidemiological information on diabetes mellitus. Given these limitations, the purpose of this study was to review the prevalence of diabetes mellitus in patients with myasthenia gravis and whether the myasthenia gravis is associated with an increased risk of gestational diabetes mellitus.

Methods: PubMed, Embase, and Web of Science were searched for articles published prior to February 2024. Endnote 21 software was used to manage all relevant records. Review Manager version 5.4 and Stata version 18.0 software were used for the statistical analysis. Funnel plots and Egger's test were used to assess publication bias.

Results: Twenty-four articles met the inclusion criteria and were included in the study. Among 23,516 myasthenia gravis patients, the prevalence of diabetes mellitus was 17% (95% CI 12~22%). In addition, the meta-analysis of the two studies showed that myasthenia gravis was significantly associated with an increased risk of gestational diabetes mellitus (OR = 1.56, 95% CI 1.26~1.93, p < 0.01).

Conclusions: Among the comorbidities of myasthenia gravis patients, diabetes mellitus is common, and the risk of gestational diabetes mellitus is increased in myasthenia gravis patients. These findings remind us that diabetes mellitus seems to be an important issue in the clinical management of myasthenia gravis patients and requires more attention.

Background: Polycystic ovary syndrome (PCOS) represents a multifaceted endocrine, reproductive, and metabolic disorder characterized by hyperandrogenism and hyperinsulinemia-induced insulin resistance (IR). Recent studies reported that the etiology of PCOS is likely correlated with genes involved in steriodogenesis, IR and glucose metabolism. Among the candidate genes in insulin signaling pathways, RAB5B, a small GTPase involved in vesicle trafficking, significantly impacts cellular pathways in ovarian follicular cells, leading to clinical and endocrine changes among women with PCOS. Additionally, RAB5B is crucial for insulin-mediated glucose uptake and is involved in PI3K, AKT, and MAPK/ERK pathways, affecting LHCGR-stimulated steroidogenesis. Despite extensive research, the precise molecular mechanisms underlying RAB5B mediated IR in PCOS remained elusive.

Objective: The study aimed to explore the potential link between RAB5B gene expression and IR among women with PCOS.

Methodology: A total of age matched 270 subjects were enrolled in this study including 135 PCOS women and 135 apparently healthy controls. These study participants were subjected to detailed medical history, clinical and physical examination. All subjects were further evaluated for biochemical, hormonal and RAB5B gene expression estimation. Expression levels of RAB5B gene were analyzed using gene-specific primers and the SYBR® Green PCR Kit (Qiagen, Germany) and their qPCR reaction mix, according to the manufacturer's guidelines. Student t-test and ANOVA were used to evaluate the differences in the means of various parameters.

Results: The HOMA-IR (2.28 ± 1.4 vs. 1.36 ± 0.73) was significantly elevated among women with PCOS than controls (p < 0.05). We also found that the QUICKI (0.35 ± 0.04 vs. 0.37 ± 0.04), MATSUDA (12.59 ± 4.71 vs. 15.47 ± 4.33) and FGIR (11.56 ± 7.06 vs. 14.32 ± 8.66) were higher in controls than women with PCOS (p < 0.05). We also observed that women with PCOS had elevated levels of RAB5B mRNA levels when compared with apparently healthy controls. Bivariate correlation analysis among HOMA-IR stratified PCOS and control subjects revealed strong negative correlation between IR⁺ PCOS and IR^- PCOS (r = -0.61, P < 0.05) and IR^- control (r = -0.37, p < 0.05) subjects respectively.

Conclusion: Our study demonstrated that there is potential link between RAB5B gene expression and IR specifically in the context of IR indices among women with PCOS.

Familial hypercholesterolemia (FH) is less rare than one might think and, despite highly effective lipid-lowering therapies (LLT), more than half of the patients treated do not reach the lipid target indicated by the guidelines. In these patients, lipoprotein apheresis (LA) is the most effective tool to lowering apo-B containing atherogenic lipoproteins. In own center, since 1994, thanks to routinely cascade testing performed in patients who start LA, we have identified a pediatric population (30 subjects) that we analyzed retrospectively. Cascade screening, performed in subject with premature cardiovascular events or inherited dyslipidemias, is an effective approach to identified pediatric FH, a condition that pediatricians should also be aware. A dedicate network is required to investigate the involved genetic mutations and to set up a management program, including lipoprotein (a) measurement and subclinical atherosclerosis evaluation. Moreover, it is important that medical staff use a therapeutic pathway to help patients overcome discomfort associated with disease and chronic LLT, as well as improve adherence to lipid-lowering drugs.

Purpose: The growth hormone (GH) level on postoperative day one (POD1), i.e., POD1GH, holds significant value in assessing surgical efficacy and predicting long-term remission in patients with acromegaly. This study aims to explore the factors that influence the GH level of POD1 after microscopic transsphenoidal surgery (mTSS) in patients with acromegaly, providing insights for preoperative clinical decisions.

Methods: A total of 85 acromegaly patients undergoing mTSS were included in this study. Sex; age; body mass index (BMI); preoperative serum hormone levels and tumor characteristics were assessed for their correlation with POD1GH levels. POD1GH level non-remission, defined as POD1GH > 2.5 ng/mL, was considered an outcome.

Results: The patients with acromegaly were divided into two groups: adult males (43 cases) and adult females (42 cases), with mean ages of 43.33 ± 11.92 years and 47.02 ± 14.18 years, respectively. Correlation and multivariate linear regression analyses revealed positive correlations of preoperative GH and prolactin (PRL) levels in females with POD1GH levels, while preoperative FT3 and TT levels in males were negatively correlated with POD1GH levels. Binary logistic regression and receiver operating characteristic (ROC) analyses identified preoperative GH levels ≥30.25 ng/mL (OR = 2.236, 95%CI = 1.402-3.567, p < 0.001), FT3 levels ≤4.415 pmol/L (OR = 0.329, 95%CI = 0.167-0.648, p < 0.001), and age ≤51 years (OR = 0.566, 95%CI = 0.352-0.911, p = 0.019) as independent risk factors for POD1GH level non-remission.

Conclusions: Preoperative GH, FT3, TT, and PRL levels are correlated with POD1GH levels, with variations observed between sex. Age, preoperative GH, and FT3 levels can predict POD1GH level non-remission. Therefore, the comprehensive consideration of multiple hormone axes is necessary for predicting postoperative efficacy.