Journal of Endocrinological Investigation最新文献

Purpose: To identify distinct Th-like regulatory T cell (Treg) subsets in the peripheral blood of individuals with type 1 diabetes (T1D) and investigate potential factors that affect Treg polarization within the context of autoimmunity.

Methods: A total of 49 T1D patients and 20 healthy controls (HCs) were enrolled in this study. Th-like Treg subsets, including Th1-like, Th2-like and Th17-like Tregs, as well as Th cell subsets in peripheral blood were assessed by flow cytometry. Single nucleotide polymorphisms in Treg-related genes were analyzed. The levels of inflammatory cytokines were measured by ELISA.

Results: We observed a decreased frequency of Th1-like Tregs in peripheral blood of T1D patients, while the proportion of total Foxp3⁺ Tregs remained unchanged. Moreover, an imbalance of Th17-like Treg/Th17 cells was noted, characterized by a decreased frequency of Th17-like Tregs and an increased proportion of Th17 cells. Further analysis revealed a correlation between the frequency of Th2-like Tregs and the risk variants of IL-2RA rs3118470. Notably, T1D patients with a normal weight exhibited a higher frequency of Th1-like Tregs compared to their lean and overweight counterparts. However, Treg plasticity was not associated with disease characteristics. Additionally, the serum levels of IL-1β, TNF-α and IL-6 in T1D patients were significantly higher than those in HCs, and the proportions of Th1-like and Th2-like Tregs were negatively associated with IL-6 and TNF-α concentrations in T1D patients, respectively. Nevertheless, the proportions of Th-like Treg subsets in the peripheral blood of HCs exhibited no significant correlation with age, BMI, or the levels of inflammatory cytokines.

Conclusion: Our study has provided novel evidence on the altered plasticity and the possible mechanisms underlying the transformation of conventional Tregs towards Th1-like and Th17-like Tregs in the peripheral blood of T1D patients. The findings serve to further augment our understanding of the Treg-mediated immune imbalance that plays a crucial role in the immunopathogenesis of T1D.

Purpose: Hypothalamic-pituitary thyrotropic activity (HPta) is crucial since TSH is the mainstay for evaluating primary hypothyroidism (hT) and replacement therapy in clinical practice. Despite TSH values, some patients experience symptoms and metabolic alterations, raising several issues about hT. The aim of the study was to investigate factors influencing the TSH values achieved after a period of hT induced in a standardized and controlled manner (TSH_time1).

Methods: Our institutional database was searched to extract records of differentiated thyroid cancer (DTC) patients undergoing a LT4 withdrawal protocol prior to radioiodine (RAI) administration. We collected clinical and biochemical parameters before LT4 discontinuation and after one month of induced hT. We performed Mann-Whitney U-test and linear regression analyses.

Results: We included 102 patients, with a median age of 44 years. In univariate analyses, TSH_time1 was correlated with age (p 0.005) and the dose pro Kg/die of LT4 assumed until the discontinuation of LT4 (LT4_dose) (p 0.023). The higher the age, the lower the TSH_time1 level. The higher the LT4_dose, the higher the TSH_time1 level. After multivariate analysis, the fittest model included age, BMI, LT4_dose, and systemic inflammation response index with an adjusted R² of 0.4.

Conclusion: The study highlights new mechanisms that influence HPta. HPta progressively reduces with age, and this must be considered when evaluating TSH values in the elderly. Furthermore, we report for the first time a rebound effect of HPta, determined by the dose pro Kg/die of LT4 taken prior to its discontinuation. Inflammation and metabolic status also affect these phenomena.

Purpose: Insulin resistance plays a pivotal role in the preclinical stages of type 1 diabetes (T1D).

Objective: This study aims at exploring the genetic, metabolic, and immunological features associated with insulin resistance among individuals at risk of developing T1D.

Methods: We retrospectively selected relatives of individuals with T1D from participants in the TrialNet Pathway to Prevention study. They were categorized into two groups: high-H (n = 27) and low-H (n = 30), based on the upper and lower quartiles of insulin resistance assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Genetic predisposition was determined using the T1D Genetic Risk Score 1 (GRS1). Additionally, glucose control was evaluated through an oral glucose tolerance test and levels of metabolic hormones and inflammatory cytokines were measured in the serum. Flow cytometry analysis was employed to assess frequency and phenotype of islet-specific CD8 T cells.

Results: While GRS1 were similar between the low-H and high-H groups, high-H individuals displayed a distinct metabolic profile, characterized by compensatory hyperinsulinemia, even while maintaining normoglycemia. Circulating cytokine levels were similar between the two groups. However, immune profiling revealed a central memory and activated profile of GAD65-specific CD8 T cells, along with an increased frequency of insulin-specific CD8 T cells in high-H individuals. The enrichment in insulin-specific CD8 T cells was independent of body mass.

Conclusion: These findings highlight the intricate interplay between insulin resistance, genetic factors, and immune activation in the context of T1D susceptibility, indicating potential connections between insulin resistance and immune responses specific to islet cells.

Purpose: scientific literature highlights risk factors linked to the onset of psychopathology in different medical pathological contexts. Acromegaly is a rare condition, particularly noteworthy due to the associated clinical psychological features. This research aimed at understanding the main psychopathological outcomes related to acromegaly, with particular emphasis to anxiety and depression.

Methods: In January 2024, in line with PRISMA guidelines, a systematic search based on PubMed, Scopus, Web of Science and PsycInfo was conducted to detect studies considering anxiety, depression and alexithymia in patients suffering from acromegaly. The Keywords used for the search phase were "Acromegaly" AND "Depression" OR "Anxiety" OR "Alexithymia".

Results: Fifty-five studies were eligible. Anxiety and depression were significantly present in patients with acromegaly, with prevalence rates variable based on disease status and psycho-diagnostic instruments. None of the included studies reported alexithymia in patients with acromegaly. No significant difference was found regarding anxiety and depressive symptoms in patients with acromegaly in comparison with patients suffering from different pituitary diseases and chronic conditions. Anxiety and depression were associated with lower perceived HR-QoL, presence of comorbidity, joint issues, delayed diagnosis, disease duration and body image concerns.

Conclusions: Anxiety and depression may be encountered in patients with acromegaly, impacting HR-QoL and the course of the disease. This systematic review suggests that a deeper evaluation of clinical psychological features in patients suffering from acromegaly is needed. Particularly, the early detection of clinical psychological symptoms may lead to multi-integrate interventions promoting individuals' well-being and a better HR-QoL.

Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Xenotropic and polytropic retrovirus receptor 1 (XPR1), identified as a cellular receptor, plays roles in many pathophysiological processes. However, the underlying function and molecular mechanisms of XPR1 in PTC remain unclear. Therefore, this study aimed to elucidate the role of XPR1 in the process of PTC and the potential mechanisms.

Methods: RNA-sequencing was performed for gene differential expression analysis in PTC patients' tissues. Immunohistochemical assay, real-time PCR, and western blotting assay were used to determine the expression of XPR1, BRAF, and P53 in PTC tissues. The function of XPR1 on the progression of PTC was explored using in vitro and in vivo experiments. The molecular mechanism of XPR1 was investigated using gene silencing, ELISA, immunofluorescence, western blotting, and real-time PCR assays.

Results: We found that XPR1 was markedly upregulated in PTC tissues compared to adjacent noncancerous tissues, suggesting that high expression of XPR1 could be correlated with poor patient disease-free survival in PTC. In addition, the expression of BRAF and P53 in PTC tissues was substantially higher than in adjacent noncancerous tissues. Silencing of XPR1 reduced the proliferation, migration, and invasion capacities of TPC-1 cells in vitro and effectively inhibited the tumorigenecity of PTC in vivo. More importantly, silencing of XPR1 in TPC-1 cells significantly decreased the expression of XPR1, BRAF, and P53 both in vitro and in vivo. Interestingly, we demonstrated that XPR1 may positively activate the BRAF-ERK-P53 signaling pathway, further promoting PTC progression.

Conclusion: The findings reveal a crucial role of XPR1 in PTC progression and prognosis via the BRAF-ERK1/2-P53 signaling pathway, providing potential therapeutic targets for treating PTC.

Purpose: Type 1 diabetes (T1D) is a chronic autoimmune illness that results in loss of pancreatic beta cells and insulin insufficiency. MicroRNAs (miRNAs) are linked to immune system functions contributing to the pathophysiology of T1D, miRNA-375 is significantly expressed in the human pancreas and its circulatory levels might correspond to beta cell alterations. Pancreatic islet cell antibodies (ICA) and Glutamic acid decarboxylase antibodies (GADA) have roles in autoimmune pathogenesis and are predictive markers of T1D. The aim of this work was to detect serum level changes of miRNA-375, ICA, and GADA in T1D patients, and their siblings compared to healthy controls and correlate them with T1D biochemical parameters.

Methods: The study included 66 T1D patients (32 males and 34 females; age range 3-18 years), 22 patients' siblings (13 males and 9 females; age range 4-17 years), and 23 healthy controls (7 males and 16 females; age range 4-17 years). MiRNA-375 levels were measured using quantitative reverse transcription polymerase chain reaction (RT-qPCR), while ICA and GADA levels were measured using enzyme-linked immunosorbent assay (ELISA). Data analysis was done utilizing SPSS-17 software.

Results: MiR-375 levels were downregulated in T1D patients and further decreased in their siblings when compared to healthy controls. Furthermore, miR-375 exhibited inverse correlations with HbA1c levels but no correlations with Total Insulin Dose, disease duration, or autoantibodies (GADA & ICA).

Conclusion: Our study indicates that miR-375 is significantly downregulated in children with T1D and their siblings, suggesting its potential role as a biomarker for beta-cell function and glycemic control.

Background: Estrogen is thought to be the reason for the higher prevalence of papillary thyroid carcinoma (PTC) in fertile women; however, more study is required to completely comprehend how estrogen affects PTC development at the cellular level. Therefore, we combined Oxford Nanopore Technologies (ONT) sequencing to explore molecular markers of PTC and to investigate the molecular mechanisms by which estrogen promotes PTC development.

Methods: The expression levels of ESR1 (ERα) and KRT19 in normal thyroid tissues and cancer tissues as well as in different cancer stages, races, genders, age groups, histological subtypes and nodular metastasis status of the TCGA database were analyzed online by Ualcan; the relationship between ESR1, KRT19 and the survival of THCA patients was analyzed. A PTC xenograft tumor model was established. An ERα specific inhibitor (MPP) was administered and an EDU cell proliferation assay was used to verify the effect of estrogen on PTC proliferation. KRT19 was knocked down in KTC-1 cells, and the proliferation, migration, and invasion abilities of PTC cells were determined using CCK-8, immunofluorescence labeling, Western blot for EMT-related proteins, scratch assay, and Transwell assay. The role of ERα in relation to KRT19 was investigated by Western blot and immunofluorescence. The effects of ERα/KRT19 signaling axis on the proliferation, migration and invasion ability of PTC cells were evaluated using EDU cell proliferation assay and Transwell. Using ONT sequencing, 15 pairs of PTC tissue and paracancer tissue samples were collected. A PPI network was constructed to validate the differential expression of KRT19 in combination with biosignature analysis, and the protein interaction between KRT19 and ESR1 was verified using STRING.

Results: Ualcan showed that the expression of ESR1 and KRT19 was higher in THCA tissues than in normal thyroid tissues. E2 activation of ERα promoted the growth of PTC cells and tissues. si-KRT19 inhibited the proliferation, migration and invasion of PTC cells. KRT19 together with ERα formed the ERα/KRT19 signaling axis. E2 activation of the ERα/KRT19 signaling axis promoted the proliferation, migration, and invasion of PTC cells. ONT sequencing and STRING website verified that KRT19 is significantly differentially expressed in PTC and that ESR1 and KRT19 have protein interactions and are related to the estrogen signaling pathway.

Conclusions: Using public databases, RNA sequencing, and bioinformatics, we discovered that E2 stimulates the ERα/KRT19 signaling axis to stimulate PTC proliferation, migration, and invasion.

Objectives: Sirolimus was found to be associated with a better outcome of Graves' orbitopathy (GO) at 24 weeks compared to methylprednisolone. We conducted a retrospective study to investigate its efficacy and safety over a longer period.

Methods: Data from 40 consecutive patients with moderate-to-severe, active GO, 20 treated with sirolimus and 20 with methylprednisolone, were collected.

Primary outcome: overall outcome (composite evaluation) of GO at 48 weeks.

Secondary outcomes: (1) GO outcome at 24 weeks, and, at 24 and 48 weeks: (2) outcome of single eye features; (3) quality of life (GO-QoL); (4) TSH-receptor antibodies; (5) GO relapse at 48 weeks; (6) adverse events.

Results: The overall GO outcome at 48 weeks did not differ between the two groups (responders: 55% vs 55%). At 24 weeks, prevalence of responders was greater in sirolimus group (65% vs 25%; P = 0.01). A reduction ≥ 1 point in clinical activity score (CAS) was more frequent in sirolimus patients at 24 (85% vs 40%; P = 0.005) and 48 weeks (75% vs 60%; P = 0.03). The proportion of GO-QoL responders (appearance subscale) at 24 weeks was greater in sirolimus group (62.5% vs 26.3%; P = 0.03). No difference was observed for the remaining outcome measures.

Conclusions: Treatment with sirolimus is followed by a greater overall response of GO compared with methylprednisolone at 24 weeks, but not at 48 weeks, when only CAS is affected. A more prolonged period of treatment may be required for a better outcome to be observed over a longer period.

Purpose: Glucocorticoid-mediated hypercoagulability can persist in patients with endogenous Cushing syndrome (CS) after curative surgery and may transiently worsen early postoperatively. These studies aimed to characterize coagulation markers at baseline in patients with CS and the impact of relacorilant or remission post-surgery in an open-label, phase 2 study (NCT02804750) and a retrospective, longitudinal, surgical cohort study.

Methods: In the relacorilant study, 34 patients received relacorilant (100-200 mg/day for up to 12 weeks or 250-400 mg/day for up to 16 weeks) and had postbaseline data. Coagulation markers were assessed before and during treatment. In the surgical study, conducted at "Federico II" University of Naples, Italy, coagulation markers were assessed in 30 patients before surgery and after biochemical remission.

Results: In the relacorilant study, significant mean changes from baseline to last observed visit were reported in factor VIII (- 18.9%, P = 0.022), activated partial thromboplastin time (aPTT) (+ 1.5 s, P = 0.046), and platelet count (- 68.8*10⁹/L, P < 0.0001), whereas von Willebrand factor was unchanged. In the surgical study, the mean time to hemostasis assessment was 6.2 months. Significant mean changes from baseline to hemostasis assessment were reported in factor VIII (- 24.2%, P = 0.044), von Willebrand factor (- 20.6%, P = 0.018), and aPTT (+ 2.0 s, P = 0.031), whereas platelet count was unchanged.

Conclusions: Several coagulation markers improved in patients with CS after 3-4 months of relacorilant treatment and within an average of 6 months after surgery. Relacorilant's positive effects on coagulation markers support further investigation of its use preoperatively in patients with CS or in patients who are not eligible for surgery.

Clinical trial registration number: NCT0280475 (registration date: 15 June 2016).