Journal of Endocrinological Investigation最新文献

Purpose: The liver is known to be protected from steatosis under the influence of high GH/IGF-1. Cytokeratin 18 (CK18) and insulin-like growth factor binding protein 7 (IGFBP7) increase in liver steatosis and fibrosis. The aim of this study was to use quantitative ultrasound techniques and biochemical markers to assess liver steatosis and liver fibrosis in newly diagnosed acromegaly.

Methods: This single-center, cross-sectional study included 23 patients with newly diagnosed acromegaly and 46 age, sex, body mass index (BMI) and waist circumference (WC)-matched controls. Liver steatosis was assessed using tissue attenuation imaging (TAI), and stiffness, indicative of fibrosis, was assessed by shear wave elastography (SWE). Serum IGFBP7 and CK18 were studied by ELISA.

Results: The acromegaly group had significantly lower liver steatosis (p = 0.006) and higher liver stiffness (p = 0.004), serum IGFBP7 (p = 0.048) and CK18 (p = 0.005) levels than the control group. The presence of fibrosis (p = 0.012) was significantly higher in the acromegaly group than in the control group. Moreover, CK18 was positively correlated with liver stiffness, WC, HOMA-IR, HbA1c, and triglyceride. In the acromegaly group, liver steatosis was negatively correlated with GH level. Stepwise multiple linear regression analysis revealed that BMI (p = 0.008) and CK18 (p = 0.015) were independent risk factors for increased liver stiffness.

Conclusion: This study showed that there was an increased presence of liver fibrosis independent of liver steatosis in newly diagnosed acromegaly. Serum CK18 appears to be a potential marker of increased liver fibrosis in acromegaly.

Purpose: Randomized controlled trials with tirzepatide (TZP) displayed unprecedented glucose and body weight lowering efficacy in individuals with type 2 diabetes and/or obesity and a safety profile similar to that of glucagon-like peptide-1 receptor agonists (GLP-1RA), mainly characterized by gastrointestinal (GI) adverse events (AE). Concerns on diabetic retinopathy, pancreato-biliary disorders, and medullary thyroid cancer were also addressed. We aimed to investigate whether the same safety issues emerged from the FDA Adverse Event Reporting System (FAERS) post-marketing surveillance database.

Methods: OpenVigil 2.1-MedDRA-v24 and AERSMine (data 2004Q1-2023Q3) were used to query the FAERS database. Reports of GI AE, diabetic retinopathy, pancreato-biliary disorders, and medullary thyroid cancer were investigated. The analysis was then filtered for age, gender, and designation as primary suspect. AE occurrence with TZP was compared to insulin, sodium-glucose cotransporter-2 inhibitors, metformin, and GLP-1RA.

Results: Disproportionate reporting of GI [i.e., nausea (ROR 4.01, 95% CI 3.85-4.19)] and pancreato-biliary disorders [i.e., pancreatitis (ROR 3.63, 95% CI 3.15-4.19)], diabetic retinopathy (ROR 4.14, 95% CI 2.34-7.30), and medullary thyroid cancer (ROR 13.67, 95% CI 4.35-42.96) was detected. TZP exhibited a similar risk of GI AE and medullary thyroid cancer and a lower risk of most pancreato-biliary AE and diabetic retinopathy vs. GLP-1RA.

Conclusions: TZP was associated with an increased risk of specific AE. However, its safety profile was similar to that of GLP-1RA, without increased risk of pancreato-biliary AE, diabetic retinopathy, and medullary thyroid cancer.

Aims and background: The alternative manner of iodide and glucose uptake found in different types of thyroid cancer, referred to flip-flop. ATC cells indicate low iodide uptake and high glucose uptake, which lack the morphology and genetic characteristics of well-differentiated tumors and become increasingly invasive. Importance placed on the discovery of innovative multi-targeted medicines to suppress the dysregulated signaling in cancer. In this research, we aimed to clarify molecular mechanism of Rutin as a phytomedicine on anaplastic thyroid cancer cell line based on iodide and glucose uptake.

Material methods: The MTT test was employed to test cell viability. Iodide uptake assay was performed using a spectrophotometric assay to determine iodide uptake in SW1736 cells based on Sandell-Kolthoff reaction. For glucose uptake detection, ''GOD-PAP'' enzymatic colorimetric assay was applied to measure the direct glucose levels inside of the cells. Determination of NIS, GLUT1 and 3 mRNA expression in SW1736 cells was performed by qRT-PCR. Determination of NIS, GLUT1 and 3 protein levels in SW1736 cells was performed by western blotting.

Results: According to our results, Rutin inhibited the viability of SW1736 cells in a time- and dose-dependent manner. Quantitative Real-time RT-PCR analysis exposed that NIS mRNA levels were increased in Rutin treated group compared to the control group. Accordingly, western blot showed high expression of NIS protein and low expression of GLUT 1 and 3 in Rutin treated SW1736 cell line. Rutin increased iodide uptake and decreased glucose uptake in thyroid cancer cell line SW1736 compared to control group.

Conclusion: Multiple mechanisms point to Rutin's role as a major stimulator of iodide uptake and inhibitor of glucose uptake, including effects at the mRNA and protein levels for both NIS and GLUTs, respectively. Here in, we described the flip-flop phenomenon as a possible therapeutic target for ATC. Moreover, Rutin is first documented here as a NIS expression inducer capable of restoring cell differentiation in SW1736 cell line. It also be concluded that GLUTs as metabolic targets can be blocked specifically by Rutin for thyroid cancer prevention and treatment.

Purpose: Given prolactin's (PRL) multifaceted roles in mammary tissue, an association between hyperprolactinemia and breast cancer has been hypothesized. Despite previous studies not identifying this risk, we aimed to investigate whether a connection exists.

Methods: This retrospective cohort study compared breast cancer incidence in patients with dopamine agonist (DA)-treated hyperprolactinemia versus matched controls in a 1:5 ratio. The primary outcome was a breast cancer diagnosis following hyperprolactinemia diagnosis.

Results: The cohort consisted of 1484 female patients with DA-treated hyperprolactinemia matched to 7418 female controls (mean age at diagnosis 32.70 ± 11.12 years; BMI 25.60 ± 5.84 kg/m²). Breast cancer was diagnosed in 27 patients with hyperprolactinemia (1.82%) and 97 controls (1.31%) (HR 1.40, 95% CI 0.91-2.14, p = 0.12). Patients who developed breast cancer were diagnosed with hyperprolactinemia later in life than those who did not (median age 42.63 vs. 29.79 years; p < 0.0001). Patients with PRL < 5× upper limit of normal (ULN) at diagnosis developed breast cancer at a higher rate than controls (2.25% vs. 1.33%; HR 1.73, 95% CI 1.09-2.75), but the difference was not significant in patients with PRL ≥ 5×ULN. Patients who exhibited longer times to PRL normalization had higher incidence of breast cancer (median 2.60 vs. 1.41 years in those who did not develop breast cancer; p = 0.03).

Conclusion: Overall, patients with DA-treated hyperprolactinemia did not show an increased risk for breast cancer compared to controls. However, the risk was significantly higher among those whose PRL levels were < 5×ULN, had advanced age of diagnosis, or prolonged time to PRL normalization.

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.

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.

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.

Objective: To assess serum osteocalcin (OC) as a potential biomarker for the early detection of rapidly progressive central precocious puberty (RP-CPP) in girls.

Methods: Serum OC levels were quantified using enzyme-linked immunosorbent assays (ELISAs). In the retrospective analysis, receiver operating characteristic (ROC) curve analysis was employed to evaluate the ability of OC to identify RP-CPP. A prospective study and screening tests were utilized to assess the potential of OC for use in the early prediction of RP-CPP. Variable selection in the multivariate analysis was conducted using the Bayesian Information Criterion (BIC) and binary logistic regression was employed to construct the diagnostic prediction model.

Results: Girls with RP-CPP had significantly higher serum OC levels compared to girls with non-rapidly progressive central precocious puberty (NRP-CPP) (149.04±40.50 vs. 89.10±31.83 ng/mL, P < 0.001). The optimal OC cut-off point for differentiating RP-CPP from NRP-CPP was 107.05 ng/mL, the area under the ROC curve (AUC) was 0.90 (95%CI: 0.851-0.949; P < 0.001), with a sensitivity of 91.1% and specificity of 70.7%. The results of the prospective study indicated that changes in OC precede alterations in estradiol (E2) and bone age (BA). A diagnostic prediction model that includes duration of breast development, BA, OC, high-density lipoprotein cholesterol (HDL-C), and uterine length achieved an AUC of 0.961, with a sensitivity of 94.1% and specificity of 91.5% for the detection of RP-CPP. If OC is excluded from the model, the AUC decreases to 0.894, with sensitivity and specificity declining to 80.5% and 83.1%, respectively.

Conclusions: Serum OC levels may serve as a promising biomarker for the early differentiation between RP-CPP and NRP-CPP in girls. The diagnostic prediction model that incorporates duration of breast development, BA, OC, HDL-C, and uterine length effectively identifies girls with RP-CPP.

Purpose: While metformin is known to regulate thyroid stimulating hormone (TSH) levels, the effects of acarbose on thyroid function remain unreported. Our study was designed to evaluate the impact of acarbose and metformin on thyroid function and thyroid hormone sensitivity in type 2 diabetic patients.

Methods: In the MARCH study, 788 patients with type 2 diabetes were randomly assigned to treat with acarbose (300 mg) or metformin (1,500 mg) for 48 weeks. Thyroid function was assessed at baseline, 24 weeks, and 48 weeks, and the thyroid feedback quantile index (TFQI) and parameterized thyroid feedback quantile index (PTFQI) were calculated. Generalized estimating equations adjusted for confounders were used to analyze changes over time.

Results: Eighty-four patients with subclinical hypothyroidism (SCH) exhibited a decrease in TSH levels (p = 0.001) with no significant differences between the two treatment groups (p = 0.460). Both TFQI (p = 0.029) and PTFQI (p < 0.001) also decreased over time. Mediation analysis revealed that these change over time were not mediated by BMI (all p < 0.05). Among the 489 euthyroid subjects, no significant changes in TSH levels were observed (p > 0.05). Stratification by baseline TSH levels revealed significant increases in TSH, TFQI, and PTFQI (all p < 0.05) in the normal-low TSH group and significant decreases in PTFQI (all p < 0.05) in the normal-high TSH group after treatment with acarbose and metformin.

Conclusions: Acarbose and metformin have similar buffering effects on TSH levels, the TFQI and the PTFQI. In patients with lower TSH levels, acarbose and metformin do not further decrease TSH levels.

Clinical trial registry number: ChiCTR-TRC-08000231.

Introduction: Insulinomas represent the most common functional pancreatic neuroendocrine tumors. Following preoperative localization, surgical excision is the curative treatment. It may be difficult to confirm a complete resection of insulinoma. We used intermittently scanned continuous glucose monitoring (isCGM) to record the fluctuation of interstitial glucose throughout surgery to help verify the tumor's complete surgical excision.

Materials and methods: In five individuals with insulinoma undergoing laparoscopic surgery we used the isCGM system (Freestyle Libre 2 Abbott) during tumor removal in order for the surgeon to understand "in real-time" the extent of tumor removal.

Results: Two patients received no preoperative treatment, while three patients received medical treatment with either lanreotide (2 patients) or diazoxide (1 patient). In the non-treated patients, following tumor resection, there was a rapid interstitial glucose increase along with stabilized glucose levels thoroughly documented by intraoperative isCGM. Lanreotide treatment, on the other hand, resulted in only a minor increase in interstitial glucose. Finally, diazoxide-treated patients had a response that was intermediate between lanreotide-treated and non-treated patients.

Conclusion: Our findings suggest that isCGM is a useful tool to monitor the outcome of surgery during pancreatic insulinoma excision, assisting the surgical team in successfully removing the tumor. Despite the limited sample size, the results are promising, and, if validated in larger studies, they make us believe that the use of CGM systems has a definite benefit for becoming a standard in the surgical treatment of insulinomas.