Endocrine Connections最新文献

Glucose-like peptide-1 (GLP-1) is a vital hormone in the intestines that regulates glucose metabolism. Although pancreatic-derived factor (PANDER) overexpression is known to suppress GLP-1, the underlying mechanisms are unclear. Our study aims to uncover how PANDER influences GLP-1 synthesis and secretion. We established a PANDER overexpression model in STC-1 intestinal cells, confirming its inhibitory effect on GLP-1 secretion. This effect was reversed in PANDER-knockout cells. Additionally, a negative correlation between PANDER and GLP-1 was observed in patients with a history of gestational diabetes. Subsequently, through whole transcriptome gene sequencing in PANDER-overexpressed STC-1 cells, we discovered that the activation of IL-6 and its related STAT3 signaling pathway was significantly inhibited, and this finding was validated by Western blotting and quantitative reverse transcription PCR. Finally, rescue experiments confirmed that the IL-6-related STAT3/Akt/GSK3β/β-catenin signaling pathway mediates the negative regulatory effect of PANDER on GLP-1. Taken together, our data identify IL-6 as a bridge connecting PANDER and GLP-1 in the STC-1 cells, demonstrating potential therapeutic targets for diabetes treatment by targeting the PANDER-IL-6-GLP-1 axis.

Background: The data on Leydig cell hypoplasia (LCH) resulting from biallelic Luteinizing hormone/chorionic gonadotropin receptor (LHCGR) inactivating variants is limited to case series.

Methods: We aim to describe our patients and perform systematic review of the patients with LHCGR inactivating variants in the literature. Detailed phenotype and genotype data of three patients from our centre and 85 (46,XY: 67; 46,XX: 18) patients from 59 families with LHCGR-inactivating variants from literature were described.

Results: Three 46,XY patients (age 6-18 years) from our center, with two reared as females, had two novel variants in LHCGR. Systematic review (including our patients) revealed 72 variants in 88 patients. 46,XY patients (n = 70, 56 raised as females) presented with pubertal delay (n = 41) or atypical genitalia (n = 17). Sinnecker score ≥3 (suggesting antenatal human chorionic gonadotropin (hCG) inaction) was seen in 80% (56/70), and hCG-stimulated testosterone was low (<1.1 ng/mL) in 77.4% (24/31), whereas puberty/postpubertal age, high luteinizing hormone (LH) (97.6%, 41/42) and low (<1.0 ng/mL) basal testosterone (94.9%, 37/39) was observed in most. Follicle stimulating hormone was elevated in 21/51 of these patients. Variants with <10% receptor function were exclusively seen in cohorts with Sinnecker 4/5 (10/15 vs 0/5, P = 0.033). 46,XX patients (n = 18) presented with oligo/amenorrhea and/or anovulatory infertility and had polycystic ovaries (7/9) with median LH of 10 IU/L (1.2-38).

Conclusion: In summary, this study comprehensively characterizes LHCGR variants, revealing genotype-phenotype correlations and informing clinical management of LCH. In 46,XY LCH patients, pubertal LH inaction is uniform with variable severity of antenatal hCG inaction. Few mutant LHCGR have differential actions for LH and hCG.

Acquired hypothalamic obesity (HO) is a rare type of obesity caused by acquired disease-related and/or treatment-related damage to the hypothalamus, most commonly craniopharyngiomas. Effective management of HO is critical due to its significant impact on quality of life and resistance to conventional treatments. This systematic review and meta-analysis aims to evaluate the 12-month, 24-month and 60-month outcomes of bariatric surgery for HO caused by CPs compared with patients with common obesity (CO). Relevant studies were identified in MEDLINE and EMBASE databases until May 2024. A total of 4 matched case-control studies were included. The results indicated that bariatric surgery significantly reduced weight in patients with hypothalamic obesity (22.98±14.22/21.47 ± 9.61/19.07±16.12 %total weight loss, 12/24/60 months after surgery) but the effect was significantly less than in common obesity controls (-6.17/-6.41/-7.72 %total weight loss 12/24/60 months after surgery). Bariatric surgery can significantly reduce body weight in craniopharyngiomas-related hypothalamic obesity, but the effect is less than in matched patients with common obesity. Further studies are necessary to determine the best surgical or multidisciplinary approach to the treatment of acquired hypothalamic obesity.

Background: Primary aldosteronism (PA) is a prevalent cause of endocrine hypertension characterized by an excess of aldosterone that can induce proinflammatory, prooxidant, and profibrotic effects on the heart. Emerging evidence indicates a heightened incidence of atrial fibrillation (AF) in patients with PA, suggesting a significant association between the two conditions. However, the underlying mechanisms remain unclear. The purpose of this study was to investigate the molecular networks associated with the development of both PA and AF.

Methods: Datasets were obtained from the Gene Expression Omnibus (GEO) database. Hub genes were identified by enrichment and protein‒protein interaction analysis. These hub genes were subsequently validated via two independent external datasets: GSE60042 and GSE41177. Following the identification of shared genes, quantitative real-time polymerase chain reaction (qPCR) was employed to verify the reliability of the dataset and to further confirm the presence of shared genes in clinical samples.

Results: The results of the common gene analysis revealed that immune and inflammatory responses may be shared features in the pathophysiology of PA and AF. One hub gene, specifically tumor necrosis factor superfamily member 10 (TNFSF10), was identified through various analyses and subsequently validated via qPCR. Compared with that in healthy controls, the expression level of TNFSF10 was lower in PA patients with AF.

Conclusion: Our findings indicate that TNFSF10 may play a role in the pathophysiology of AF complications associated with PA conditions, suggesting that it could serve as a potential target for the diagnosis or treatment of PA patients complicated with AF.

Aim: Incretin therapies, including dipeptidyl peptidase-4 inhibitors (DPP-4is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs), are crucial for type 2 diabetes treatment. Evidence on their association with gallbladder, biliary diseases and liver injury remains inconsistent. This study evaluated the association between incretin therapies and hepatobiliary adverse events using FDA's Adverse Event Reporting System (FAERS) data.

Methods: Case reports involving incretin therapies and hepatobiliary events from January 2006 to December 2023 were extracted from FAERS. The association between these agents and hepatobiliary adverse events (hAEs) was analyzed using reporting odds ratios and empirical Bayesian geometric means. Descriptive analyses were conducted to characterize the demographic and clinical features of the hAE cases. Additionally, subgroup analyses calculated reporting odds ratios to evaluate the strength of association between specific incretin drugs and hAEs.

Results: Among 68,351 case reports associated with incretin-based therapies, 1,327 (1.941%) involved hepatobiliary adverse events. DPP-4 inhibitors demonstrated statistically significant associations with multiple hepatobiliary events like cholelithiasis, cholecystitis chronic, and biliary diseases. In contrast, GLP-1 receptor agonists showed weaker associations, primarily linked to gallbladder and biliary disease risks. Subgroup analyses revealed stronger positive correlations with hepatobiliary events for liraglutide and semaglutide among GLP-1 agonists, and for sitagliptin, linagliptin, and vildagliptin among DPP-4 inhibitors. The pooled reporting odds ratio of 2.85 indicated a positive correlation between these drugs and studied adverse events.

Conclusions: This study found statistically significant associations between DPP-4 inhibitors and hepatobiliary adverse events like cholelithiasis and cholecystitis. GLP-1 agonists showed weaker gallbladder/biliary disorder links but higher acute cholecystitis risk. Subgroup analyses revealed varying correlations among specific drugs, potentially dose-dependent. Further large-scale studies are needed to evaluate class effect differences and elucidate mechanisms for guiding clinical use.

Purpose: Our study aimed to assess the relationship between serum adipokines and insulin resistance (IR) in women with polycystic ovary syndrome (PCOS), as well as explore the predictive value of adipokines on IR in PCOS.

Methods: This was a prospective cross-sectional study. 154 women with PCOS were included from July 2021 to September 2022 who underwent gonadal steroid hormone measurement, lipid profile, oral glucose tolerance test and homeostasis model assessment (HOMA)-IR. Adiponectin (APN), leptin and secreted frizzled-related protein (Sfrp5) were measured by immunoturbidimetry and enzyme-linked immunosorbent assay. Women with PCOS were categorised based on the presence of IR.

Results: Women with PCOS with IR (n=99) had significantly lower APN level and APN to leptin ratio (A/L ratio) than those without IR (n=55), whereas serum levels of leptin and Sfrp5 were similar between the two groups. In multivariable linear regression analysis, serum log (APN) and log (A/L ratio) were associated with log(HOMA-IR), the association was statistically significant after adjusting for body mass index (BMI) and free androgen index. The area under the ROC curve (95% CI) for APN and A/L ratio were 0.726 (0.644-0.807; P<0.001) and 0.660(0.569-0.751; P<0.01), with cutoff values of 5.225 mg/L (Youden index ¼ 0.364) and 1.438 (Youden index ¼ 0.265) respectively.

Conclusion: Our study demonstrated that serum APN was negatively related to IR. Serum APN may be useful as a clinical marker for IR in women with PCOS. Our findings warrant further investigations into the function of APN in the pathogenesis of IR in women with PCOS.

Objective: Increasing numbers of pregnancies are complicated by pregestational diabetes mellitus, especially type-2 diabetes. Some studies have reported similar or greater risk of adverse pregnancy outcomes among women with type-2 diabetes (T2DM) relative to type 1 diabetes (T1DM). We aimed to compare the risk of four pregnancy complications: pre-eclampsia, preterm delivery, macrosomia, and perinatal mortality, in pregnant women with T2DM versus T1DM in high-income countries.

Design: Systematic review with meta-analyses.

Methods: Systematic literature searches in Medline and Embase were performed. We included observational studies with original data of outcome occurrence in both women with pregestational T2DM and T1DM. Two researchers independently evaluated full-text studies for inclusion and assessed risk of bias using the Newcastle-Ottawa scale. Finally, we performed four meta-analyses.

Results: We included 35 publications in total. Meta-analyses demonstrated that, compared to T1DM, having T2DM was associated with lower risk of pre-eclampsia (risk ratio 0.76; 95% CI: 0.68-0.85), preterm delivery (risk ratio 0.69; 95% CI: 0.62-0.77) and macrosomia (risk ratio 0.75; 95% CI: 0.60-0.94). Perinatal mortality was more likely in pregnancies with T2DM (risk ratio 1.26; 95% CI: 1.06-1.50).

Conclusion: Summation of the research literature demonstrated that, compared to T1DM, women with T2DM had lower risk of pre-eclampsia, preterm delivery and macrosomia, and higher risk of perinatal mortality.

Erythrocytosis, or elevated hematocrit, is a common side effect of testosterone therapy (TTh) in male hypogonadism. Testosterone stimulates erythropoiesis through an initial rise in erythropoietin (EPO), the establishment of a new EPO/hemoglobin 'set point', and a parallel decrease in the master iron regulator protein hepcidin, as well as several other potential mechanisms. Evidence shows an increased thrombotic risk associated with TTh-induced erythrocytosis. Several guidelines by endocrine organizations for the treatment of male hypogonadism recommend against starting TTh in patients presenting with elevated hematocrit at baseline or stopping TTh when its levels cannot be controlled. Besides dose adjustments, therapeutic phlebotomy or venesection is mentioned as a means of reducing hematocrit in these patients. However, evidence supporting the efficacy or safety of therapeutic phlebotomy in lowering hematocrit in TTh-induced erythrocytosis is lacking. In light of this dearth of evidence, the recommendation to lower hematocrit using therapeutic phlebotomy is notable, as phlebotomy lowers tissue oxygen partial pressure (pO2) and eventually depletes iron stores, thereby triggering various biological pathways which might increase thrombotic risk. The potential pros and cons should therefore be carefully weighed against each other, and shared decision-making is recommended for initiating therapeutic phlebotomy as a treatment in patients on TTh who present with increased hematocrit.

Context: Cytochrome C oxidase (COX) is the fourth component of the respiratory chain and is located within the internal membrane of mitochondria. COX deficiency causes an inherited mitochondrial disease with significant genetic and phenotypic heterogeneity. Four clinical subtypes have been identified, each with distinct phenotypes and genetic variants. Mitochondrial complex IV deficiency nuclear type 4 (MC4DN4) is a form of COX deficiency associated with pathogenic variants in the SCO1 gene.

Case description: We describe three patients with MC4DN4 with developmental and epileptic encephalopathy (DEE), hypopituitarism, and SCO1 pathogenic variants. These patients' phenotypes considerably differ from previously reported MC4DN4 phenotypes as they associate DEE with progressive hypopituitarism and survival beyond the first months after birth. Pituitary deficiency in these patients progressively worsened and mainly involved growth hormone secretion and thyroid function.

Conclusions: Our findings expand knowledge of phenotypic variability in MC4DN4 and suggest that SCO1 is a candidate gene for genetic hypopituitarism and DEE.

Significance statement: Our paper describes three patients affected by MC4DN4 with hypopituitarism and developmental and epileptic encephalopathy (DEE), two features that have never been associated with this condition. In addition, we reviewed the clinical features of all previous cases of MC4DN4 to give the other clinicians a wide picture of the clinical phenotype of this genetic disease. We hope that the publication of our data may help others to identify this disease and consider the chance to analyze the SCO1 gene in cases of DEE associated with pituitary dysfunction. Our article contributes to expanding the spectrum of genetic hypopituitarism and proposes a model to explain an association between this condition, mitochondrial anomalies, and neurodevelopmental defects.

Primary hyperparathyroidism has emerged as a prevalent endocrine disorder in clinical settings, necessitating in most cases, surgical intervention for the removal of the diseased gland. This condition is characterised by overactivity of the parathyroid glands, resulting in excessive parathyroid hormone production and subsequent disturbances in calcium homeostasis. The primary mode of management is surgical treatment, relying on the accurate localisation of the pathological parathyroid gland. Precise identification is paramount to ensuring that the surgical intervention effectively targets and removes the diseased gland, alleviating the hyperfunctioning state. However, localising the gland becomes challenging, as discrepancies between the clinical manifestation of active parathyroid and radiological identification are common. Based on our current knowledge, to date, no comprehensive review has been conducted that considers all factors collectively. This comprehensive review delves into the factors contributing to false-negative 99mTc-Sestamibi scans. Our research involved an exhaustive search in the PubMed database for hyperparathyroidism, with the identified literature meticulously filtered and reviewed by the authors. The results highlighted various factors, including multiple parathyroid diseases, nodular goitre, mild disease, or the presence of an ectopic gland that causes discordance. Hence, a thorough consideration of these factors is crucial during the diagnostic workup of hyperparathyroidism. Employing intraoperative PTH assays can significantly contribute to a successful cure of the disease, thereby providing a more comprehensive approach to managing this prevalent endocrine disorder.