Frontiers in Endocrinology最新文献

Purpose: Visceral white adipose tissue (vWAT) accumulation causes systemic inflammation, insulin resistance, metabolic syndrome, and senescent cell accumulation that are risk factors for Alzheimer's disease (AD). Visceral fat removal (VFR) improves metabolism and reduces pro-inflammatory cytokines. We hypothesized that VFR removal in AD mice would improve metabolism and cognition.

Methods: Male and female APP^NL-F mice underwent sham or vWAT surgical resection (periovarian or epididymal and perirenal) at 4 (pre-symptomatic) and 16 (symptomatic) months of age to understand interventional and therapeutic effects, respectively. At 18 months of age, glucose metabolism and novel object recognition (NOR) memory were assayed followed by assessment of body composition and tissue-specific markers of metabolism, cell senescence, inflammation, or amyloid accumulation.

Results: Male and female APP^NL-F mice showed distinct VFR responses. In pre-symptomatic males, increased vWAT lipolysis and hepatic lipogenesis led to ectopic liver lipid accumulation, with reduced adiponectin and leptin, elevated visfatin, and impaired glucose metabolism. Symptomatic males showed reduced vWAT lipogenesis, enhanced hepatic lipolysis, glycolysis, and glycogenesis, lowering liver lipids and improving insulin sensitivity. Only symptomatic males improved NOR, linked to elevated hippocampal learning and memory markers. Female vWAT reaccumulation was due to increased lipogenesis and lower lipolysis. Pre-symptomatic females had lower hepatic lipogenesis, while glycolysis and glycogenesis declined with disease progression. Hippocampal senescence and inflammation were elevated early in the disease that persisted symptomatically.

Discussion: Sex-specific differences in glucose and lipid metabolism and lipid accumulation underlie the divergent responses to VFR in APP^NL-F mice, with symptomatic males showing the only beneficial outcomes in metabolism and cognition.

Objective: The triglyceride-glucose (TyG) index is a surrogate marker of insulin resistance and metabolic dysregulation. We aimed to examine its association with incident type 2 diabetes mellitus (T2DM) in Chinese and Japanese adults and to quantify the mediating role of body mass index (BMI). However, ethnic differences in the TyG-diabetes association, population-specific thresholds, and potential mediating mechanisms-remain unclear. This study aimed to evaluate the association between the TyG and incident T2DM in Chinese and Japanese adults and to quantify the mediating role of BMI in these associations.

Methods: We conducted a retrospective cohort study using data from the China Rich Healthcare Group (n=199,050) and the Japanese NAGALA database (n=15,464). TyG was calculated as ln[fasting triglycerides (mg/dL) ×fasting plasma glucose(mg/dL)/2]. Incident T2DM was defined according to American Diabetes Association criteria. Multivariable Cox models, restricted cubic splines, and two-piecewise regression were used to characterize linear and nonlinear associations between TyG and diabetes risk. Predictive performance was assessed using receiver operating characteristic (ROC) curves. Mediation analysis with 5,000 bootstrap replications quantified the proportion of the TyG-diabetes association mediated by BMI.

Results: During a median follow-up of 5.0 years, 2,563 participants developed T2DM. Recent reviews and experimental studies indicate that Japanese adults often develop type 2 diabetes at relatively modest levels of adiposity, frequently with insufficient insulin secretion and a disproportionately high burden of visceral and ectopic fat (fully adjusted HR per 1-unit increase, 2.32; 95% CI, 2.16-2.47), with clear gradients across TyG quartiles in both cohorts. BMI partially mediated the TyG-diabetes association (19.06% in Chinese vs 14.22% in Japanese adults), supporting adiposity-related pathways and population differences in metabolic mediation. Nonlinear analyses suggested cohort-specific inflection points, with risk rising more steeply above TyG ≈8.98 in Chinese and ≈7.88 in Japanese adults. TyG showed moderate discrimination for 5-year diabetes risk (AUC ≈0.74), outperforming triglycerides alone; fasting plasma glucose (FPG) remained more discriminative, and ROC results are reported descriptively.

Conclusions: Higher baseline TyG was associated with incident T2DM in both Chinese and Japanese adults, with BMI partially mediating the TyG-diabetes association. These findings suggest that TyG captures triglyceride-glucose dysregulation beyond overall adiposity, with population-specific differences in metabolic pathways. The identification of nonlinear patterns underscores the need for population-tailored risk stratification based on TyG.

Background: Polycystic ovary syndrome (PCOS) is characterized by altered follicular development and metabolic dysfunction, frequently exacerbated by obesity. The follicular fluid (FF) microenvironment plays a critical role in supporting oocyte maturation and granulosa cell function; however, the extent to which FF from women with PCOS and obesity is associated with alterations in granulosa cell metabolism remains unclear. This study aimed to evaluate how does the FF from women with PCOS and/or obesity shapes granulosa cell glycolytic and mitochondrial activity.

Results: FF from women with PCOS showed significantly increased concentrations of total testosterone and Δ4-androstenedione compared with controls, irrespective of BMI (p < 0.05 and p < 0.01, respectively). Exposure of human granulosa cell line (HGrC1) to FF from women with PCOS and obesity was associated with a marked reduction in glycolytic capacity (p < 0.05) and decreased mRNA expression of key glycolytic regulators, including GLUT1, HK2 and LDHA (p < 0.05). Mitochondrial function was also altered, as evidenced by reduced maximal respiration and mitochondrial membrane potential (p < 0.05), while reactive oxygen species levels remained unchanged. Metabolomic profiling revealed elevated glucose concentrations in FF from women with PCOS and obesity compared with normal-weight controls, consistent with potential alterations in glucose metabolism within the follicular environment.

Conclusion: Granulosa cells depict metabolic dysregulation, with reduced glycolytic activity and impaired mitochondrial function, when exposed to FF from women with PCOS, which is further exacerbated in the presence of obesity. These findings from a pilot hypothesis-generating study suggest that the intrafollicular environment may be associated with granulosa cell metabolic disturbances, which warrant mechanistic studies to establish causality and elucidate the downstream consequences for follicular maturation and ovulatory function.

Introduction: The gonadal soma-derived factor (Gsdf) is a member of the Transforming Growth Factor-β (TGF-β) superfamily, with key roles in teleost reproduction, particularly in males. Previously considered teleost-specific, its presence in non-teleostvertebrates indicates a more ancient evolutionary origin. It is still classified as an orphan ligand with uncharacterized signaling pathways, and its evolution, regulatory mechanisms, and functional divergence remain unclear.

Methods: The roesent work provides a comprehensive characterization of two gsdf paralogues in European sea bass (Dicentrarchus labrax), integrating phylogenetic, synteny, transcriptional regulation, and protein localization analyses, together with stage-specific gene expression profiling during ontogeny, puberty onset and adult reproductive cycle.

Results: Phylogenetic reconstruction of 31 species revealed that gsdf duplications are independent, lineage-specific events unrelated to the teleost-specific whole genome duplication (3R). Synteny analyses showed that gsdf1 retains strong conservation with ancestral loci, whereas gsdf2 resides in a distinct but conserved genomic context, suggesting complex rearrangement. Comparative promoter analysis identified conserved transcription factor binding sites, supporting a shared regulatory framework across teleosts. Expression profiling revealed that both paralogues are gonad-enriched, expressed from early gonadal differentiation, and downregulated at the onset of precocious male puberty. In adults, gsdf1 was predominantly expressed in males, especially during pre-meiotic stages, while gsdf2 was more abundant in females, particularly in follicular cells during pre-vitellogenesis. Immunolocalization confirmed stage- and sex-specific presence in Sertoli and follicular cells, indicating local action.

Conclusions: These results support the subfunctionalization of gsdf paralogues in sea bass, with sexspecific partitioning of reproductive roles, and provide new insight into the evolutionary plasticity of gonad-related genes in teleosts.

Objective: To investigate the interaction between circadian rhythm disorders and related gene polymorphisms (SNPs) in the risk of developing type 2 diabetes (T2DM).

Methods: Cross-sectional study included 4,070 coal miners who underwent occupational health examinations between 2017 and 2018. We constructed comprehensive indicators of circadian rhythm disorder (CICRD) using factor analysis. In case-control analysis, 424 cases and 464 controls were randomly selected from 3,878 male coal miners. Logistic regression models were used to examine the relationship between CICRD, selected SNPs, and T2DM. Gene-gene and gene-environment interactions were evaluated using log-linear models and the generalized multifactor dimensionality reduction (GMDR) method.

Results: The CICRD captures 79.771% of seven circadian rhythm disorder assessment indicators. Higher CICRD and variants at rs10830963 (MTNR1B), rs7958822 (BMAL2), and rs11605924 (CRY2) were associated with an increased risk of T2DM (P < 0.05).A CICRD score ≥ 0.2782 with each high-risk SNP (rs10830963, rs1387153, rs7958822, rs11605924) significantly increased T2DM risk (P < 0.05).The five-factor interaction model (rs10830963-rs7950226-rs7958822-rs11605924-CICRD) based on the GMDR method significantly increased T2DM risk in the full dataset (P < 0.05).

Conclusion: The interaction between circadian rhythm disruption and high-risk SNP genotypes further amplifies the risk of T2DM among coal miners. Notably, the five-factor interaction model (rs10830963-rs7950226-rs7958822-rs11605924-CICRD) provides a standardized basis for assessing circadian rhythm disruption, screening high-risk populations, and identifying that high-risk genetic combinations are unsuitable for shift work, offering scientific evidence for the precision prevention of T2DM in coal miners.

Background: Owing to the limited characterization of lymph nodes around the entrance point of the recurrent laryngeal nerve (LN-epRLN) in clinical lymph node negative (cN0) papillary thyroid carcinoma (PTC), this study sought to develop machine learning (ML) models to predict LN-epRLN metastasis, identify the optimal model, and improve interpretability using explainable artificial intelligence techniques.

Methods: We retrospectively reviewed 1,800 patients with cN0-PTC who underwent central lymph node dissection (CLND) with systematic LN-epRLN sampling. Histopathological evaluation confirmed metastatic status. Patients were randomly divided into training and testing sets at a 7:3 ratio. Nine ML models were constructed and optimized through 10-fold cross-validation and grid search. Performance was assessed using 11 metrics, including AUC, accuracy, sensitivity, and specificity. The best-performing model was compared against traditional nomograms via probability-based ranking analysis (PMRA).

Results: LN-epRLNs were identified in 149 out of 1800 PTC patients, with a metastasis rate of 19.46%. The Random Forest (RF) model outperformed others, achieving training/testing scores of 0.914/0.911 accuracy, 0.956/0.919 AUC, 0.993/0.974 specificity, and 0.609/0.500 sensitivity. A simplified model incorporating seven key predictors-total central lymph node metastasis number and ratio, pretracheal lymph node metastasis number and ratio, tumor size, age, and paratracheal lymph node metastasis number-retained high predictive performance. SHAPley Additive exPlanations (SHAP) analysis highlighted central compartment metastasis burden (number and ratio) as the most influential predictors.

Conclusion: The interpretable ML model developed in this study, leveraging the RF, provides a reliable tool for preoperative and intraoperative prediction of LN-epRLN metastasis in cN0 PTC patients. This approach has the potential to guide individualized surgical planning, optimizing the balance between oncological resection completeness and functional preservation.

Aims: Considering the growing evidence linking metabolic abnormalities with liver diseases, in adults with type 2 diabetes mellitus (T2DM), this research examined the relationship between serum uric acid (UA), hyperuricemia, and non-alcoholic fatty liver disease (NAFLD) in T2DM patients.

Methods: Between January 2024 and January 2025, 952 individuals with T2DM were enrolled in a single-center cross-sectional investigation conducted at the Zhengzhou People's Hospital. Associations of UA and hyperuricemia with NAFLD were evaluated using multivariate logistic regression, accompanied by subgroup and sensitivity analyses. Restricted cubic spline (RCS) and generalized additive models (GAM) anlyses were applied to examine the non-linear dose-response association between UA and NAFLD.

Results: Using the fully adjusted multivariate logistic regression model, hyperuricemia was found to be independently linked to a higher risk of NAFLD (OR 1.660, 95% CI: 1.094-2.521, p = 0.017). For serum UA, a rise of 1 μmol/L and a single standard deviation (SD) in its concentration corresponded to a 0.3% and 26.6% greater likelihood of developing NAFLD, respectively (OR 1.003, 95% CI: 1.001-1.005; OR 1.266, 95% CI: 1.050-1.526). Subgroup analyses revealed that hyperuricemia remained independently linked to NAFLD among individuals aged > 60 years, with hypertension, overweight/obesity, or without hyperlipidemia (p < 0.05). Furthermore, an elevation of one SD for UA levels was associated with a greater likelihood of NAFLD in several subgroups, including patients aged > 60 years, males, those without hyperlipidemia, and those with overweight/obesity (p < 0.05). Sensitivity analysis excluding patients with chronic kidney disease yielded consistent results: hyperuricemia remained significantly associated with NAFLD (OR 1.678, p = 0.032), and each 1-SD increase in UA was associated with a 31.6% increased risk (OR 1.316, p = 0.010). RCS analysis revealed a notable linear association for UA levels with the likelihood of NAFLD (p overall < 0.05, non-linearity p > 0.05). Similarly, GAM analysis further confirmed a statistically significant linear relationship between UA and NAFLD.

Conclusion: Serum UA levels and hyperuricemia are independently linked to a greater likelihood of NAFLD among individuals with T2DM, underscoring the importance of UA surveillance in this group to facilitate prompt detection and precise intervention for NAFLD.

Background: The monocyte-to-lymphocyte ratio (MLR) has emerged as a novel marker of inflammation. Nevertheless, its potential utility in predicting the development of left ventricular aneurysm (LVA) remains unexplored. This study aims to investigate the association between MLR and the risk of LVA in patients presenting with acute ST segment elevation myocardial infarction (STEMI).

Methods: A total of 551 patients were enrolled in the first cohort, and 471 patients were included in the validation cohort. To evaluate the predictive value of MLR for LVA, multivariable logistic regression analysis, restricted cubic splines (RCS) analysis, and receiver operating characteristic (ROC) analysis were employed.

Results: The prevalence of LVA was 14.5% in the first cohort and 13.6% in the validation cohort. The multivariable logistic regression analysis revealed that individuals in the highest quartile of MLR (Q4) exhibited a significantly increased risk of LVA formation compared to those in the lowest quartile (Q1) in both cohorts (first cohort: OR = 3.07, 95% CI = 1.33-7.08, P = 0.009; validation cohort: OR = 3.55, 95% CI = 1.34-9.42, P = 0.011). The RCS analysis identified a positively nonlinear association in the first cohort and a positively linear association in the validation cohort between MLR and the risk of LVA (overall P < 0.05). Furthermore, the discriminative ability of MLR for LVA is 0.69 in the first cohort and 0.71 in the validation cohort, exceeding that of both monocyte and lymphocyte alone. The subgroup analyses further substantiated the robustness of our findings.

Conclusion: An elevated MLR was independently linked to an increased risk of LVA development in patients with STEMI who received primary PCI. This readily available inflammatory index may offer supplementary prognostic information and could be considered for inclusion in future risk stratification models.

Background: Type 2 diabetes mellitus (T2DM) is a major global health challenge due to high cardiovascular risk. Sodium-glucose cotransporter 2 (SGLT2) inhibitors can offer glycemic and cardiorenal benefits. Most agents are available in low and high doses, with the assumption that higher doses improve glycemic control. However, previous evidence shows only marginal hemoglobin A1c (HbA1c) reduction (≈0.08-0.18%) with high doses, raising uncertainty about their clinical necessity. Patient factors such as baseline HbA1c and renal function influence SGLT2 efficacy, but whether these factors modify dose response remains unclear. This study evaluates dose-dependent effects across HbA1c and renal function strata.

Objective: To assess the glycemic impact of high- versus low-dose SGLT2 inhibitors in T2DM, stratified by HbA1c and renal function.

Methods: This analysis followed PRISMA guidelines (PROSPERO ID: CRD42024605351). PubMed, the Cochrane Library, and EMBASE were systematically searched for randomized controlled trials involving SGLT2 inhibitors in adults with T2DM through November 24, 2024. The primary outcome was change in glycated hemoglobin, stratified by hemoglobin A1c (HbA1c) and glomerular filtration rate (GFR) levels. Subgroup analyses were performed based on different SGLT2 inhibitors and dosages.

Results: A total of 23 studies were included for the meta-analysis. Seventeen studies (n = 7,021) were stratified by HbA1c, and eight (n = 7,998) by GFR. Overall, high-dose SGLT2 inhibitors showed a slightly better glycemic control than low-dose SGLT2 inhibitors, with an additional 0.08% (95%CI: -0.12, -0.04) reduction in HbA1c levels. High-dose vs. low-dose SGLT2 inhibitors showed a 0.06%-0.16% further HbA1c reduction across varying glycemia levels (with HbA1c under or over 8%, 8.5%, 9%) and a change in HbA1c levels ranging from -0.07% to 0.04% across varying GFR levels (with GFR under or over 45, 60, 90 ml/min/1.73m²).

Conclusion: Dose escalation had minimal effect on HbA1c across glycemic and renal strata; higher doses of SGLT2 inhibitors offer limited additional benefit for glycemic control in poorly controlled T2DM.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024605351.

Objective: Prolactin (PRL) is increasingly recognized as a pleiotropic hormone with potent immunoregulatory properties; however, its involvement in systemic inflammation among diabetic kidney disease (DKD) patients has not been defined. This study aimed to investigate the potential association between serum PRL levels and micro-inflammation in patients with DKD.

Methods: In this cross-sectional investigation, 994 patients with type 2 diabetes mellitus (T2DM)-associated DKD were enrolled. Multivariable linear mixed-effects models were used to quantify the relationship between serum PRL and the systemic immune-inflammation index (SII) and other clinical parameters. Restricted cubic spline (RCS) analyses were fitted to test for non-linearity and stratified and sensitivity analyses were performed to assess robustness.

Results: The median serum PRL level was 344.40 mIU/L (interquartile range: 258.80-463.10). After multivariable adjustment, serum PRL were positively associated with white blood cell count, neutrophil count, serum ferritin, serum phosphorus and intact parathyroid hormone (iPTH) levels, and inversely associated with serum albumin. For every 100 mIU/L increase in serum PRL, the SII increased by an average of 7.10 units (95% CI: 3.13 to 11.07; p = 5.12 × 10^-4). Stratified and sensitivity analyses confirmed the robustness of this association. RCS analysis revealed a significant nonlinear relationship between serum PRL and SII (p for nonlinearity = 0.002), with an inflection point at 282.85 mIU/L. PRL levels above this inflection point showed a significant positive association with SII, whereas levels below it showed a negative association.

Conclusion: In patients with DKD, serum PRL exhibits an independent, nonlinear association with SII, characterized by a threshold around 282.85 mIU/L. This finding suggests that PRL may be linked to the dysregulated immune-inflammation axis in DKD, warranting further mechanistic and longitudinal investigation.