Frontiers in Endocrinology最新文献

Background and aims: The risk of heart failure (HF) is significantly higher in patients with type 2 diabetes mellitus (T2DM). Recent studies have shown that an imbalance in the sympathetic nervous system (SNS) is a target for sodium-glucose cotransporter-2 inhibitors (SGLT-2i), which have been proven to reduce the risk of adverse HF outcomes in several clinical trials. However, the specific central mechanisms involved remain unclear. Therefore, our research investigates how dapagliflozin (DAPA) regulates blood pressure through SNS and explores the central neural and endocrinological pathways by which DAPA, an SGLT-2i, influences SNS activity and its impact on the cardiovascular system in the treatment of HF in T2DM.

Material and methods: Twenty-one male C57BL/6 mice aged 8-10 weeks were randomly divided into three groups (n = 7 each): control (CTRL), DAPA, and DAPA-Cyanine 3 (DAPA-Cy3). Blood pressure (BP), heart rate (HR), and blood glucose (BG) were measured after a single dose of treatment. DAPA-Cy3 was designed to assess its ability to cross the blood-brain barrier (BBB). Additionally, histological co-localization analyses of immunoreactivity for c-Fos, neuronal nitric oxide synthase (nNOS), corticotropin-releasing hormone (CRH), and vasopressin (VP) across groups were performed to explore how SGLT-2 inhibitors regulate the central sympathetic nervous system (SNS).

Results: 1) DAPA significantly reduced both systolic blood pressure (SBP) and diastolic blood pressure (DBP) in mice, without notably affecting the heart rate (HR); 2) SGLT-2 was found to be extensively expressed in the central nervous system (CNS), especially in the hypothalamus and brainstem; 3) DAPA-Cy3 was able to cross the blood-brain barrier (BBB) and disperse throughout the brain; and 4) DAPA clearly influenced the activity of specific neurons expressing nNOS, CRH, and VP in the hypothalamus.

Conclusion: DAPA, as an SGLT-2 inhibitor, crosses the BBB and binds to the innate SGLT-2 in the hypothalamus and brainstem of mice. This significantly influences the tone of the SNS through indirect regulation by modulating nNOS, CRH, and VP, which are believed to be the upstream regulatory points of SGLT-2 in interacting with the SNS.

The perception of taste is a complex physiological process that extends far beyond the simple detection of flavor molecules, serving as a critical interface between nutrient sensing, metabolic regulation, and feeding behavior. Emerging evidence reveals that this process is profoundly modulated by endocrine and neuromodulatory systems, creating a sophisticated gut-brain-taste axis that integrates peripheral gustatory signals with central homeostatic and hedonic mechanisms. Hormones such as glucagon-like peptide-1, leptin, ghrelin, and CCK not only regulate appetite and energy balance but also directly influence taste receptor expression and function in the tongue and gastrointestinal tract. Concurrently, neuromodulators like dopamine, serotonin, and norepinephrine fine-tune taste sensitivity at both peripheral (taste buds) and central (reward circuitry) levels, linking chemosensation to motivational states. These interactions are further complicated by metabolic conditions such as obesity and diabetes, where hormonal resistance (e.g., leptin, insulin) and neurotransmitter dysregulation contribute to altered taste preferences and compulsive eating behaviors.

Background: To investigate the association of the triglyceride-glucose (TyG) index with severe tubular atrophy/interstitial fibrosis (T2 lesions) and renal outcomes in patients with IgA nephropathy (IgAN).

Methods: We retrospectively analyzed 1,791 biopsy-proven IgAN patients between October 2014 and September 2024. Receiver operating characteristic (ROC) curve analysis assessed TyG index performance for predicting T2 lesions. Multivariable logistic regression and restricted cubic spline (RCS) models were applied to assess the relationship between the TyG index and T2 lesions. Renal survival was evaluated using Kaplan-Meier analysis and Multivariable Cox regression analysis.

Results: Among 1,791 enrolled IgAN patients, 122 (6.8%) exhibited T2 lesions. The TyG index showed predictive value for T2 lesions (AUC = 0.699, 95%CI: 0.656-0.741), with an optimal cut-off of 8.69 (specificity 64.5%, sensitivity 65.6%). After 1:1 PSM, the high-TyG group (>8.69) had a higher prevalence of severe tubulointerstitial lesions, elevated BMI, serum creatinine, 24-hour urinary protein, lower eGFR (all P < 0.001), and a higher incidence of the primary endpoint (P = 0.020). Multivariable logistic regression confirmed that a high TyG index (TyG>8.69) was independently associated with T2 lesions (OR = 2.365, 95% CI: 1.104-5.062, P = 0.027). RCS analysis indicated a linear dose-response relationship (P for overall<0.001;P for nonlinearity=0.082). Kaplan-Meier analysis showed significantly worse renal survival in the high-TyG group both before and after matching (log-rank=13.59, P<0.001 after matching). Multivariable Cox regression identified a high TyG index as an independent predictor of adverse renal outcomes (HR = 1.561, 95% CI: 1.046-2.330, P = 0.029).

Conclusion: The TyG index is independently associated with severe tubulointerstitial damage and poor renal survival in IgAN, with a value >8.69 effectively identifying high-risk patients for progressive renal injury.

Background: Early diabetic kidney disease (DKD) remains difficult to diagnose accurately since microalbuminuria lacks sensitivity and specificity. Tumor necrosis factor receptors (TNFRs), especially TNFR1 and TNFR2, have emerged as potential markers of renal inflammation and injury. Dyslipidemia, particularly reduced high-density lipoprotein cholesterol (HDL), is associated with the inflammatory milieu in type 2 diabetes mellitus (T2DM).

Objective: To investigate the association of serum TNFR1 and TNFR2 with early renal injury in T2DM and to determine the impact of HDL on TNFRs levels.

Methods: A cross-sectional study was conducted in 258 T2DM patients (135 with normoalbuminuria, 123 with microalbuminuria) and 100 age- and sex-matched healthy controls. Serum TNFR1, TNFR2, lipid profile, fasting blood glucose (FBG), and estimated glomerular filtration rate (eGFR) were measured. Group differences were analyzed, and correlation and multivariable regression analyses were performed to identify determinants of TNFR levels.

Results: Both TNFR1 and TNFR2 were significantly higher in patients with microalbuminuria compared with healthy controls (P < 0.001). TNFR1 levels increased progressively from healthy controls to normoalbuminuric and microalbuminuric groups, showing the strongest associations with UACR, eGFR, diabetes duration, and HDL. In multivariable regression, HDL emerged as the most significant negative predictor of both TNFR1 and TNFR2, independent of glycemic measures and other metabolic factors. Age was also independently associated with higher TNFR concentrations.

Conclusion: Serum TNFR1 and TNFR2 are a sensitive biomarker for early renal injury in T2DM. Importantly, low HDL is independently associated with elevated TNFR1 levels, suggesting that lipid metabolism, beyond glucose control, plays a critical role in DKD progression. Monitoring HDL levels and targeting dyslipidemia may aid in the early prevention and intervention of DKD.

Introduction: Surge release of luteinizing hormone (LH) from the pituitary is essential for fertility, as it triggers ovulation. Secretoneurin (SN), a conserved peptide derived from secretogranin-2, stimulates LH release, but its relationship to periovulatory changes in classical reproductive hormones remains unclear.

Methods: We measured fluctuations of two reproductive steroids and three peptides in the hypothalamus, pituitary, and ovary of female mice during the periovulatory period using a novel nano LC-MS/MS protocol. Immunohistochemistry for SN and GnRH was performed on brain samples. GT1-7 GnRH neuronal cells were exposed to various doses of SN and processed for PCR determination of Gnrh1 mRNA levels. A subset of these samples was subjected to RNA sequencing for pathway analysis.

Results: P4, E2, AVP, GnRH1, and SN varied across the cycle, whereas OXT was relatively stable. Ovarian P4 was highest at proestrus, while E2 peaked at diestrus. Hypothalamic P4 was elevated at diestrus, whereas pituitary P4 remained low and variable. AVP peaked at proestrus in both the hypothalamus and pituitary. SN levels were highest in the hypothalamus and pituitary at proestrus. GnRH1 increased in the hypothalamus and pituitary at proestrus but was undetectable in ovary. Regression analysis revealed a moderate positive association between hypothalamic SN and GnRH1. SN-immunoreactive fibers were found near GnRH neurons in the median and medial preoptic areas. In vitro, SN increased Gnrh1 mRNA in GT1-7 cells in a time- and dose-dependent manner. RNA sequencing after 6 h SN treatment highlights key signaling cascades including MAPK, transcriptional regulation, and calcium signaling pathways. Six upregulated TFs predicted to bind to the mouse Gnrh1 promoter were also linked to significant enrichment in ribosome-related processes, protein synthesis, and cellular component organization pathways.

Conclusion: These findings identify a periovulatory association between SN and GnRH1 and provide a foundation for targeted studies needed to test causality in the mammalian reproductive neuroendocrine network.

Objective: Evidence regarding the association between the total cholesterol, high-density lipoprotein, and glucose (CHG) index and diabetic retinopathy (DR) remains limited. This study aimed to explore the relationship between CHG and the prevalence of DR and evaluate its discriminative ability for DR.

Methods: This cross-sectional study analyzed data from 1,909 individuals with diabetes mellitus (DM), aged 45-90 years, whose information was collected between August and December 2011. To determine the association between CHG and DR, binary logistic regression models were employed. The discriminative ability of CHG for DR was assessed using receiver operating characteristic (ROC) analysis. Additionally, a series of sensitivity analyses and subgroup analyses were conducted.

Results: After multivariable adjustment, binary logistic regression analysis showed that each 0.1-unit increase in CHG was associated with a 14.2% higher prevalence of DR (OR = 1.142; 95% CI: 1.081-1.206). Additionally, CHG demonstrated the highest area under the curve (AUC) for discriminating DR (0.6673, 95% CI: 0.6287-0.7059), outperforming triglyceride-glucose body mass index (TyG-BMI, 0.4958, 95% CI: 0.4548-0.5368), triglyceride to high-density lipoprotein cholesterol ratio (THR, 0.5118, 95% CI: 0.4704-0.5532), and triglyceride-glucose index (TyG, 0.5720, 95% CI: 0.5314-0.6125). Sensitivity analysis and subgroup analyses further confirmed the reliability of these results.

Conclusion: This study demonstrates that elevated CHG is independently and positively associated with DR in adults with DM. Moreover, CHG shows a certain discriminative ability for DR and may have potential utility in DR assessment.

Context: Thyroid hormones affect neurological development and function, but detailed studies of thyroid hormones and metabolites in autism are lacking.

Objective: To characterize thyroid function and metabolism in autistic children.

Methodology: This cross-sectional study compared 788 autistic children (mean age 7.6 ± 3.9 years, 78% male) with 301 non-autistic children (mean age 7.8 ± 4.0 years, 48% male; comprising 215 (71.4%) non-autistic siblings of participants and 86 (28.6%) unrelated individuals). Plasma TSH, free T4 (FT4) and free T3 (FT3) were measured by automated immunoassay, and total T4, total T3 and thyroid hormone metabolites by customized liquid chromatography-tandem mass spectrometry (LCMS/MS). Regression analyses were adjusted for age and sex.

Results: TSH concentrations were similar in autistic and non-autistic children (median 2.3 vs 2.1 mU/L, P = 0.64). FT4 was significantly lower in autistic children (18.4 vs 18.7 pmol/L, P = 0.0003), as was FT3 (7.0 vs 7.1pmol/L, P<0.0001), with no significant difference in the FT4:FT3 ratio (P = 0.24). Total T4 was lower in autistic children (178 vs 194 nmol/L, P = 0.0026, as was total T3 (2.2 vs 2.4 nmol/L, P = 0.018), with no significant difference in the T4:T3 ratio (P = 0.099). Two metabolites were significantly lower in autistic children: 3,5-T2 (0.010 vs 0.021 nmol/L, P<0.0001) and 3,3'-T2 (0.12 vs 0.16 nmol/L, P<0.0001), whereas T0 levels were higher (1.5 vs 1.1 nmol/L, P = 0.028).

Conclusions: Circulating thyroid hormones and metabolites differ between autistic and non-autistic children, although the observed differences are small. The study demonstrates the utility of LCMS/MS for in-depth characterization of thyroid hormone economy, with potentially wide applications.

Background: The global rise in precocious puberty (PP) is increasingly linked to exposure to endocrine-disrupting chemicals (EDCs). However, the mechanisms by which environmentally relevant, low-dose mixtures of EDCs influence PP remain inadequately explained by direct endocrine disruption.

Objective: This systematic review evaluates a novel hypothesis: that disruption of the gut-brain axis (GBA) serves as a pivotal mechanism in EDC mixture-induced PP.

Methods: We synthesized evidence from 87 studies (45 human, 32 animal, 10 in vitro) following PRISMA 2020 guidelines. An exploratory Random Forest analysis was employed to identify key mediators and estimate the relative contribution of the GBA pathway.

Results: Perinatal exposure to low-dose EDC mixtures consistently induced gut dysbiosis, characterized by reduced microbial diversity (Shannon Δ = -1.8), a 40% decrease in Lactobacillus, and a 1.5-fold increase in Bacteroides. This dysbiosis was linked to impaired production of butyrate (↓50%) and secondary bile acids, increased intestinal permeability (FITC-dextran ↑80%), and systemic inflammation (IL-6 ↑1.8-fold). Fecal microbiota transplantation from PP donors into germ-free mice recapitulated early pubertal onset, supporting a causal role for gut microbiota. Exploratory modeling suggested that mediators within the GBA pathway could be associated with a large share (approximately 68%) of the model-internal variance explanation for PP risk at low experimental doses (≤1 μg/kg/day), indicating its potential prominence over direct endocrine disruption in this analysis. Significant synergistic effects (Synergy Index > 2.3) were observed under mixture exposures.

Conclusion: This review identifies the GBA as a critical and previously underappreciated mechanism for low-dose EDC mixture-induced precocious puberty in a dose-dependent manner. Our findings underscore the need for regulatory paradigms and future research to integrate this pathway when assessing the risks of complex, real-world chemical mixtures.

Objective: Obstructive sleep apnea (OSA) has been linked to disturbances in glucose and lipid metabolism. The independent association between sleep apnea-specific novel hypoxic metrics and metabolic dysregulation in OSA, however, remains unclear.

Methods: Anthropometric and polysomnographic data were obtained from OSA patients treated. Novel hypoxic indices-percentage of sleep time with the duration of respiratory events causing desaturation (pRED_3p) and sleep breathing impairment index (SBII)-were derived from the SpO₂ channel. Biochemical parameters were simultaneously assessed. Multiple linear regression models were applied to examine independent associations of pRED_3p, SBII, and apnea-hypopnea index (AHI) with glucose and lipid profiles. Logistic regression was further performed to estimate odds ratios (ORs) for abnormal glucose and lipid parameters across quartiles of pRED_3p, SBII, and AHI.

Results: After controlling for confounding variables, pRED_3p demonstrated significant associations with fasting blood glucose (FBG) (β=0.122), fasting insulin (FIN) (β=0.410), HOMA-IR (β=0.325), total cholesterol (TC) (β=0.309), triglycerides (TG) (β=0.173), low-density lipoprotein cholesterol (LDL-C) (β=0.260), TC/HDL-C (β=0.182), TG/HDL-C (β=0.121), LDL-C/HDL-C (β=0.195), AI (β=0.182), LCI (β=0.663), visceral adiposity index (VAI) (β=0.115), and lipid accumulation product (LAP) (β=0.139). SBII was independently related to FBG (β=0.079), FIN (β=0.240), HOMA-IR (β=0.191), TC (β=0.179), TG (β=0.115), LDL-C (β=0.139), LDL-C/HDL-C (β=0.081), LCI (β=0.093), and LAP (β=0.098), all with p<0.05. In quartile-based comparisons, higher pRED_3p categories corresponded to progressively increased ORs for elevated FBG (2.372, 4.054, and 4.131), hyperinsulinemia (5.789, 22.644, and 26.188), high HOMA-IR (6.655, 36.637, and 43.807), hypercholesterolemia (2.751, 7.109, and 9.607), hypertriglyceridemia (1.976, 4.248, and 4.412), and elevated LDL-C (3.593, 8.050, and 12.048). Similarly, higher SBII quartiles were associated with increased ORs for elevated FBG (1.863, 3.819, and 3.874), hyperinsulinemia (5.002, 25.085, and 25.942), high HOMA-IR (5.879, 35.603, and 51.799), hypercholesterolemia (3.074, 7.297, and 8.867), hypertriglyceridemia (1.963, 4.101, and 4.757), and elevated LDL-C (3.627, 7.684, and 11.515). All linear trends were positive (p<0.001).

Conclusion: pRED_3p and SBII were associated not only with established glucose and lipid metabolism parameters-including elevated FBG, FIN, HOMA-IR, hypercholesterolemia, hypertriglyceridemia, and elevated LDL-C-but also with composite lipid indices, exhibiting consistent linear trends. Greater OSA severity corresponded to more marked disturbances in glucose and lipid metabolism. These novel hypoxic metrics may serve as predictive indicators for metabolic dysregulation in OSA.