Frontiers in Endocrinology最新文献

Background: Type 2 diabetes (T2D) is increasing its burden worldwide; therefore, research focused on its prediction and prevention is essential.

Methods: We performed an untargeted metabolomics analysis using ultra high-performance liquid chromatography-mass spectrometry to discover metabolic biomarkers and biological pathways associated with incident T2D with a nested case-control design, followed by validation with targeted metabolomics in an independent cohort. In the discovery phase, plasma samples from 352 subjects (209 controls and 143 incident cases) were analyzed, collected with a mean (standard deviation) of 7.40 (0.76) years before they acquired the condition. Using this discovery phase cohort, six metabolites were identified using standards and were subsequently quantified in an independent validation phase cohort of 2,044 subjects (167 incident cases). Additionally, pathway enrichment was conducted in the discovery cohort.

Results: Guanine, ecgonine, adenine, pregnenolone sulfate, phenyl sulfate, and citrulline were significantly associated with incident T2D in at least one of the analyses performed in the discovery phase. Among these, guanine, pregnenolone sulfate, and citrulline maintained their significant associations with incident T2D in the validation cohort. Additionally, several pathways were significantly altered, with nucleotide metabolism and ABC transporter pathways among the most consistently affected.

Conclusion: We identified significant associations of guanine, pregnenolone sulfate, and citrulline with incident T2D.

Chemokine signaling networks have emerged as pivotal regulators of skeletal homeostasis, integrating inflammation, angiogenesis, and immune activation with the processes of bone remodeling and regeneration. Recent evidence demonstrates that dysregulated chemokine-receptor interactions, including CCL2/CCR2, CCL5/CCR5, and CX3CL1/CX3CR1, disrupt the equilibrium between osteogenesis and osteoclastogenesis, thereby contributing to the pathogenesis of osteoporosis, osteoarthritis, multiple myeloma, and bone metastasis. This review synthesizes current insights into how chemokine-mediated signaling cascades intersect with canonical pathways such as JAK/STAT3, NF-κB, PI3K/Akt, and Wnt/β-catenin to coordinate cellular communication within the bone microenvironment. Furthermore, it highlights recent progress in therapeutic strategies targeting chemokine axes to mitigate inflammatory bone loss and promote tissue regeneration, while addressing translational barriers including receptor redundancy, context-dependent specificity, and limited in vivo validation. By positioning chemokines as dynamic mediators at the interface of the immune and skeletal systems, this review establishes a conceptual foundation for the development of precision therapeutics aimed at restoring bone homeostasis and treating skeletal disorders.

Resistin, a cysteine-rich adipokine, exhibits significant species-specific divergence in its cellular origins and pathophysiological functions. In humans, it is primarily secreted by monocytes, macrophages, and bone marrow-derived cells, positioning it as a pivotal mediator of inflammation and cardiometabolic disease rather than a direct regulator of glucose metabolism. This review synthesizes current evidence on the multifaceted role of resistin in cardiovascular pathophysiology, emphasizing its engagement with key receptors-toll-like receptor 4 (TLR4) and cyclase-associated protein-1 (CAP-1)-to activate downstream proinflammatory signaling cascades including nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. These mechanisms promote endothelial dysfunction, increase leukocyte adhesion and migration, and accelerate early atherogenesis. Beyond the vasculature, resistin exerts direct detrimental effects on the myocardium by impairing cardiomyocyte calcium handling and mitochondrial energetics, inducing pathological hypertrophy, and stimulating cardiac fibrosis via JAK/STAT3 and transforming growth factor-beta (TGF-β) signaling. Its ability to modulate neurohormonal pathways, including sympathetic activation and interactions with the endocannabinoid system, further integrates resistin into a complex network that exacerbates hypertension, arrhythmogenesis, and adverse cardiac remodeling. Clinically, elevated circulating resistin levels are consistently associated with acute coronary syndromes, heart failure progression, and major adverse cardiovascular events, often providing prognostic value beyond traditional risk factors, particularly in heart failure with reduced ejection fraction and cardiometabolic disease. However, significant heterogeneity exists across populations due to comorbidities such as renal dysfunction, ethnic variations influenced by genetic polymorphisms, and disease-specific contexts. The translational potential of resistin as a therapeutic target is underscored by preclinical studies demonstrating that its suppression ameliorates cardiovascular injury, though causal evidence in humans remains limited. Future research must prioritize elucidating resistin's full receptor signaling repertoire, defining isoform-specific functions, and validating its utility in multimodal biomarker panels to enhance risk stratification and pave the way for targeted therapies in cardiovascular diseases. This review advances the field by resolving conflicting receptor data through a critical evaluation of CAP-1 and TLR4 signaling, and by integrating clinical evidence with molecular mechanisms.

Premature ejaculation (PE) is a common disease of the male reproductive system, which seriously affects the quality of life of patients and their partners. Currently, PE is regarded as a biopsychosocial disease with complex etiologies and diverse treatment methods. Oral selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for PE, with advantages such as high safety, rapid onset of action, and non-invasiveness. However, topical anesthetics, behavioral and psychological therapies, device-assisted treatments, and traditional Chinese medicine (TCM) can also serve as alternative therapies for patients intolerant to SSRIs. With the rapid development of technology, some new methods-such as low-intensity extracorporeal shock wave therapy (Li-ESWT) and transcutaneous electrical nerve stimulation (TENS)-can even improve PE through mechanisms like regulating nerve conduction and improving local microcirculation. These are all important directions for the future treatment of male PE. In this mini-review, we will elaborate on these therapeutic approaches.

Purpose: This study was designed with the goal of exploring miR-99a expression in T2DM patients suffering from comorbid MASLD and clarifying the importance of miR-99a in this pathological context.

Methods: A total of 137 subjects were included in this study, including 50 T2DM patients with MASLD (T2DM +MASLD group),48 T2DM patients without MASLD (T2DM group), and 39 healthy subjects (Control group). We measured the levels of IL-6, mTOR and SOD in the serum of the subjects by ELISA. The plasma miR-99a levels was detected by RT-PCR. The correlation between serum miR-99a level and other indicators was analyzed.

Results: Serum miR-99a levels (median 0.79 vs 0.16 vs 0.03, P < 0.001) were significantly lower in the T2DM group than the healthy population and further decreased in the T2DM with MASLD patients (P < 0.001). After adjusting for age, gender, illness duration and BMI, spearman correlation analysis showed that TG, HbA1c, FPG, HOMA-IR, Hs-CRP, IL-6, HDL-C, mTOR(P < 0.05) remained independently linked with serum miR-99a. And stepwise linear regression analysis showed that HbA1c, IL-6 and mTOR are independent serum miR-99a correlation variables (P < 0.05). Moreover, the ROC results indicated that serum miR-99a has a high diagnostic value for T2DM with MASLD. In conclusion, serum miR-99a may be utilized as a screening biomarker for T2DM with MASLD.

Conclusions: These data highlight a potential role for miR-99a as a regulator of the comorbid incidence of T2DM and MASLD, suggesting that measuring the levels of miR-99a can effectively predict the risk of MASLD in those with T2DM.

Objective: To investigate the associations between thyroid nodules and two emerging biomarkers-Metabolic Score for Insulin Resistance (METS-IR) and Systemic Immune-Inflammation Index (SII)-in adults undergoing routine health checkups.

Methods: In this retrospective cross-sectional study, we analyzed data from 49,835 adults (65.50% male, 34.50% female) who underwent health checkups in 2023. Thyroid nodules were classified using the Thyroid Imaging Reporting and Data System (TI-RADS) categories (2, 3, ≥4). Statistical analyses, including chi-square tests and multiple logistic regression, were used to evaluate the relationships between nodule prevalence, sex, age, thyroid-stimulating hormone (TSH) levels, METS-IR, and SII.

Results: Thyroid nodules were detected in 60.12% of the participants. The prevalence of TI-RADS 2, 3, and ≥4 nodules were 20.61%, 37.81%, and 1.69%, respectively. Nodule prevalence was significantly higher in women (70.07%) than in men (54.87%, P < 0.001). After multivariable adjustment, TI-RADS categories 2, 3, and ≥4 nodules were independently associated with female sex and increasing age (all P < 0.001). Notably, TI-RADS 2 and 3 nodules exhibited an inverse association with serum TSH levels (P < 0.001 for both), whereas TI-RADS 3 and ≥4 nodules showed positive associations with elevated METS-IR and SII values (P < 0.05 for all comparisons).

Conclusion: Thyroid nodules are highly prevalent, particularly among women and older individuals. Lower-grade nodules (TI-RADS 2 and 3) show an inverse correlation with TSH levels, whereas higher-grade nodules (TI-RADS 3 and ≥4) are independently linked to increased insulin resistance (METS-IR) and systemic inflammation (SII). These findings suggest that METS-IR and SII could serve as valuable biomarkers for thyroid nodule assessment.

Introduction: Lipomas are the most common benign adipocytic tumors and are traditionally regarded as incidental findings with cosmetic significance. However, their frequent occurrence in adults with obesity and metabolic risk factors raises the possibility that lipomas may reflect systemic metabolic dysfunction rather than isolated adipose overgrowth. The present study evaluated whether adults with lipomas have a higher prevalence of metabolic syndrome components, obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus (T2DM), compared with population benchmarks.

Methods: We conducted a retrospective, multicenter, cross-sectional analysis of electronic health records from three Israeli hospitals (Barzilai, Shamir, and Galil Medical Centers) between January 2000 and December 2022. Adults aged ≥21 years with a clinical diagnosis of lipoma (ICD-9-CM 214) were included. Data were harmonized using the Observational Medical Outcomes Partnership (OMOP) Common Data Model and analyzed via the Lynx real-world health data platform. Prevalence of obesity, dyslipidemia, hypertension, and T2DM was compared against age- and sex-specific benchmarks from the 2023 Israeli Knowledge, Attitudes, and Practices (KAP) survey. Subgroup comparisons used Z-tests or exact binomial tests with α = 0.05, reporting absolute differences with 95% confidence intervals.

Results: A total of 7,868 adults with lipomas were analyzed (mean [SD] age, 53.0 [15.0] years; 53.6% women). Compared with population benchmarks, lipoma patients showed consistently higher prevalence of all four metabolic traits. Dyslipidemia was most overrepresented, followed by hypertension and obesity, while T2DM showed a uniform excess across all age and sex subgroups. Clustering of three or more metabolic traits-consistent with metabolic syndrome, was common after age 35 and most pronounced in midlife.

Conclusion: Adults with lipomas exhibit a substantially higher burden of metabolic syndrome components compared with population norms. These findings suggest that lipomas may serve as visible clinical indicators of systemic metabolic dysfunction. Recognizing lipomas as potential cutaneous markers of cardiometabolic risk could improve early identification of individuals at risk for obesity-related and endocrine diseases and support integration of dermatologic and metabolic screening practices.

Background: The objective of this study was to assess the trade-off between cycle continuation and cancellation in slow ovarian response (SOR) patients, and to evaluate the impact of SOR on embryo developmental potential and clinical pregnancy outcomes.

Methods: A retrospective analysis was performed on 482 patients with PCOS. Patients were stratified into the SOR group (n = 113) and control group (n = 343) in accordance with follicular growth dynamics. Furthermore, data derived from the cycle cancellation group due to SOR (C-SOR group, n = 18) were incorporated for comparative assessment. Clinical outcomes among the respective groups were subsequently subjected to comparative analysis.

Results: The average follicular growth rate in the control group was (1.41 ± 0.45) mm/day, which was significantly higher than that in both the SOR group (1.09 ± 0.55 mm/day, P < 0.05) and the C-SOR group (0.25 ± 0.24 mm/day, P < 0.05). Both SOR and C-SOR groups required significantly more days of Gn and a higher total Gn dose. Notably, supplementation with hCG showed potential for improving ovarian response in patients with SOR. However, if the subsequent follicular growth rate remained below 1.0 mm per day, cycle cancellation was recommended. Although oocytes retrieved was significantly lower in the SOR group than in controls, no intergroup differences were observed in normal fertilization rate, transferable embryo rate, and high-quality embryo rate. Similarly, clinical pregnancy rates after fresh or frozen embryo transfer did not differ between SOR and control groups. However, the SOR group exhibited significantly lower cumulative clinical pregnancy rates (75.22% vs. 88.34%, P < 0.05) and cumulative live birth rates (57.52% vs. 68.8%, P < 0.05) compared with controls. Logistic regression analysis, after adjustment, revealed that the association between SOR and cumulative live birth rates was not statistically significant (adjusted OR = 0.77, 95% CI: 0.47-1.25, p = 0.29).

Conclusions: Assessment of follicular growth rate in patients with SOR may facilitate clinical decision-making regarding continuation of ovarian stimulation or cycle cancellation. PCOS patients with SOR may benefit from hCG supplementation to enhance ovarian reactivity, thereby facilitating cycle completion and promoting the chance of clinical pregnancy.

Background: While treatment algorithms for the most common forms of monogenic diabetes (MD) are well established, managing affected pregnancies remains a clinical challenge. This study aimed to evaluate the clinical management and pregnancy outcomes in patients with the two prevalent MD subtypes: GCK and HNF1A.

Methods: We analyzed 36 pregnancies from 27 patients: 18 pregnancies occurred in the context of 14 patients with GCK-hyperglycemia, and 18 pregnancies in 13 patients with HNF1A-MD. Patients' characteristics, mode of treatment, glycemic control assessed by HbA1c, glycemia and pregnancy outcomes were evaluated.

Results: The mean age of participants was 31.64 ± 3.91 years, similar between groups. Time from the diagnosis of diabetes was longer in subtypes HNF1A-MD (8.00 ± 6.20 vs. 3.46 ± 4.05 years, p=0.046). Preconception BMI and HbA1c were similar between groups. HbA1c during pregnancy was within recommended limits but significantly lower in the HNF1A group during the second trimester (33.2 ± 6.0 vs 38.0 ± 6 mmol/mol, p=0.032). Mean fasting glucose was higher in the GCK-hyperglycemia group in the first trimester (5.6 ± 0.8 vs. 4.9 ± 1.4 mmol/l, p=0.044). Before pregnancy diet therapy predominated in GCK-hyperglycemia (56.0% vs 0%, p<0.001), while insulin therapy was more frequent in HNF1A-MD (67.0% vs. 17.0%, p=0.006). All patients were switched to insulin therapy during pregnancy. Incidences of miscarriages were limited to 2 cases in HNF1A-MD; 1 case of prolonged neonatal hypoglycemia occurred in GCK-hyperglycemia. Maternal and neonatal outcomes were generally favorable.

Conclusions: Pregnancy outcomes in patients with subtypes of monogenic diabetes: GCK-hyperglycemia and HNF1A were comparable and generally favorable. Individualized insulin therapy, regular monitoring and structured outpatient care support safe management even without fetal genotyping, though universal insulin in GCK subtypes diverges from emerging genotype-based practice.

Glucose is vital for brain physiological function, acting as the primary energy source that supports cognitive processes, neurotransmitter production, and overall health. The brain requires a constant supply of glucose, and the body has evolved protective mechanisms to maintain this supply during hypoglycemia. Increased appetite and food intake is a fundamental protective response. The precise network of brain regions, nerves, and connections responsible for initiating and coordinating these responses has not been fully identified or mapped. Neuroendocrine centers within the hypothalamus and brainstem monitor metabolic signals such as glucose, insulin, and leptin to regulate autonomic outflow, endocrine function, and behavior. Disruption of these central regulatory circuits contributes significantly to the pathogenesis of metabolic disorders, including obesity and type 2 diabetes mellitus (T2DM). Interestingly, incretin-based pharmacotherapies and bariatric surgery suppress food intake by acting on the brain, thereby enhancing the regulation of glucose homeostasis. This review summarizes current knowledge on the neural and hormonal pathways, including incretin signaling, involved in physiological glucose regulation, the mechanisms underlying their dysfunction in disease states, and the recent advances pointing to potential central targets for therapeutic intervention.