The Journal of Clinical Endocrinology & Metabolism

BackgroundThyroid autoimmunity (TAI) is frequently reported in women with polycystic ovary syndrome (PCOS), yet its clinical relevance for cardiometabolic and androgenic severity remains uncertain. We evaluated whether TAI identifies a metabolically or androgenically more severe PCOS phenotype using pre-specified exposure definitions and cardiometabolic endpoints. MethodsThis cross-sectional study included 1,300 women with confirmed PCOS in the source dataset. Thyroid autoimmunity was defined a priori using three definitions: anti-thyroid peroxidase antibodies above the laboratory upper limit of normal (TAI_A, primary definition), anti-TPO positivity combined with thyroid-stimulating hormone >4.0 mIU/L (TAI_B), and high-titer anti-TPO >100 IU/mL (TAI_C). The primary endpoint was triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C) >3.5. Secondary endpoints included non-HDL-C [≥]130 mg/dL and 120-minute oral glucose tolerance test (OGTT) glucose [≥]140 mg/dL. Associations were assessed using age-adjusted Firth logistic regression models in complete-case cohorts. Sensitivity analyses included restriction to euthyroid participants, alternative TAI definitions, trimming of extreme values (1-99%), and bootstrap-based confidence intervals. Exploratory hormonal comparisons were adjusted using the Benjamini-Hochberg false discovery rate. ResultsTAI_A was not significantly associated with the primary endpoint (TG/HDL >3.5) (OR 0.77, 95% CI 0.21-1.67). No significant associations were observed for secondary endpoints including non-HDL-C [≥]130 mg/dL (OR 1.09, 95% CI 0.61-1.76) or impaired glucose tolerance on OGTT (OR 1.27, 95% CI 0.63-2.18). Results remained directionally consistent across alternative TAI definitions and sensitivity analyses, including restriction to euthyroid women and trimming of extreme values. In exploratory analyses, thyroid-stimulating hormone levels differed between TAI-positive and TAI-negative women, while no androgenic or cardiometabolic parameters remained significant after false discovery rate correction. Model diagnostics did not indicate major violations of model assumptions. ConclusionIn this large cross-sectional cohort of women with PCOS, thyroid autoimmunity was not associated with an adverse cardiometabolic or androgenic phenotype. Anti-TPO positivity alone therefore does not appear to identify a metabolically high-risk PCOS subgroup under the studied conditions. Prospective studies are needed to clarify the longitudinal implications of thyroid autoimmunity in PCOS.

ContextPolycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder associated with reproductive dysfunction and long-term cardiometabolic risk. Traditional phenotype classifications based on diagnostic criteria may not fully capture the multidimensional biological variability underlying endocrine and metabolic risk profiles, particularly in young women. ObjectiveTo identify data-driven endocrine-metabolic phenotypes in young women with PCOS and evaluate their association with established cardiometabolic risk markers. Design and SettingCross-sectional study conducted at a tertiary Gynecological Endocrinology Clinic in Poland between January 2018 and May 2025. ParticipantsA total of 1300 young women diagnosed with PCOS according to Rotterdam criteria were included. The primary analytic cohort comprised 1032 participants aged 16-25 years with complete endocrine-metabolic biomarker data. Main Outcome MeasuresEndocrine-metabolic phenotypes were derived using principal component analysis followed by Gaussian mixture model clustering. Cardiometabolic risk endpoints included impaired glucose tolerance (2-hour plasma glucose during an oral glucose tolerance test [≥]140 mg/dL), an atherogenic lipid profile (triglycerides (TG)/high-density lipoproteins (HDL-C) ratio >3.50), elevated non-HDL cholesterol ([≥]130 mg/dL), and a composite outcome of any abnormality. ResultsPrincipal component analysis retained 10 components explaining 81.9% of total variance. Unsupervised clustering identified two stable phenotypes (silhouette = 0.392; ARI = 0.842). Cluster 0 (n=954; 92.4%) represented a mixed endocrine-metabolic profile, whereas cluster 1 (n=78; 7.6%) was enriched for thyroid/autoimmune features, with higher anti-thyroid peroxidase antibody levels and higher thyroid-stimulating hormone. Cluster 1 showed a higher prevalence of an atherogenic lipid profile compared with cluster 0, while differences in glucose intolerance and non-HDL cholesterol were modest. Logistic regression analyses suggested phenotype-specific variation in cardiometabolic risk markers. ConclusionsIn a large cohort of young women with PCOS, data-driven analysis identified two reproducible endocrine-metabolic phenotypes, including a distinct thyroid/autoimmune-enriched subgroup. These findings highlight clinically relevant heterogeneity beyond traditional diagnostic phenotypes and support the potential value of integrated endocrine-metabolic profiling for early risk stratification in PCOS.

Cushings disease is caused by the overproduction of cortisol. The effects of this disease are well known in a general population, including high blood pressure, diabetes, and weight gain. Cushings disease causes both obesity and metabolic related symptoms, and it can be difficult to discern the obesity-dependent from the obesity-independent mechanisms of Cushings disease. To identify patients with Cushings disease, we identified 476 Michigan Medicine patients between January 1st 2000-2025 along with propensity-matched control cases. We stratified our participants by obesity status and into a Cushings disease group and a control group. As expected, the Cushings group had an elevated BMI compared to the control group (34 kg/m2 vs 29 kg/m2). We found a higher proportion of females diagnosed with Cushings compared to males (287 vs 72). Cushings disease was associated with an increase in the fasting glucose levels in both non-obese and obese patients. In both the obese, and non-obese patients, there was an increase in ALT and AST levels regardless of Cushings disease status, but the increase due to Cushings disease was much greater in the patients with obesity (73.4 vs 35.1 mg/dL). Cushings disease also had a moderating effect on blood pressure, with participants a BMI under 30 kg/m2 increasing by 12.6 mmHg and participants with obesity increasing by only 7.9 mmHg. These findings highlight the need to consider obesity status when evaluating the effects of Cushings disease.

BackgroundThis study was designed to investigate the relationship between visceral fat metabolic score (METS-VF), lipid accumulation product (LAP), visceral adiposity index (VAI) and thyroid function. MethodsUtilizing data from the National Health and Nutrition Examination Survey (NHANES) 2007-2012, participants were excluded if they lacked data on METS-VF, LAP, VAI or thyroid function, or were under 18 years of age. Multiple linear regression, smooth curve fitting, and subgroup analyses were performed to determine the independent relationship between lipid accumulation and thyroid function. ResultsAfter full covariate adjustment, all three visceral adiposity indices showed significant positive associations with FT3 (LAP: {beta}=0.028, VAI: {beta}=0.024, METS-VF: {beta}=0.026; all P<0.001), FT3/FT4 ratio, TT3, TT4, and TgAb. LAP and VAI demonstrated inverse associations with FT4 ({beta}=-0.218 and -0.183, respectively; both P<0.001), while VAI and METS-VF were positively associated with TSH ({beta}=0.149, P=0.041; {beta}=0.167, P=0.025). Quartile analyses confirmed dose-dependent relationships, with Q4 participants showing elevated FT3, FT3/FT4, TT3, TT4, and reduced FT4 compared to Q1. RCS analyses revealed distinct non-linear patterns: LAP exhibited non-linearity with FT3, TSH, TT3, and TT4 (all P-nonlinear<0.05) but linear inverse associations with FT4. VAI displayed reverse L-shaped curves for FT3, TSH, and TT3 with plateaus at higher levels, while TT4 showed an inverted U-shape. METS-VF demonstrated non-linear increases for FT3 and TT3, linear associations with TSH and TT4, and an inverted U-curve for FT4. Stratified analyses identified age, race, and smoking as consistent modifiers of FT3/FT4 associations across all indices (interaction P<0.05), with stronger effects in younger/older adults, males, White participants, and high-income groups. TT3 and TT4 modification patterns varied by index. Thyroid autoantibodies showed minimal associations across all indices. ConclusionVisceral lipid accumulation is closely associated with thyroid dysfunction, and this association exhibits significant non-linear characteristics, which are modulated by factors such as age, race, and lifestyle habits. These findings provide new perspectives for the early identification and intervention of obesity-related thyroid dysfunction.

BackgroundHeterozygous c.283+1G>A and c.283G>A variants in the THRB gene, encoding for thyroid hormone receptor (TR){beta}1 and {beta}2, lead to autosomal dominant macular dystrophy (ADMD). We report the detailed clinical characterization of two first-degree relatives with ADMD, heterozygous for THRB c.283+1G>A, and an unrelated ADMD patient with a novel variant, c.283G>C. The genomic and molecular consequences of both variants were studied. MethodsgDNA and mRNA were obtained from leukocytes. Clinical characterization included biochemistry, bone density and body composition, ECG, echocardiography, ultrasound, audiometry and color-vision. In vitro assays investigated TR function and DNA binding. ResultsThe patients manifested no resistance to thyroid hormone beta (RTH{beta}) and had normal FT4 and TSH. Detailed studies in two patients showed no goiter, tachycardia, hypercholesterinemia or hepatic steatosis. Hearing was not impaired. Both had impaired color vision and reduced bone density. RT-PCR from all three patients revealed skipping of exon 4 exclusive to TR{beta}1, producing a deletion of 87 amino acids in the N-terminal domain (TR{beta}1{Delta}NTD). In vitro, DNA-binding affinity of TR{beta}1{Delta}NTD to DR4-TRE with or without RXR was comparable to TR{beta}1WT. Surprisingly, TR{beta}1{Delta}NTD was transcriptionally twice more active than TR{beta}1WT with a similar EC50 for T3, demonstrating gain-of-function of TR{beta}1{Delta}NTD. THRA expression in leukocytes was increased by 3-fold compared to unrelated controls and different from RTH{beta} patients. ConclusionThese THRB splice site variants produce TR{beta}1 exon 4 skipping, resulting in a gain-of-function mutant, TR{beta}1{Delta}NTD. This explains the dominant ADMD phenotype devoid of RTH{beta} and suggests a TR{beta}1 gain-of-function syndrome.

Polycystic ovary syndrome (PCOS) is a heterogenous reproductive disorder that is often associated with metabolic dysfunction, as well as comorbidities such as pregnancy complications. Although metabolic traits like hyperinsulinemia (i.e., elevated insulin without hypoglycemia) likely exacerbate the reproductive and metabolic features of PCOS, the precise impacts of specific metabolic traits on PCOS pathogenesis, symptom severity, and comorbidity incidence are not known. The aim of our study was to investigate the relationships between insulin levels, PCOS-like traits, and pregnancy complications by limiting endogenous insulin production in a mouse model of PCOS. Using Ins1-null mice with modulated Ins2 gene dosage (Ins1-/-:Ins2+/- versus Ins1-/-:Ins2+/+ littermates), we longitudinally assessed metabolic and reproductive phenotypes in PCOS-like mice generated via prenatal anti-Mullerian hormone (PAMH) exposure. We observed mild reproductive characteristics of PCOS in PAMH mice of both genotypes, including increased anogenital distances, delayed puberty, and disrupted estrous cycling, but did not detect robust PAMH-induced metabolic changes across six months. In the absence of PAMH-aggravated metabolic dysfunction or hyperinsulinemia--even in mice fed a high-fat, high-sucrose diet--reducing Ins2 gene dosage did not notably change most measured traits. However, high-fat, high-sucrose-fed PAMH pregnant dams exhibited a diminished pregnancy-induced insulinogenic response and a trend for reduced {beta}-cell mass compared to control mice, together with superior blood glucose homeostasis despite the physiological challenges of pregnancy. Therefore, while Ins1-null PAMH mice did not manifest pronounced PCOS-like metabolic features, prenatal AMH exposure can cause shifts in metabolic homeostasis during pregnancy.

BackgroundAcute appendicitis (AA) is a common surgical emergency. Observational studies have reported associations between obesity-related anthropometric traits and AA, but these associations may be affected by confounding and reverse causation. We used Mendelian randomization (MR) to investigate the potential causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on AA risk. Methods and FindingsWe obtained genome-wide association study (GWAS) summary statistics for BMI (ukb-b-19953), WHR (ieu-a-73), and AA (finn-b-K11_APPENDACUT) from the IEU Open GWAS database. We conducted single-variable MR (SVMR) and multivariable MR (MVMR) analyses. The primary estimator was inverse-variance weighted (IVW) MR, complemented by MR-Egger, weighted median, weighted mode, and simple mode methods. Instrument strength was assessed using the variance explained and F-statistics. Sensitivity analyses included Cochrans Q for heterogeneity, MR-Egger intercept and MR-PRESSO global test for horizontal pleiotropy, leave-one-out analysis, and Steiger directionality testing. We mapped instrumental variants to cis-eQTL genes (eQTLGen) and performed GO and KEGG enrichment analyses. In SVMR, genetically predicted BMI (OR 1.145, P = 0.0006) and WHR (OR 1.336, P = 0.0040) were associated with higher AA risk. Instruments were strong (BMI: [Formula]; mean/min F-statistic= 64.15/29.76; WHR: [Formula]; mean/min F-statistic= 48.41/29.75). Sensitivity analyses did not show strong evidence of heterogeneity or directional pleiotropy, and Steiger tests supported the hypothesized direction (exposure -> outcome). In MVMR including both traits, WHR remained associated with AA risk (OR 1.374, P = 0.0110), whereas BMI was not (P = 0.8000). Enrichment analyses suggested WHR-mapped genes were enriched in pathways related to adipocyte differentiation, while BMI-mapped genes were enriched in terms including nuclear envelope and endocytosis-related pathways. ConclusionsThese MR analyses are consistent with a potential causal relationship between obesity-related traits and AA risk, with WHR showing an association independent of BMI in multivariable models. Further work in diverse populations and with additional sensitivity analyses is warranted to assess robustness to pleiotropy and generalizability.

Study questionHow is glycodelin, a glycoprotein secreted by reproductive tissues, causally related to reproductive diseases and traits? Summary answerWe present evidence for a causal role of sex hormones in determining glycodelin levels, but limited evidence that glycodelin subsequently causally impacts reproductive traits. What is known alreadyGlycodelin is expressed in female and male reproductive tissues and has four glycoforms (-A, -C, -F and -S), with the glycosylation pattern determining its function. Differences in the levels of glycodelin are associated with reproductive traits, including fertility, endometriosis, preeclampsia, and female-specific malignancies. Study design, size, durationWe used cross-sectional data from the UK Biobank to investigate relationships between glycodelin and reproductive-related traits in men and women by performing genome-wide association studies (GWAS) and Mendelian randomization (MR) analyses. Participants/materials, setting, methodsWe included individuals of European genetic ancestry aged 40-69 in 2006-2010, with genetic data in the UK Biobank v3 release. We performed GWAS of glycodelin levels in 46,468 people, stratified by sex (21,368 men and 25,100 women) and menopause status (6,409 pre- and 18,691 post-menopausal women). We tested bidirectional casual associations between glycodelin levels and 19 reproductive-related traits using one- and two-sample MR analyses. Main results and the role of chanceNine genetic signals reached genome-wide significance (P<5x10-8) across the glycodelin phenotypes. A known genetic signal (rs9409964) near the PAEP gene, which encodes glycodelin, was most strongly associated (P<3x10-80 across all phenotypes), and had heterogeneous effects (effect (SD) per A allele of 1.31 in men vs 0.60 in women, and 0.4 in pre- vs 0.9 in post-menopausal women). Higher serum concentrations of bioavailable testosterone raised glycodelin in men (effect = 0.14 SD, IVW P=4.1x10-13), while effects in women depended on menopause status (pre-menopausal effect = -0.16 SD, IVW P=3.6x10-3; post-menopausal effect = 0.10 SD, IVW P=5.9x10-4). There was no strong evidence that differences in glycodelin levels were caused by, or were the cause of, other reproductive-related traits. Limitations, reasons for cautionProteomic measurements of glycodelin did not differentiate between glycoforms and were derived from blood and might not reflect levels in reproductive tissues. The sample size for the pre-menopausal GWAS was modest, reducing our power to detect relationships with reproductive conditions. Genetic instruments are assumed to be proxies for average lifelong exposure, which does not reflect variation in hormones and biomarkers over lifetime. Wider implications of the findingsWe suggest that reported associations of glycodelin with reproductive conditions are likely to result from the effects of sex hormones rather than being directly causal. These findings may help reconcile previously conflicting associations between glycodelin and reproductive traits.

BackgroundPolycystic ovary syndrome (PCOS) is a prevalent endocrine disorder with substantial metabolic comorbidities, including obesity, insulin resistance, and dyslipidaemia. Beyond their classical digestive role, bile acids (BAs) function as metabolic signalling molecules that regulate glucose and lipid homeostasis and inflammation through receptors such as the farnesoid X receptor (FXR) and Takeda G-protein receptor 5 (TGR5). However, bile acid dysregulation in PCOS remains inadequately characterised. MethodsTargeted serum bile acid profiling was performed in PCOS (n = 86) and healthy controls (n = 60) using a validated LC-MS/MS method. Individual bile acids were quantified and classified into primary, secondary, and conjugated forms. Multivariate analyses were applied to identify group-level metabolic patterns. Functional bile acid indices reflecting hepatic conjugation and microbial transformation were calculated. Correlation analyses assessed between bile acids and clinical variables. ResultsPCOS women exhibited significantly higher serum levels of cholic acid and conjugated bile acids. Multivariate analyses revealed distinct bile acid signatures differentiating PCOS from controls, with deoxycholic acid, taurocholic acid, and cholic acid contributing most strongly to group separation. Pathway-based indices demonstrated an expanded conjugated bile acid pool, an increased conjugated-to-unconjugated bile acid ratio, and altered secondary-to-primary bile acid balance in PCOS. Several bile acids showed significant associations with androgen levels and gonadotropin ratios. ConclusionPCOS is characterised by coordinated alterations in bile acid metabolism, including hepatic synthesis, conjugation, and gut microbial transformation, highlighting bile acids as integrative metabolic signals linking endocrine and metabolic dysfunction in PCOS.

ObjectiveHbA1c thresholds used to define dysglycemia in autoantibody-positive individuals at risk for type 1 diabetes do not account for age-related increases in HbA1c and may overestimate progression risk in adults. We evaluated whether age-adjusted HbA1c or a higher HbA1c threshold improves risk stratification across age groups. Research Design and MethodsWe analyzed 5,024 autoantibody-positive relatives (3,720 children and 1,304 adults) participating in the TrialNet Pathway to Prevention study. Age-related HbA1c effects were modelled using 6,273 adults from the population-based Exeter 10,000 cohort. Progression risk was compared using the standard dysglycemia threshold (HbA1c [&ge;] 5.7% [39 mmol/mol]), age-adjusted HbA1c, and an alternative threshold of HbA1c [&ge;]6.0% (42 mmol/mol). ResultsUsing HbA1c [&ge;] 5.7%, children had higher 1-year progression risk than adults among single autoantibody-positive participants (38% [95% CI 28, 47] vs. 13% [7.2, 19]) and multiple autoantibody-positive participants (55% [49, 60] vs. 38% [27, 47]; both p<0.001). Age adjustment reduced these differences; progression risk was similar among single autoantibody-positive participants (38% [28, 47] vs. 27% [13, 39]; p=0.32), with attenuated differences among multiple autoantibody-positive participants. An HbA1c threshold [&ge;]6.0% yielded comparable progression risk between adults and children across autoantibody subgroups. In post hoc analyses, adults aged <30 years had progression risk similar to children (p=0.1). ConclusionsAge-related variation in HbA1c influences dysglycemia classification in adults at risk for type 1 diabetes. Age-adjusted HbA1c or a higher HbA1c threshold ([&ge;]6.0% [42 mmol/mol]) in adults [&ge;]30 years identifies individuals with progression risk comparable to children and may improve age-specific risk stratification in prevention seungs.

Stratifying progression from early-stage type 1 diabetes to clinical disease is essential for optimally timing disease-modifying therapies. We previously developed a progression likelihood score (PLS) that includes quantitative IA-2 autoantibody (IA-2A) measurements. This study aligned IA-2A thresholds used for PLS calculation between the radiobinding assay (RBA) and a commercially available RSR IA-2A ELISA to support broader clinical application. Serum samples from 349 children with stage 1 type 1 diabetes were analyzed using both assays. IA-2A positivity was similar by RBA (61.6%) and ELISA (59.0%). Centile-based alignment of ELISA-positive samples defined thresholds corresponding to RBA IA-2A categories. ELISA-derived PLS low (PLS < 0.5), moderate (PLS 0.5-4.0) and high (PLS > 4.0) risk groups stratified progression to stage 3 disease comparably to RBA-derived groups. The 3-year progression rate for children with an ELISA IA-2A PLS >4.0 was 52.4% (95% CI, 30.5- 66.1), similar to the RBA-derived PLS >4.0 group (58.7%; 95% CI, 37.1-72.8). These results demonstrate that the commercial ELISA can be used for PLS-based risk stratification.

Abstract Context Lipoprotein(a) [Lp(a)] is a genetically determined and independent cardiovascular risk factor, traditionally considered stable across the lifespan, supporting a single lifetime measurement strategy. However, its longitudinal behavior during childhood and adolescence remains poorly characterized, particularly in individuals with type 1 diabetes who are at increased lifetime risk of cardiovascular disease. Objective We aimed to characterize intra- and inter-individual trajectories of Lp(a) in youth with type 1 diabetes and to assess the implications of variability for cardiovascular risk classification. Methods We conducted a retrospective single-center cohort study of children and adolescents with type 1 diabetes followed at Geneva University Hospitals between 2012 and 2023. Annual fasting Lp(a) concentrations were analyzed longitudinally. Variability was assessed in participants with more than two measurements. Clinically relevant thresholds were used to evaluate risk reclassification. Statistical analyses included paired Wilcoxon tests, Pearson and Kendall correlations, and Holm-adjusted p-values. Results A total of 287 participants contributed 1,408 Lp(a) measurements over a median follow-up of 6.2 years (IQR 2.9-9.6). At baseline, 26% had elevated Lp(a) (above or equal 300 mg/L). Among participants with serial measurements, 32% exhibited intraindividual fluctuations exceeding 50% of their maximum value. Reclassification across the 300 mg/L threshold occurred in 11.9% of participants. Lp(a) concentrations peaked between ages 10 and 13 years and declined thereafter. Modest seasonal variation was observed, with higher levels in autumn and winter (P < 0.05). Conclusions In youth with type 1 diabetes, Lp(a) demonstrates clinically relevant intraindividual variability over time. These findings suggest that reliance on a single lifetime measurement may lead to misclassification of cardiovascular risk and support repeated assessment, particularly during adolescence, to improve risk stratification.

Purpose: To evaluate the efficacy and safety of oral L-ergothioneine (EGT) in improving ovarian reserve and clinical symptoms in women with diminished ovarian reserve (DOR). As a proof-ofconcept study, we explored correlations between hormonal shifts and symptom amelioration. Methods: This single-center, open-label trial enrolled 40 women (aged 35-45 years) with DOR (baseline AMH: 1.0-3.0 ng/mL) and menstrual disorders. Participants received oral EGT (120 mg/day) for three consecutive menstrual cycles. The primary outcome was the change in serum AMH. Secondary outcomes included sex hormones (FSH, E2), antral follicle count, and validated clinical questionnaires (modified Kupperman Index [KI], PSQI, SF-36, and Menstrual Symptom Score). Results: Thirty-six participants completed the intervention without product-related adverse events. EGT significantly improved core ovarian markers: mean AMH increased from 1.79 {+/-} 0.71 to 2.47 {+/-} 1.52 ng/mL (p = 0.029). Concurrently, basal FSH decreased (8.22 {+/-} 2.93 to 7.05 {+/-} 2.47 mIU/mL, p = 0.032) and E2 increased (46.00 {+/-} 22.70 to 63.46 {+/-} 50.10 pg/mL, p = 0.030). Clinical assessments showed progressive reductions in KI (5.42 {+/-} 3.66 to 1.90 {+/-} 2.16, p < 0.0001) and PSQI scores (6.89 {+/-} 1.82 to 5.50 {+/-} 1.40, p < 0.0001), alongside improved menstrual and SF-36 scores (p < 0.001). Subgroup analysis revealed upward AMH trends across both the 35-39 and 40-45 age cohorts. Crucially, endocrine restoration ({Delta}FSH) significantly correlated with improvements in sleep quality ({Delta}PSQI, r = 0.43, p < 0.05) and E2 increases (r = -0.46, p < 0.05), linking hormonal stabilization directly to systemic relief. Conclusion: Oral EGT safely enhances serum AMH and optimizes the FSH/E2 balance in women with DOR, yielding substantial relief from peri-menopausal and sleep disturbances. This pilot proofof- concept study provides the first clinical evidence supporting EGT's systemic benefits in reproductive aging, laying the groundwork for future placebo-controlled trials. Trial Registration: ChiCTR2500104484; Prospectively registered on 2025-06-18. Keywords: L-Ergothioneine, diminished ovarian reserve, anti-Mullerian hormone (AMH), oxidative stress, clinical trial

Prediabetes is a high-risk dysglycemic state. We used a real-world endocrine/diabetes clinic registry from Najaf, Iraq to characterize patients labeled as having pre-diabetes and to explore factors associated with follow-up engagement. We identified prediabetes visits using keyword-based case finding (English and Arabic terms including prediabetes/pre-diabetes, IFG, IGT, and impaired fasting glucose/tolerance) across semi-structured registry fields. Visit-level data were collapsed to patient-level records. Binary indicators of hypertension, dyslipidemia/statin use, obesity/weight management, smoking, and common glucose-lowering therapies were derived from registry text using keyword/brand-name matching. The primary outcome was follow-up engagement defined as [&ge;]2 recorded visits. The prediabetes subset comprised 242 unique patients and 302 visits. Median age was 45 years (IQR 35-55); 47 patients (19.4%) had [&ge;]2 visits. Median follow-up duration was 0 days (maximum 321). Obesity/weight-management indicators were frequent (71.1%), as were hypertension (43.4%) and dyslipidemia/statin indicators (46.3%). In multivariable logistic regression, no evaluated predictor reached conventional statistical significance for follow-up engagement. Registry enhancements to capture laboratory confirmation and standardized follow-up fields may improve the ability to evaluate diabetes prevention pathways.

BackgroundPET-CT scans of radioactive exendin-4, a ligand of the GLP-1 receptor, are claimed to provide a biomarker of pancreatic beta cell mass (BCM), although the GLP-1 receptor is expressed also in the exocrine pancreas (PX). Parotid glands may be a reference tissue for GLP-1 receptor expression in exocrine cells of the GI system. Our aims were 1. To assess biomarker(s) of BCM derived from 68Ga-NODAGA-exendin-4 PET-CT scans in participants with long-standing type 1 diabetes (T1DM) or in subjects with obesity (OBESE); 2. To investigate the relationship between biomarker(s) of BCM and a biomarker of beta cell functional mass (BCFxM) in OBESE. MethodsT1DM (n=8, Age: 50.4{+/-}3.8 yrs; T1DM duration: 34.2{+/-}3.0 yrs; BMI: 26.6{+/-}1.1 kg/m2; HbA1c: 7.5{+/-}0.36%) and OBESE (n=9; Age:48.2{+/-}2.2 yrs; BMI: 37.4{+/-}1.1 kg/m2; HbA1c: 5.4{+/-}0.17%) underwent two studies: 1) 68Ga-NODAGA-exendin-4 PET-CT scan of both PX and parotid glands 45-60 after i.v. injection and with CT-assessment of PX volume to compute biomarkers of BCM based on SUV (BCMSUV) or clearance (CLEAR; BCMCLEAR); 2) Mixed meal test (MMT), with measurement of plasma glucose, C-peptide, GLP-1 and GIP curves to assess BCFxM with state-of-art mathematical modeling. ResultsThe C-peptide response to the MMT in T1DM participants was absent or negligible, whereas the OBESE displayed a robust BCFxM. The PX volume was smaller in T1DM than in OBESE (51.7{+/-}6.6 vs 92.9{+/-}10.9 cc; p=0.007). The biomarkers of BCM, as assessed by 68Ga-NODAGA-exendin-4 SUV or CLEAR, were 6.6-fold (p=0.003) and 5.0-fold (p=0.002) lower, respectively, in T1DM than in OBESE. BCFxM was correlated in OBESE to both biomarkers of BCM (r=0.91 p<0.001, and r=0.82 p=0.006, respectively). Conclusion/interpretation68Ga-NODAGA-exendin-4 derived biomarkers of BCM can discriminate T1DM from OBESE. In OBESE 68Ga-NODAGA-exendin-4 derived BCM appears to be a pivotal determinant of the beta cell response to MMT and may be valuable to compare and monitor BCM both in research and in clinical settings. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIChanges in pancreatic beta cell functional mass are at the heart of alterations in glucose regulation, including diabetes mellitus. Beta cell functional mass can be assessed by mathematical modeling of the in vivo beta cell response to intravenous or oral challenges. C_LIO_LIBeta cell functional mass is the product of beta cell mass times beta cell function per mass unit, i.e. the result of two distinct entities, mass and function. No in vivo methods can dissect out beta cell mass and function. C_LIO_LIPancreatic 68Ga-exendin-4 uptake, as measured by PET-CT, has been proposed as a non-invasive biomarker of beta cell mass. However, the ratio of 3.6:1 between endocrine and exocrine pancreas 68Ga-exendin 4 uptake suggests that there is room for improvement. C_LI What are the key questions?O_LIDoes an improved 68Ga-exendin4 method provide a better separation between participants with type 1 diabetes and expected zero/nil beta cell mass vs people with nondiabetic obesity? C_LIO_LIWhat is the role of beta cell mass in determining beta cell functional mass in people living with obesity? C_LI What are the new findings?O_LIThe improvement in the quantitation of beta cell 68Ga-exendin-4 binding to beta cells resulted in a clearcut separation of participants with type 1 diabetes and expected zero/nil beta cell mass from people living with obesity C_LIO_LIIn people living with obesity, beta cell mass, as assessed by 68Ga-exendin-4 PET-CT scan, is a pivotal determinant of beta cell functional mass, as assessed by mathematical modeling of a frequently sampled mixed meal test C_LI How might this impact on clinical practice in the foreseeable future?O_LIThis method has the potential to track changes in beta cell mass both between-subjects and within-subjects over time C_LIO_LINatural history of glucose (in)tolerance and the impact of disease modifier candidates in diabetes mellitus can be assessed with the present method C_LI

Obesity-driven type 2 diabetes (T2D) is characterized by pathological alterations in visceral white adipose tissue (vWAT). While microRNAs (miRNAs) are key post-transcriptional regulators, comprehensive human vWAT profiling across metabolic states remains limited. This study characterized vWAT miRNA expression in lean, obese, and obese+T2D individuals to identify regulatory networks associated with metabolic failure. Deep miRNA sequencing was performed on vWAT samples from a discovery cohort, followed by validation via qPCR in an independent replication cohort. Differentially expressed miRNAs across the three groups were bioinformatically integrated with matched mRNA transcriptomic data to construct functional regulatory modules and identify enriched pathways underlying metabolic impairment. Several miRNAs exhibited robust and reproducible differential expression between obesity and obesity with T2D. Integrated miRNA-mRNA analyses revealed coherent regulatory modules involving inflammation, lipid metabolism, insulin signaling, and iron homeostasis. Specifically, miR-141-3p, miR-200b-3p, miR-15b-3p, miR-12136, and miR-585-3p showed consistent differential expression. Notably, miR-141-3p and miR-200b-3p were markedly upregulated and inversely associated with metabolic stress-related genes, including TF and FBXO32. Several miRNAs correlated with clinical markers of metabolic dysfunction, supporting their biomarker potential. By comparing lean, obese, and diabetic populations, this study provides a comprehensive characterization of the vWAT miRNA landscape and identifies specific miRNA-mRNA regulatory circuits that orchestrate the transition from healthy adiposity to pathological adipose tissue dysfunction. These findings pinpoint novel molecular drivers of type 2 diabetes progression and offer potential targets for therapeutic intervention in metabolic endocrine disorders.

Background/ObjectivesIndividuals with Down syndrome (DS) are at increased risk of obesity and metabolic comorbidities, yet the mechanisms underlying these conditions remain unclear. Here we investigated how DS-associated genetic condition interacts with diet and metabolic pathways in the Dp(16)1Yey mouse model of DS. MethodsUntargeted plasma metabolomics was performed in Dp(16)1Yey and control mice, subjected to either control or high-fat diet (HFD). Raw data were processed, and features were annotated. Statistical analyses were conducted in R, and pathway analysis was performed with MetaboAnalyst v5.0. Fecal microbiome was obtained using 16SrRNAseq and analyzed using phyloseq in R. ResultsDiet exerted the strongest effect on mice plasma metabolome, followed by sex and genotype. Seventy-five diet-responsive metabolites were enriched in amino acid and nucleotide metabolism. Genotype-driven changes affected 34 metabolites, notably impacting amino acid and taurine-hypotaurine metabolism. Fifty-six sex-associated metabolites highlighted disruptions in aromatic amino acid biosynthesis and pyrimidine metabolism. A significant Diet*Genotype interaction was observed for five metabolites, including a marked reduction in the microbiota-derived metabolite 3-indolepropionic acid (IPA) in Dp(16)1Yey mice on HFD. Both genotype and diet exerted pronounced effects on fecal microbiome with selective depletion of the IPA-producing Clostridia in Dp1Yey mice under HFD. ConclusionSegmental trisomy in Dp(16)1Yey mice modulates the host metabolic response to dietary fat, partly through microbiota-derived metabolites such as IPA. These findings highlight the importance of genotype, diet, and microbiome interactions in shaping metabolic disease risk in DS and point toward microbiota-targeted dietary interventions.

Menopausal hormone therapy (MHT) is prescribed for climacteric symptoms including hot flushes and weight gain and contains estrogens such as 17 beta-estradiol (17{beta}E2). However, estrogen receptor activation by MHT may increase reproductive cancers and cardiovascular event risk in some people. As the protective metabolic effects of 17{beta}E2 are partly mediated through the arcuate nucleus of the hypothalamus, restricting 17{beta}E2 actions to the brain could serve as a safer mechanism of MHT. 10{beta},17{beta}-Dihydroxyestra-1,4-dien-3-one (DHED) is a prodrug of 17{beta}E2 which is enzymatically converted to the parent hormone exclusively within the brain. DHED has demonstrated positive benefit in rodent models of centrally-mediated maladies including hot flushes, depression and cognitive decline, without peripheral hormonal burden. Therefore, we hypothesized that DHED treatment in obese female mice would act within the hypothalamus to provide the same beneficial metabolic effects as 17{beta}E2. Female mice were ovariectomized, placed on a high fat diet and split into either control, DHED, or 17{beta}E2 treatment groups. Body weight, uterus weight and glucose tolerance were recorded along with gonadal hormone receptor expression in the brain. Delivery of DHED at a similar dose as 17{beta}E2 failed to improve metabolic parameters or recapitulate the hypothalamic responses induced by 17{beta}E2. Delivery of DHED at higher doses, which elicited estrogen-like actions within the brain, still failed to improve metabolic health. Our findings suggest that peripheral actions, in addition to hypothalamic targets, may be required to mediate 17{beta}E2s protective effects on metabolism and that brain-targeted MHT may be unsuitable for improving metabolic health during menopause.

Background: Genetic variants impacting red blood cell biology disrupt the relationship between glycaemia and glycated haemoglobin (HbA1c), with implications for diagnosis and management of type 2 diabetes (T2D). Thalassaemia trait is estimated to affect 350 million people globally, but its impact on T2D and related outcomes is not clear. Methods: We explored associations between thalassaemia trait, HbA1c, and T2D diagnosis and complications in 43,088 British Bangladeshi and Pakistani participants in the Genes & Health study with linked multisource England National Health Service (NHS) electronic health record data and whole exome sequencing. Findings: 2,490 participants (5.8%) were heterozygous carriers of ClinVar pathogenic / likely pathogenic thalassaemia variants, however 3 in 4 of these were not diagnosed with thalassaemia in their NHS health records. rs33950507, a common variant causal for HbE thalassaemia, was associated with increased HbA1c (beta=0.13, 95%CI:0.08-0.18, p=7.8x10-8), but not glucose levels (beta=0.01, 95%CI:-0.04-0.06, P=0.72). rs33950507 was associated with increased hazards of prediabetes (HR=1.38, 95%CI:1.26-1.52, p=2.2x10-6) and T2D (HR=1.11, 95%CI:1.01-1.22, p=0.03), and reduced hazards of diabetic eye disease (HR=0.74, 95%CI:0.56-0.96, p=0.02) and cerebrovascular disease (HR=0.44, 95%CI:0.20-0.94, p=0.03). Sensitivity analyses suggested mediation by overdiagnosis and overtreatment of T2D. Interpretation: Alternatives to HbA1c, and/or precision medicine approaches to defining and managing hyperglycaemia, are needed, particularly on a global scale. This may be particularly relevant to individuals from ancestral groups among whom erythrocytic traits are more common but often undiagnosed. Funding: Wellcome Trust, MRC, NIHR, Barts Charity, Genes & Health Industry Consortium

AimWe examined associations between smoking and HbA1c among U.S. adults, and whether these associations vary by diabetes status. MethodsWe analyzed NHANES data from 2015-2018 for adults aged [&ge;]20 years. Smoking was assessed by self-report and serum cotinine. Survey-weighted multivariable linear regression was used to evaluate the association between smoking and HbA1c in the full population (N=9,214) and in adults without diabetes (N=7,328), adjusting for demographics, blood pressure, waist circumference, lipids, and C-reactive protein. ResultsAfter adjustment for cardiometabolic covariates, there was no significant association between smoking and HbA1c in the full population (former: {beta}=0.029%, p=0.30; current: {beta}=0.053%, p=0.13). Among adults without diabetes, former smoking was not associated with HbA1c, whereas current smoking remained significantly associated (former: {beta}=-0.001%, p=0.923; current: {beta}=0.067%, p<0.001). These findings were similar when cotinine was used as the exposure measure, with active smoking ([&ge;]3.0 ng/mL) associated with higher HbA1c among non-diabetic adults (p<0.001), but not in the full population. ConclusionsAmong adults without diabetes, current but not former smoking was associated with higher HbA1c. The absence of an association in former smokers suggests that this effect may attenuate following cessation. These findings support early cessation interventions and may inform cessation counseling and diabetes screening.