The Journal of Clinical Endocrinology & Metabolism

Polyendocrine metabolic ovarian syndrome (PMOS), previously called polycystic ovary syndrome (PCOS) - the most common reproductive endocrinopathy in women of reproductive age, is frequently associated with chronic low-grade inflammation and immune dysregulation. Beyond hyperandrogenism and ovulatory dysfunction, women with PMOS exhibit reduced regulatory T cell (Treg) levels and impaired STAT5 phosphorylation. This study investigates the molecular basis of the defective STAT5 signalling in PMOS. No significant difference in plasma IL2 levels is observed in PMOS women versus normal subjects. Analysis of 102 PMOS patients and 102 controls reveals significantly decreased JAK2 expression alongside increased expression and activity of the phosphatases PTP1B (Protein Tyrosine Phosphatase 1B), TCPTP (T cell Protein Tyrosine Phosphatase), and DUSP4 (Dual Specificity Protein Phosphatase), in leukocytes of PMOS women. In isolated Tregs, only PTP1B and DUSP4 were significantly upregulated. DUSP4 expression positively correlates with serum testosterone and luteinizing hormone levels, linking hormonal imbalance with immune defects. Functional experiments show that silencing PTP1B and DUSP4 enhances IL2-induced Treg generation. Our collective findings identify phosphatase-mediated inhibition of STAT5 signalling as a key mechanism underlying Treg deficiency in PMOS and highlight PTP1B and DUSP4 as potential therapeutic targets to restore immune tolerance and improve reproductive outcomes.

Background: Recent primary aldosteronism (PA) guidelines proposed probability-based stratifications, and use of aldosterone suppression testing, to predict lateralizing PA subtype. This guideline framework was based on very low-quality evidence. Methods: The discriminatory capacity of guideline-endorsed probability frameworks for PA subtyping were evaluated in this retrospective study of 319 PA patients, from two large tertiary centers in Bangkok, Thailand, who underwent subtyping assessments regardless of probability status. PA subtypes were determined by adrenal venous sampling (AVS) and/or post-adrenalectomy outcomes using PASO criteria. The main objectives were to evaluate the accuracy of predicting PA subtype using: 1) guideline-endorsed classification to high, intermediate, and low probabilities of lateralization; and 2) the seated saline suppression test (SST). Results: The majority of PA patients were characterized as having intermediate probability for lateralizing PA (75%); however, lateralizing PA was ultimately confirmed in 61-78% of all patients, regardless of guideline-based probability classification. The vast majority of SST results were positive using guideline-derived criteria, regardless of probability stratification or ultimate subtype: 89.3% of patients with lateralizing PA and 80.6% of those with bilateral PA had a positive SST. Among patients with intermediate probability of lateralizing PA, where guidelines specifically endorse the value of SST, the SST had a sensitivity of 89.4% and specificity of 22.0% for detecting lateralizing PA, with 78.0% false-positive and 10.6% false-negative rates. Consistently, post-SST aldosterone concentrations exhibited near-complete overlap between those with and without lateralizing PA. Conclusion: Guideline-endorsed probability frameworks, and the use of SST, lacked discriminatory capacity to predict PA subtype.

ObjectivesLow serum testosterone (T) in men with obesity suggesting T deficiency may be misinterpreted by confounding changes in serum SHBG, Ts circulating carrier protein. Measuring or calculating "free" testosterone (FT) concentrations to define a low T is problematic as cFT is not a valid analytical variable lacking certified standard, quality control or reference range. We developed a novel metric, Scaled Testosterone (ST), comparing standardized serum T (LCMS) and SHBG without invoking hypothetical serum T fractions. MethodsSerum T and SHBG in men (n=10,027) pooled from three population-based studies in Australia were expressed as standardized (Z) scores (ZT, ZSHBG) and their difference ST = ZT-ZSHBG. ST was evaluated in a clinical trial of 51 men with severe obesity undergoing 1 year of diet-induced weight loss. ResultsZT and ZSHBG displayed linear correlation (r=0.44, 10-11) with ST approximating zero (-0.33 {+/-}2.14 SD). In non-obese men with low serum T suggestive of organic hypogonadism displayed very low ST indicating ST can evaluate whether a low serum T is proportionate to a concomitant serum SHBG. In men with obesity, low pre-treatment serum T and SHBG both increased during diet-induced weight loss with no change in serum LH while ST which remained within standard limits at each time. ConclusionsThe low serum T in men with obesity may better be considered as the pseudo-hypogonadism of obesity comprising low serum T with proportionately low serum SHBG in the presence of normal serum LH {+/-} FSH serving as a tissue androgen sensor.

Aims/Hypothesis: Behavioral and phenotypic characteristics do not fully explain variability in African Americans with youth-onset type 2 diabetes (Y-T2D) treated with metformin with or without liraglutide. We hypothesized that biological heterogeneity, including genetic variation in the metformin transporter OCT1, influences metformin pharmacokinetics and hepatic glucose flux. Therefore, we sought to characterize metformin pharmacokinetics in Y-T2D and evaluate genetic variants known to modulate metformin efficacy in adults to determine the mechanisms underlying variation in treatment response. Methods: We evaluated genetic variants related to metformin transport and mechanisms of action in 30 Y-T2D using a candidate-gene approach to evaluate the association of pharmacogenetic variants with fasting glucose and gluconeogenesis. In a subset of Y-T2D randomized to 3 months of metformin (n=11) or metformin and liraglutide (n=8), we constructed a metformin population pharmacokinetic model and evaluated gene variant associations. Results: A one-compartment first-order absorption and elimination pharmacokinetic model provided the optimal fit. Metformin pharmacokinetic parameters were similar by group and not related to glycemia. The rs628031_OCT1 A allele was associated with greater metformin clearance. The rs622342_OCT1 C allele was associated with lower post-treatment fractional gluconeogenesis ({beta} [95% CI] = -8.8 [-14.13, -3.47] %, Adjusted R2 = 0.56, P = 0.003). The rs7903146_TCF7L2 T allele was associated with greater reductions in fasting glucose among those treated with metformin + liraglutide ({beta} = -1.32 [-2.42, -0.22] mmol/L, Adjusted R2 = 0.8, P<0.002), but baseline glucose and gluconeogenesis (P<0.0001) were the strongest predictors of post-treatment glycemia. Conclusion/interpretation: In Y-T2D, OCT1 gene variants rs628031 and rs622342 were associated with metformin clearance and gluconeogenesis, respectively. TCF7L2 variant rs7903146 may contribute to differences in glycemic response in youth treated with metformin and liraglutide. These findings suggest genetic variants may be important for understanding variable metformin response in Y-T2D.

Background Chronic gastritis and duodenitis (CGD) are highly prevalent among patients with type 2 diabetes (T2D). However, the prognostic impact of their comorbidity and the potential role of MRI-derived phenotype-tailored dietary strategies remain unclear. Methods This prospective cohort study included 453,768 UK Biobank participants. Primary endpoints were myocardial infarction, stroke, end-stage renal disease (ESRD), dementia, Parkinson's disease, and all-cause mortality. Time-dependent multivariable Cox regression assessed outcome associations, while additive interaction analyses evaluated synergistic effects between T2D and CGD. Eight healthy dietary pattern scores were analyzed. Latent profile analysis classified MRI-derived body composition phenotypes based on fat distribution and organ volume. Results T2D and CGD were positively associated, and their comorbidity increased risks of cardiovascular events, ESRD, dementia, and all-cause mortality. Additive interaction analyses demonstrated synergistic effects on myocardial infarction and all-cause mortality. The comorbidity was further associated with aggravated lipid metabolic abnormalities and multiorgan atrophy. Higher adherence to the Healthful Plant-Based Diet Index (HPDI) and Dietary Approaches to Stop Hypertension (DASH) diets attenuated the excess mortality risk related to this synergy. Dietary associations varied across T2D, CGD, and comorbid populations, while MRI-based latent profiles modified diet-outcome relationships. A nomogram integrating demographic, dietary, and body composition data demonstrated reliable long-term predictive performance for myocardial infarction, stroke, and all-cause mortality. Conclusions Comorbid T2D and CGD substantially increase adverse clinical risks and exhibit synergistic effects on myocardial infarction and all-cause mortality. These findings support routine CGD screening in T2D care and provide population-based evidence for MRI-derived phenotype-tailored dietary strategies.

Objective To develop clinically operational, population-representative risk-score models for detecting metabolic syndrome (MetS) in U.S. adults by incorporating the NHANES survey design. Research Design and Methods We analyzed 36,812 U.S. adults from NHANES 1988--2018. Seven models of increasing clinical complexity were trained and evaluated, ranging from basic demographics to full biochemical panels. We used a new deep-learning methodology for survey data with a predictive uncertainty quantification model. Results A model combining anthropometrics, vital signs and a basic lipid panel achieved an AUC of 0.923 at an estimated cost of 0.40 eur per individual. Adding diabetes-specific biomarkers, including fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c), yielded only marginal improvements. Conclusions This low-cost population-representative screening tool for MetS may help identify at-risk individuals and support data-driven public health interventions.

Background: Repeated metabolic-bariatric surgery (MBS, r-BS) represents 10-25% of all MBS procedures and is commonly performed for recurrent weight gain after initial weight loss. How weight loss followed by regain reshapes adipose tissue biology remains unclear. We hypothesized that women undergoing r-BS exhibit a distinct adipose tissue signature compared with those undergoing primary bariatric surgery (p-BS). Methods: We analyzed subcutaneous and visceral adipose tissues (SAT, VAT, respectively) from women undergoing either p-BS, or r-BS with documented >15% weight loss after prior MBS. Tissues were assessed histologically, molecularly, and functionally (activation of human microglia cells (HMC3) by SAT secretome). Results: Consistent with other cohorts, women undergoing r-BS (n=21) trended to be older (47.2 vs. 40.5 y, p=0.06) than those undergoing p-BS (n=35), with a lower BMI (42.3 vs. 45.6 kg/m2, respectively, p=0.103), and a trend for improved cardiometabolic risk parameters such as fasting insulin, CRP and HDL-c. Adipose tissue histological features (adipocyte size, fibrosis, macrophage and crown-like structure abundance) were similar, while adipose mast cells were slightly (though insignificantly) more prevalent in r-BS. A single-nucleus RNA-seq-based deconvolution algorithm applied to bulk RNA-seq confirmed the absence of a major shift in adipose tissue cell-type composition. Yet, it uncovered a unique SAT transcriptome, with activation of inflammatory pathways in r-BS. Consistently, SAT explants from r-BS secreted higher protein concentrations of NFkB-regulated cytokines IL6 and IL8. Biological impact of the more inflammatory secretome was demonstrated by its increased ability to activate human microglia cells. Conclusions: Prior BS with significant weight loss-regain in women is associated with an inflammatory SAT transcriptome and secretome, possibly reflecting altered adipose-brain endocrine communication.

BackgroundVertical sleeve gastrectomy (VSG) improves glycaemic control in type 2 diabetes (T2D) through mechanisms that extend beyond weight loss. The interaction between glucocorticoid metabolism and inflammation in this context remains unclear. MethodsWe investigated the role of 11{beta}-hydroxysteroid dehydrogenase type 1 (11{beta}HSD1) in mediating the metabolic effects of VSG in humans and mice. Subcutaneous adipose tissue biopsies were collected before and 6 months after VSG. Parallel studies were conducted in lean and high-fat diet-fed mice undergoing VSG or sham surgery, alongside 11{beta}HSD1 knockout models. Glucose tolerance and expression of 11{beta}HSD1 and interleukin-6 (IL6) were assessed. Mechanistic interactions were examined in IL6-treated human hepatocytes. ResultsVSG reduced 11{beta}HSD1 and IL6 expression in human adipose tissue and improved insulin resistance. In lean mice, VSG improved glucose tolerance and downregulated both markers independently of weight loss. 11{beta}HSD1 knockout mice exhibited improved glucose tolerance despite increased adiposity, partially recapitulating the VSG phenotype. Both interventions reduced circulating and tissue IL6 levels. IL6 stimulation increased HSD11B1 expression in hepatocytes. Conclusions11{beta}HSD1 links glucocorticoid metabolism, inflammation, and glucose homeostasis following VSG. Targeting this pathway may offer a strategy to replicate key metabolic benefits of metabolic bariatric surgery.

Importance: Despite the benefits of statin therapy in individuals with diabetes, fewer than 70% of adults with diabetes meet contemporary guidelines for statin therapy and reducing low-density lipoprotein cholesterol (LDL) to <100 mg/dL. Evidence describing delays in statin initiation after diabetes diagnosis and associated clinical outcomes may motivate process of care interventions to improve guideline recommended care in individuals newly diagnosed with type 2 diabetes mellitus (T2D). Objective: To examine the timing of statin initiation and achievement of LDL <100 mg/dL after diabetes diagnosis, and to determine the association of early LDL reduction among statin initiators with incident atherosclerotic cardiovascular disease (ASCVD). Design: Retrospective observational cohort study using data from 2005-2021 Setting: Veterans Affairs Health Care System (VA) Participants: Individuals with newly diagnosed T2D Exposure: Primary exposure was ASCVD risk based on ACC/AHA Pooled Cohort Equations; secondary exposure was LDL <100 mg/dL in the first year after T2D diagnosis among statin initiators Main Outcomes and Measures: Co-primary outcomes were initiation of statin therapy and achievement of LDL <100 mg/dL within 5 years of diabetes diagnosis; incident 5-year ASCVD was a secondary outcome. Results: Among 100,406 individuals with newly diagnosed T2D, 59,615 were prescribed statin therapy within five years (59.4%), and 44,783 (57.5%) of those with LDL above goal achieved LDL <100 mg/dL within 5 years. Relative to those at low (<7.5%) 10-year ASCVD risk, individuals at intermediate (7.5-20%) and high (>20%) risk were more likely to be initiated on a statin (intermediate: Hazard Ratio [HR] 1.14 [95% CI 1.11, 1.17]; high: HR 1.16 [95% CI 1.13, 1.19]) and to achieve LDL <100 mg/dL (intermediate: HR 1.23 [95% CI 1.19, 1.26]; high: HR 1.34 [95% CI 1.30, 1.38]). Among those prescribed a statin within one year of diabetes diagnosis, achieving LDL <100 mg/dL in the first year after diabetes diagnosis was associated with lower risk of 5-year incident ASCVD (HR 0.84 [95% CI 0.77, 0.92]). Conclusions and Relevance: Gaps in guideline-directed primary prevention of ASCVD arise early following initial diabetes diagnosis. Guideline recommended early LDL lowering among statin initiators was associated with improved clinical outcomes.

Background: C-terminal binding protein 2 (CtBP2) has been implicated in metabolic regulation, but its association with specific measures of adiposity and lipid profiles in humans remains unclear. This study examined the relationship between circulating CtBP2 levels and key components of metabolic syndrome, focusing on body fat distribution and lipid markers. Methods: Data from 508 participants (259 men, 249 women) from a publicly available dataset were analyzed. Serum CtBP2 concentrations were measured using ELISA. Associations with obesity markers (BMI, waist circumference, waist-to-hip ratio) and lipid profiles (triglycerides, HDL cholesterol) were assessed using Spearman correlation and linear regression, adjusting for age and sex. Results: CtBP2 levels showed weak but statistically significant positive correlations with all measures of adiposity, with the strongest association observed for waist circumference ({rho} = 0.150, p < 0.001), followed by BMI ({rho} = 0.120, p = 0.007) and waist-to-hip ratio ({rho} = 0.098, p = 0.027). No significant correlations were found with triglycerides or HDL cholesterol. In the regression model predicting BMI, age, and sex were significant predictors, while CtBP2 demonstrated a trend toward association ({beta} = 0.080, p = 0.052). Conclusion: Circulating CtBP2 appears to be modestly associated with measures of adiposity, particularly abdominal fat, but not with lipid abnormalities. These findings suggest a potential role for CtBP2 in obesity-related metabolic dysregulation and underscore the need for further mechanistic studies to clarify its clinical relevance.

Polycystic ovary syndrome (PCOS) is linked to adverse pregnancy outcomes and increased cardiometabolic risk in offspring, yet the placental mechanisms underlying these risks remain poorly understood. Metformin is prescribed during PCOS pregnancies despite limited mechanistic justification. Using multi-modal molecular analyses of placentas from healthy controls and women with PCOS randomized to placebo or metformin (PregMet trial), restricted to uncomplicated pregnancies, we characterized direct PCOS associated placental alterations independent of confounding complications. PCOS placentas showed transcriptional downregulation across multiple cell types and shifts in cell type proportions. Specifically, syncytiotrophoblasts exhibited reduced expression activity of growth hormone receptor signaling and glycosaminoglycan biosynthesis. Endothelial cells displayed diminished receptor tyrosine kinase pathway activity, including VEGFC, despite increased cell proportion and hypervascularity. Intercellular communication networks were globally suppressed, including reductions in PDGF signaling from Hofbauer cells to fibroblasts. Notably, metformin did not reverse most PCOS-associated molecular alterations and induced transcriptional changes correlated to birth weight and childhood BMI. These findings indicate that PCOS-associated placental features are driven by cell type specific dysregulation of growth factor, angiogenic signaling pathways that are largely unresponsive to metformin. This underscores the need to develop mechanism based, placenta targeted therapeutic alternatives for future pregnancy management.

Background: Acute pancreatitis (AP) is an established risk factor for diabetes, with approximately 20% of children developing either prediabetes or diabetes within one year of their first episode. Little is known about the diabetes pathophysiology or which individuals are at highest risk. We aimed to evaluate whether genetic risk scores (GRS) for type 1 (T1D) and polygenic risk scores (PRS) type 2 diabetes (T2D) are associated with progression to dysglycemia following AP. Methods: Clinical data were available for 123 children (mean age (IQR), 12 (8-15) years; mean body mass index (BMI), 21.8) with AP who were followed for >1 year. Array genotyping coupled with imputation using the TOPMed reference panel was performed. Genetic ancestry was predicted using a random forest classifier. GRS for T1D and T2D were calculated using either an ancestry-appropriate (T1D-GRS) or a multi-ancestry (T2D-PRS) weighted framework. To evaluate risk compared to the population we used predefined GRS thresholds from UK Biobank. Results: Among the 123 subjects, 24 developed dysglycemia (5 with diabetes and 19 with prediabetes). The majority (75.6%, n=93) of children were of European ancestry. Comparison of the T1D-GRS burden with the UK BioBank showed numerically higher proportions for any given threshold. At the top 5% threshold, 9.7% of our cohort were classified as high-risk compared to 5% in UK Biobank (p<0.05). The elevated T1D-GRS could be primarily attributed to non-HLA variants and was more enriched in those testing positive for [&ge;]1 islet-autoantibody. The T2D-PRS was also elevated in the dysglycemic group but only reached statistical significance in those who were obese. Conclusion: These findings highlight the potential role of both T1D-GRS and T2D-PRS in investigating diabetes susceptibility following AP.

Background: Endometrial cancer incidence and mortality are increasing, particularly among Black women and for aggressive subtypes. Allostatic load (AL), a composite measure of physiologic dysregulation across metabolic, cardiovascular, and immune systems, varies by racial category and tumor subtype in other cancers. Endometrial cancer is strongly associated with obesity, and it is unknown whether AL scores maintain sufficient heterogeneity to evaluate differences across subgroups or with clinical outcomes. Objective: To describe the performance of AL scoring in endometrial cancer patients and examine associations with tumor characteristics (grade/histology) and survival outcomes. Methods: We evaluated AL among 398 participants newly diagnosed with endometrial cancer. AL score was calculated by assigning 1 point for each ''high-risk'' value (by clinical reference range or distribution-based) for 15 biologic variables for vital signs, anthropometrics, blood-based biomarkers, and medical comorbidities. Results: Distribution-based thresholds for variables were used to preserve heterogeneity in this obesity-dominant context. Overall, 68.7% of Black women had high AL compared to White (56.7%), Hispanic (56.7%), and other race (32.3%) women. Decision tree analyses revealed grade-dependent associations between AL and survival. For women with low-grade tumors, higher AL was associated with poorer overall survival. For high-grade tumors, intermediate AL ([&ge;]4, <8) were associated with shortest overall survival. Black women with low-grade disease experienced shorter progression-free survival regardless of AL. Conclusions: AL scoring maintains heterogeneity despite high obesity prevalence in endometrial cancer. Varying relationships between AL and survival by tumor grade and ethnoracial group suggest cumulative physiologic burden and social/structural factors may jointly shape endometrial cancer disparities.

Gestational diabetes mellitus (GDM) is a major metabolic complication of pregnancy with significant maternal and fetal adverse consequences. Beyond classical mechanisms, emerging evidence suggests that gut-derived metabolic endotoxemia may contribute to dysglycemia. Intestinal alkaline phosphatase (IAP), a key enzyme involved in maintaining gut barrier integrity and detoxifying lipopolysaccharides, has been linked to type 2 diabetes mellitus; however, its role in GDM remains largely unexplored. This hospital-based cross-sectional analytical study evaluated fecal IAP levels and their association with GDM among 198 pregnant women recruited from three antenatal care clinics representing three tiers of ANC services. Participants were screened for GDM using a 75-g oral glucose tolerance test and classified as having GDM (n=55) or normal glucose tolerance (NGT; n=143) according to WHO 2013 criteria. Stool samples were collected, and fecal IAP levels were measured using an enzymatic colorimetric assay. Fecal IAP level was significantly lower in women with GDM than in those with NGT (median 23.59 vs 46.48 U/g stool; p<0.001). Lower IAP level remained independently associated with GDM after adjustment for body mass index and previous GDM (adjusted OR 0.98 per unit increase; 95% CI 0.97-0.99; p<0.001). A graded relationship was observed between declining IAP level and GDM. Receiver operating characteristic analysis demonstrated modest discrimination (AUC 0.676), while a threshold of approximately 65 U/g stool yielded high sensitivity (89.1%) but lower specificity. Reduced fecal IAP is independently associated with GDM, supporting a potential role of gut-derived metabolic dysregulation in gestational glucose intolerance. While not suitable as a standalone diagnostic tool, fecal IAP may serve as a complementary biomarker for risk stratification during pregnancy. Prospective studies are warranted to determine its predictive value and explore its potential as a therapeutic target.

Background: Consensus continuous glucose monitoring (CGM) metrics, including time in range (TIR), time above range (TAR), time below range (TBR), mean glucose, glucose management indicator, and glycemic variability, are essential for modern glucose assessment. However, these whole-day summaries do not explicitly partition nocturnal basal from daytime ambulatory glycemic burden. Objective: To develop and evaluate a complementary domain-based CGM framework that quantifies basal and daytime ambulatory glycemic exposure across oral glucose tolerance test (OGTT)-derived dysglycemia phenotypes. Methods: In this observational, clinic-based study, 253 individuals underwent OGTT with insulin measurement and CGM. Participants were classified using a prespecified OGTT-derived phenotyping algorithm, implemented through a deterministic rules-based web calculator, and collapsed into five groups: NoDM, Increased insulin resistance, Midzone Glycemia, Prediabetes, and Diabetes. CGM files were uniformly reprocessed by selecting the latest contiguous episode and retaining the most recent 15 calendar days with data. The 24-hour profile was partitioned into nocturnal basal (00:00 to <06:00) and daytime ambulatory (06:00 to <24:00) domains. Derived indices included Area of Basal Glycemia (ABG), Area of Prandial/Daytime Ambulatory Glycemia (APG), incremental ABG (iABG), incremental APG (iAPG), and exploratory deficit indices dABG and dAPG. Results: The final dataset contributed 3,647 analyzable CGM days. APG remained higher than ABG across all groups. Mean ABG/APG increased from 80.45/86.38 mg/dL in NoDM to 111.96/124.70 mg/dL in Diabetes. Mean iABG/iAPG increased from 5.65/6.60 to 34.12/38.91 mg/dL, whereas dABG/dAPG declined as dysglycemia worsened. Conclusions: The ABG/APG framework provides interpretable, domain-resolved CGM burden metrics that separate basal from daytime ambulatory exposure and distinguish total burden from above-threshold excess. These indices are proposed as adjunctive metrics to support dysglycemia phenotyping, early risk recognition, and treatment monitoring, but are not intended to replace established consensus CGM metrics or diagnostic criteria. External, prospective validation is required.

Objective: Patients and physicians frequently focus on HbA1c and weight alone. We hypothesized that individuals with similar HbA1c and BMI may present markedly distinct metabolic backgrounds. We investigated whether the adipo-B index- composite of adipose insulin resistance (adipo-IR) and beta-cell function (HOMA-B)-can uncover hidden heterogeneity in this clinically homogeneous population. Methods: A total of 399 newly diagnosed, drug-naive Japanese subjects with T2DM were analyzed. Histograms of HbA1c and BMI demonstrated peak distributions within HbA1c 8-10% and BMI 24-26. Based on these distributions, a clinically homogeneous subgroup was defined to minimize confounding by glycemic severity and adiposity. Metabolic parameters including FBG, insulin, FFA, HOMA-R, HOMA-B, adipo-IR, adipo-B, T-C, TG, HDL-C and non-HDL-C were analyzed. Simple regression, multivariable linear regression, and subgroup stratification analyses were performed. Results: Despite comparable HbA1c and BMI by design, adipo-B stratification revealed significant differences in HOMA-B, FFA, non-HDL-C, and TG, whereas HOMA-R stratification identified only higher insulin and adipo-IR without differences in lipids or HOMA-B. Thus, adipo-B-but not HOMA-R-identified a lipotoxic, beta-cell-stressed phenotype invisible to conventional markers. Simple regression showed significant positive correlations between adipo-B and HbA1c, FBG, FFA, T-C, TG, and non-HDL-C, and negative correlations with insulin and HOMA-B. Multivariable linear regression confirmed that adipo-B was independently associated with non-HDL cholesterol, TG, and FFA after adjustment for HbA1c and BMI. Conclusion: Even among patients with identical HbA1c and BMI, the adipo-B index uncovers clinically relevant metabolic heterogeneity, supporting its role as a functional marker of the adipose-pancreas axis and a potential tool for precision phenotyping in early T2DM.

Objective: To characterize pregnancy outcomes and menstrual irregularities in Mexican women with systemic lupus erythematosus (SLE) and identify clinical factors associated with adverse pregnancy outcomes and early-onset menopause. Methods: We conducted a cross-sectional study of women with SLE enrolled in the Mexican Lupus Registry (LupusRGMX) between May 2021 and September 2024. Clinical and reproductive data were collected using standardized questionnaires. Menopause was defined as the absence of menstruation for [&ge;]12 consecutive months, and early menopause as onset before age 40. Univariable and multivariable logistic regression analyses were used to identify factors associated with pregnancy complications and early menopause. Results: A total of 210 women were included. Median age was 38 years (IQR 29-46) and median disease duration was 4 years (IQR 1-10). Among women with a history of pregnancy (47%), full-term delivery predominated (61%), while pregnancy loss occurred in 26% and preterm delivery in 13%. Pregnancy complications were reported in 9.6%, most commonly preeclampsia (6.7%). Younger maternal age was independently associated with pregnancy complications (OR 0.89, 95% CI 0.83-0.95) and adverse outcomes (OR 0.95, 95% CI 0.92-0.98). Higher disease activity was associated with complications in univariable analysis. Most pregnancies (68.3%) occurred before diagnosis. Early menopause was observed in 6.2% and independently associated with longer disease duration and older age. Conclusion: Younger maternal age was independently associated with adverse pregnancy outcomes, whereas disease activity showed an association in univariable analysis. Most pregnancies occurred prior to SLE diagnosis. Early menopause was associated with longer disease duration, suggesting impact of cumulative disease burden on ovarian function.

Aims CGM devices report glucose only within fixed limits (typically 40-400 mg/dL; 2.2-22.2 mmol/L), truncating extreme values to a boundary ("capping"). We characterised prevalence, duration, and consequences of capping in type 1 diabetes trial data. Materials and Methods We analysed 46,990,617 CGM readings from 948 participants across four publicly available clinical trial datasets (Dexcom G4 Platinum or G6 sensors). Capping prevalence, run duration, and associations with age, HbA1c and sex were characterised across all datasets. In the 77 participants of the Replace-BG trial CGM-plus-blood glucose monitor (BGM) arm, CGM-derived metrics were compared with contemporaneous BGM measurements across 1,162 non-overlapping 14-day windows. Results Between 93.5% and 100% of participants had at least one capped reading, and capped values comprised 0.47-0.98% of all readings. In the three datasets for which duration could be calculated, over 70% of upper-cap runs exceeded 15 minutes and over one third exceeded 60 minutes. Upper-limit capping was inversely associated with age (Spearman {rho} -0.20 to -0.47, p[&le;]0.002) in three of the datasets, and positively associated with baseline HbA1c ({rho} 0.39-0.62, p<0.001) in all four datasets. A within-participant analysis showed that capping burden did not predict CGM-BGM divergence in any summary metric (all p>0.2), and a systematic CGM-BGM offset in mean glucose and time in range (TIR) reflected the physiological lag between blood and interstitial fluid rather than capping artefact. Conclusions Sensor limit capping is near-universal in type 1 diabetes, produces sustained periods of right-censored glucose data disproportionately affecting younger patients, and does not substantially distort standard summary metrics at the population level. Clinicians and trialists should be aware that CGM data can confirm extreme glucose events but cannot quantify their severity.

Objective Fatty Acid esters of Hydroxy-Fatty Acids (FAHFAs) are anti-diabetic and anti-inflammatory lipokines produced mainly by adipose tissue (AT). As exercise training enhances FAHFA levels, we investigated the impact of acute exercise (AE) and exercise-mimicking conditions on circulating and adipocyte FAHFA levels. Methods Clinical trial (NCT05572905) in 60 women, grouped by BMI (lean vs. obese) and age (young vs. older), was combined with in vitro experiments on human adipocytes. Following baseline characterization (body composition, VO2max, insulin sensitivity, AT/plasma FAHFAs), women underwent a cross-over AE and control interventions with repeated blood sampling for FAHFA analysis. Results In AT, lean and older women exhibited higher FAHFA levels than obese and young women, respectively; older women also showed a shift toward higher levels of 13/12-carbon-branched FAHFAs. Circulating FAHFA levels were similar across all groups and were not positively associated with insulin sensitivity, VO2max or FAHFA levels in AT. Although AE increased circulating free fatty acids (FFA), plasma FAHFAs dropped in response to both AE and control interventions. In adipocytes, FAHFAs were unaffected by glucocorticoids but increased in response to lipolysis together with gene expression related to FFA oxidation (FAO). Nevertheless, blocking mitochondrial FAO partially mimicked the lipolytic effect, while peroxisomal inhibition synergistically boosted FAHFA lipolysis-driven production despite having no effect alone. Conclusions While adiposity and aging modulate FAHFA levels in AT, circulating levels remain stable and unaffected by AE, challenging subcutaneous AT as their primary systemic source. In vitro, FAHFA synthesis is driven by high FFA availability but limited by competing peroxisomal FAO.

Objective: Despite the complex and non-linear progression of diabetes, its shared pathways with atherosclerotic cardiovascular disease (ASCVD) are conventionally described using models based on single time points. We identified longitudinal diabetes clusters before diagnosis using deep learning and studied their association with ASCVD events and mortality. Methods: We analyzed 157,670 visits from 15,871 adults (25-65 years) without diabetes from four pooled U.S. cohorts (median follow-up: 22 years [IQR: 9-30]). A gated recurrent unit model with decay (GRU-D) was used to predict 1-year risk of diabetes or censoring within 10 years, by learning longitudinal embeddings across 25 clinical characteristics and biomarkers. Parallel Factor Analysis-2 (PARAFAC-2) and Gaussian mixture models (GMM) were used to group longitudinal participant representations as clusters. Landmark time Cox proportional hazards regressions, relative to last observation in the training window, were used to study covariate-adjusted associations of clusters with ASCVD and mortality. Prognostic utility of clusters beyond the PREVENT risk score was assessed using Harrell's C-index. Findings were replicated in a fifth cohort. Results: The analytic sample was aged 49 years [SD: 11], 58% female, and 68% white; 1,202 (8%) developed diabetes within the first 10 years. We identified five clusters (Cluster A to E) that differed in their clinical characteristics over time. Cluster E (46%) had the highest cumulative incidence of diabetes in the study period, followed by Cluster C (40%) and Cluster A (38%). Cluster C, which was defined by older age, high blood pressure, and suboptimal renal function at the first visit, had higher rates of ASCVD (HR: 1.09, 95%CI: 0.98-1.21) and mortality (HR: 1.08, 95%CI: 1.00-1.16), relative to Cluster A despite being similar in age and BMI at the first visit. Relative to Cluster A, all other clusters had similar or lower rates of ASCVD and mortality. We observed substantial cluster effects for three clusters (Clusters C to E), which were based on only two cohorts. The two clusters (Clusters A and B) that included participants from all four cohorts were reproduced in the fifth cohort and showed similar rates of outcomes. Clusters did not improve ASCVD prognosis, relative to a model that included only the PREVENT risk score. Conclusions: Longitudinal clusters reveal substantial heterogeneity in the period before diabetes diagnosis, and their risk for ASCVD and mortality. However, clusters discovered may, in part, be explained by cohort effects from variations in recruitment and visit patterns after recruitment.