Prediabetes is highly prevalent and biologically heterogeneous, yet current glycaemic definitions do not adequately capture differences in cardiometabolic and kidney risk. We aimed to identify metabolically defined subtypes of prediabetes using circulating metabolites and to examine their associations with cardiovascular–kidney–metabolic outcomes. We analyzed 24,638 participants with prediabetes from the UK Biobank who had metabolomics data available. Metabolomic biomarkers related to type 2 diabetes, cardiovascular disease, and chronic kidney disease were identified using machine learning–based feature selection methods, and unsupervised clustering was applied to derive metabolic subtypes. Associations between subtypes and cardiometabolic outcomes were evaluated, and interactions between dietary patterns and metabolic subtypes were explored. Mendelian randomization analyses were conducted to investigate potential causal roles of key metabolomic biomarkers. Three metabolically distinct subtypes of prediabetes were identified, representing low-, intermediate-, and high-risk metabolic profiles. These subtypes showed progressively higher risks of developing type 2 diabetes, cardiovascular disease, and chronic kidney disease during follow-up, and the associations between diet quality and disease outcomes differed across subtypes. Several metabolomic biomarkers demonstrated potential causal links with cardiometabolic outcomes. These findings highlight the metabolic heterogeneity of prediabetes and suggest that metabolomic-based subtypes may improve risk stratification and support precision prevention strategies.

Introduction Deutaleglitazar (AP303) is a novel dual peroxisome proliferator-activated receptor (PPAR) α and γ agonist, which has the potential to offer the combined clinical benefit on diabetic kidney disease (DKD) management by normalizing the elevated glomerular capillary pressure, ameliorating podocyte depletion, as well as correcting diabetic dyslipidemia and hyperglycemia Methods Three single-center, randomized, placebo-controlled single-ascending-dose and/or multiple-ascending-dose studies investigated its pharmacokinetics (PK), pharmacodynamic, safety and tolerability in healthy participants with different ethnicities and in patients with diabetic kidney disease (DKD) and reduced kidney function. Results A total of 80 healthy participants, and 18 patients with DKD and estimated glomerular filtration rate (eGFR) 30-60 mL/min/1.73m2 from Australia and China received either placebo, a single oral dose or multi-dose of deutaleglitazar for 14 days. Deutaleglitazar exposure increased in a dose-dependent manner both after a single dose and at steady state, with no accumulation. Minor differences of PK profiles in Caucasian vs. Asian participants, and in those with normal vs reduced kidney function are considered unlikely to be clinically significant. Reduction in eGFR with reversibility after drug discontinuation was evident. Improvement in diabetic dyslipidemia and hyperglycemia were observed. Few adverse events were reported, only neutropenia was dose related. Conclusion The PPARα and PPARγ related effects occurred over similar dose ranges, indicating that deutaleglitazar is a balanced agonist of the two receptor subtypes targeting on the root cause and multi-pathway of DKD progression.

BACKGROUND:Maternal Graves' disease (GD) has been linked to neonatal thyroid dysfunction, but its relationship with offspring neurodevelopment remains unclear. We examined the associations of maternal GD-related thyroid factors with neonatal thyroid function and neurodevelopment at 24 months. We also explored whether neonatal thyroid function might partly explain this association. METHODS:This single-center bidirectional cohort study included pregnant women with GD and their offspring delivered between January 1, 2019, and December 31, 2023. Maternal thyroid-related variables, including thyrotropin (TSH), free T4, thyrotropin receptor antibodies (TRAbs), and antithyroid drug exposure, were collected across pregnancy. Neonatal thyroid function was assessed at 7-14 days after birth, and neurodevelopmental screening at a corrected age of 24 months was performed using the Ages and Stages Questionnaire, Third Edition. Logistic regression was used to identify factors associated with neonatal thyroid dysfunction and abnormal neurodevelopmental screening results. Covariates were selected with guidance from a directed acyclic graph, and exploratory mediation analysis was performed using PROCESS Model 4. RESULTS:Among 159 neonates, 60 (37.7%) had thyroid dysfunction, with hyperthyrotropinemia as the most common abnormality (28.9%). Higher maternal third-trimester TRAb was independently associated with neonatal thyroid dysfunction (odds ratio [OR] = 1.59 [confidence interval or CI: 1.29-1.97], p < 0.001). Of the 143 offspring with follow-up data, 23 (16.1%) had abnormal neurodevelopmental screening results at 24 months. Higher maternal third-trimester TRAb (OR = 1.15 [CI: 1.04-1.27], p = 0.005) and higher neonatal TSH (OR = 1.11 [CI: 1.02-1.20], p = 0.016) were independently associated with abnormal neurodevelopmental screening results. Exploratory mediation analysis did not support a significant mediating role of neonatal TSH. CONCLUSIONS:Higher maternal third-trimester TRAb levels were associated with both neonatal thyroid dysfunction and abnormal neurodevelopmental screening results at 24 months in offspring of mothers with GD. This association with neurodevelopmental screening results may not be explained primarily by neonatal thyroid function alone.

Background:Gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDPs) are common maternal complications. We sought to evaluate the independent and joint association of GDM and HDPs with all-cause, premature, and cause-specific mortality. Methods:We used data from the UK Biobank, which included 220 953 women who reported at least one live birth. Individual and joint associations of GDM and HDPs with all-cause, premature, and cause-specific mortality were estimated using Cox regression models. Results:During a follow-up of 12.9 years, women who experienced GDM had a higher risk of all-cause (hazard ratio (HR) = 1.57; 95% confidence interval (CI) = 1.26-1.96), premature (HR = 1.60; 95% CI = 1.24-2.06) and cardiovascular disease (CVD) mortality (HR = 2.60; 95% CI = 1.70-3.96). Women with a history of HDPs had an increased risk for CVD mortality (HR = 2.07; 95% CI = 1.51-2.83), but the association with all-cause death and premature death was not significant. Individuals who encountered both GDM and HDPs had a 3.9-fold higher relative risk of all-cause mortality (HR = 3.93; 95% CI = 1.88-8.24]) and a 4.3-fold higher risk of premature mortality (HR = 4.31; 95% CI = 1.94-9.57), compared to those without GDM or HDPs. Conclusions:Women with GDM have a higher risk of all-cause, premature mortality and both risks were higher than the impacts of a history of HDPs based on a large-scale population. The co-occurrence of GDM and HDPs will deteriorate the aforementioned situation compared to a single cardiometabolic pregnancy complication.

Objectives To develop and evaluate a knowledge graph-augmented large language model (LLM) framework that synthesizes epidemiological evidence to infer life-course exposure-outcome pathways, using gestational diabetes mellitus (GDM) and dementia as a case study.Materials and Methods We constructed a causal knowledge graph by extracting empirical epidemiological associations from scientific literature, excluding hypothetical assertions. The graph was integrated with GPT-4 through four graph retrieval-augmented generation (GRAG) strategies to infer bridging variables between early-life exposure (GDM) and later-life outcome (dementia). Semantic triples served as structured inputs to support LLM reasoning. Each GRAG strategy was evaluated by human clinical experts and three LLM-based reviewers (GPT-4o, Llama 3-70B, and Gemini Advanced), assessing scientific reliability, novelty, and clinical relevance.Results The GRAG strategy using a minimal set of abstracts specifically related to GDM-dementia bridging variables performed comparably to the strategy using broader sub-community abstracts, and both significantly outperformed approaches using the full GDM- or dementia-related corpus or baseline GPT-4 without external augmentation. The knowledge graph-augmented LLM identified 108 maternal candidate mediators, including validated risk factors such as chronic kidney disease and physical inactivity. The structured approach improved accuracy and reduced confabulation compared to standard LLM outputs.Discussion Our findings suggest that augmenting LLMs with epidemiological knowledge graphs enables effective reasoning over fragmented literature and supports the reconstruction of progressive risk pathways. Expert assessments revealed that LLMs may overestimate clinical relevance, highlighting the need for human-AI collaboration in interpretation and application.Conclusion Integrating semantic epidemiological knowledge with LLMs via GRAG strategies provides a promising framework for life-course epidemiology, enabling early detection of modifiable risk factors and guiding variable selection in cohort study design.

AIM: To evaluate the predictive value of urinary albumin creatinine ratio (UACR), albumin excretion rate (AER), and estimated glomerular filtration rate (eGFR) for vision-threatening diabetic retinopathy (VTDR) in individuals with diabetes. METHODS: A comprehensive literature search across PubMed, Embase, Web of Science, Scopus, and the Cochrane Library from their inception to February 2024 were performed. The diagnostic accuracy of microalbuminuria (MA; including UACR and AER) and eGFR in predicting VTDR using sensitivity, specificity, positive likelihood ratio and negative likelihood ratio, diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristic (ROC) curve were assessed. Analyses incorporated both bivariate generalized linear mixed models and random-effects models to ensure a robust and unbiased interpretation of the data. RESULTS: The review included 14 studies with a total of 87 223 patients. The pooled sensitivity and specificity of MA and eGFR for predicting VTDR were 0.77 [95% confidence interval (CI), 0.57–0.89] and 0.51 (95%CI, 0.31–0.72), respectively. The DOR was 3.47 (95%CI, 1.94–6.18), with the area under the summary ROC curve at 0.70 (95%CI, 0.66–0.74). Notably, UACR as a predictor showed a sensitivity of 0.88 (95%CI, 0.43–0.99) and specificity of 0.55 (95%CI, 0.22–0.84), with an area under the curve of 0.78 (95%CI, 0.74–0.82). Despite significant heterogeneity among the studies (P<0.01), no publication bias was detected. CONCLUSION: UACR is a highly sensitive but moderately specific indicator for early detection and management strategies in this high-risk population.

Background Abnormal birth weights are associated with adverse pregnancy outcomes and future metabolic consequences. We aimed to examine cord blood lipidomes from low, normal and high birth weight (LBW, NBW, HBW) infants to identify core lipid signatures associated with non-optimum birth weight, and to derive biological insights through trans-omics data integration with placental proteome, maternal plasma lipidome and clinical phenome. Methods We conducted quantitative lipidomics of cord blood samples from two independent cohorts: a retrospective discovery cohort (n = 147) and a prospective validation cohort (n = 73). Integration with placental proteomics, maternal plasma lipidomics and clinical phenomics was conducted to elucidate potential biological implications. Findings We identified substantial reductions in cord blood polyunsaturated phospholipids (PUFA-PLs) (FDR <0.05) associated with placental vesicle trafficking and formation in LBW, and altered neutrophil degranulation in HBW. Combinatorial analyses of paired maternal plasma and cord blood samples indicated that cord blood PUFA-PL reductions were not attributable to deficient maternal supply, but rather to impeded assimilation (LBW) and increased utilisation (HBW). Interpretation Our findings provide biological insights that may inform targetable, lipid-oriented nutritional and/or pharmacological strategies to modulate foetal growth and development, with the goal of optimising clinical outcomes for both mother and child. Funding This work was supported by the National Natural Science Foundation of China (82170854, 81870579, 81870545, 82571043, 2357308); National High Level Hospital Clinical Research Funding (2022-PUMCH-C-019); Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0530200 and 2024ZD0530204); Beijing Municipal Science & Technology Commission (Z201100005520011); Peking University Clinical Scientist Training Program (No. BMU2023PYJH022); Beijing Municipal Natural Science Foundation (7202163, 7184252).

Background:Insulin-like growth factor-1 (IGF-1) receptor (IGF-1R) inhibitors have changed the treatment landscape for moderate-to-severe thyroid eye disease (TED), but the longitudinal behavior of circulating IGF-1 during and after therapy remains insufficiently characterized. This study aimed to describe serum IGF-1 dynamics in patients with TED treated with IGF-1R inhibitor teprotumumab N01 and to explore their relationship with glycemic changes. Methods:In this retrospective cohort study, 92 patients with moderate-to-severe TED treated with teprotumumab N01 who had longitudinal IGF-1 measurements were included. IGF-1 dynamics were characterized at infusion-based visits and during post-treatment follow-up. Glycemic changes were assessed using fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and glycated albumin (GA). Patients were classified by baseline glycemic status. Associations between IGF-1 metrics and glycemic changes were evaluated using multivariable linear regression for continuous glycemic outcomes and logistic regression for threshold-defined glycemic events, with sequential adjustment for age, sex, baseline glycemic markers, and baseline IGF-1 when applicable. Additional analyses were performed according to baseline glycemic status and baseline HbA1c quartiles. Results:Baseline serum IGF-1 was 151.0 ng/mL (IQR 116.8-187.3). IGF-1 increased markedly after treatment initiation, with a median early-treatment peak fold change of 3.5 (IQR 3.0-4.3) and a median on-treatment peak concentration of 649.5 ng/mL (IQR 520.8-753.8), corresponding to a 4.2-fold increase from baseline (IQR 3.5-5.0). IGF-1 remained elevated during the first 3 months after the last infusion and then declined progressively, generally approaching baseline by 6-9 months or later. Glycemic markers showed modest increases, with median peak increases from baseline of 0.40% (IQR 0.20-0.77) for HbA1c, 1.63% (IQR 0.95-2.39) for GA, and 0.65 mmol/L (IQR 0.30-1.14) for FBG. Glycemic deterioration was most pronounced in patients with baseline dysglycemia. In contrast, neither baseline IGF-1 nor IGF-1 dynamic metrics were consistently identified as independent correlates of glycemic changes after adjustment for age, sex, and baseline glycemic markers and IGF-1. Similar findings were observed in subgroup and HbA1c quartile analyses. Conclusion:Teprotumumab N01 treatment was associated with a substantial, early, and broadly reversible increase in circulating IGF-1 in patients with moderate-to-severe TED, but IGF-1 dynamics did not serve as an independent indicator of glycemic deterioration.

Background and Objective: IgG4-related Hashimoto's thyroiditis (IgG4 HT) is characterized by rapid progression and may be associated with an increased risk of papillary thyroid carcinoma (PTC). The diagnosis of IgG4 HT relies primarily on postoperative pathological analysis. Early identification of IgG4 HT is crucial for guiding patient management. This study assessed the possibility of thyroid core needle biopsy (CNB) in diagnosing IgG4 HT. Methods: One hundred and twenty HT patients who underwent color Doppler-guided CNB and subsequent thyroid surgery were collected in Peking University First Hospital. Clinical, serological, sonographic, and histopathological features were also collected. The numbers of IgG4 and IgG plasma cells were counted in five high power fields (HPF), then the average numbers of IgG4+ and IgG+ plasma cells per HPF were calculated respectively. Results: Based on the IgG4 and IgG immunohistochemistry results of 120 surgical specimens, cases were subclassified as IgG4 HT (n = 18) and non-IgG4 HT (n = 102) groups by the thyroid-specific diagnostic criteria (IgG4+ plasma cells > 20/HPF and IgG4+/IgG+ plasma cell ratio > 30%). CNB samples from IgG4 HT patients were subsequently subjected to IgG4/IgG immunostaining. However, only eight of the corresponding CNB tissues met the IgG4 HT diagnostic criteria. The remaining ten patients had IgG4+ positivity ranged in 10-20 cells/HPF and an IgG4+/IgG+ plasma cell ratio ranging from 20% to 67%. Histopathological characteristics of thyroid tissue were consistent between the surgical and CNB samples. Conclusion: IgG4/IgG immunostaining of CNB samples derived from thyroid tissue may serve as a valuable tool for supporting the diagnosis of IgG4 HT.

IgG4-positive Hashimoto’s thyroiditis (IgG4-HT) is an aggressive HT subtype that may be misdiagnosed as primary thyroid lymphoma (PTL) due to overlapping clinical and imaging features. This study aimed to evaluate the utility of ultrasound for non-invasive differentiation between IgG4-HT and PTL. Data from 13 IgG4-HT and 19 PTL patients (all pathology-proven) were retrospectively collected. Clinical characteristics, laboratory findings, and sonographic features were compared between the two groups. IgG4-HT patients were younger than PTL patients (40.31 ± 11.38 vs. 69.00 ± 10.25 years, P < 0.001). No significant differences in sex distribution, compressive symptoms, or thyroid function were found. On ultrasound, PTL showed larger anterior-posterior thyroid diameters (left lobe: 3.00 ± 1.29 cm vs. 1.65 ± 0.32 cm, P < 0.001; right lobe: 3.19 ± 1.24 cm vs. 1.62 ± 0.44 cm, P < 0.001), more frequent linear hyperechoic areas (89.5

Introduction and Objective: Gestational Diabetes Mellitus (GDM) has long-term implications for both maternal and child health. Our study aims to assess the awareness of these implications and explore its link to long-term cardiometabolic outcomes. Methods: 300 women from the LEGEND cohort were analyzed. Awareness was assessed via a online questionnaire including Knowledge-Attitude-Practice (KAP) three parts. Factors influencing knowledge level were analyzed. Based on the average total KAP score, participants were divided into a good (n=138) and a poor awareness group (n=162) to further assess the link between the awareness and long-term cardiometabolic health. Results: The mean age of participants was 46.1±4.3 years and a median postpartum time of 14 years. 56.3% had glucose metabolism disorders, 53.3% had hyperlipidemia, 7.7% had coronary artery calcification (CAC) and 3.3% had peripheral artery disease (PAD). The average knowledge score was 9.6 ± 7.8 (out of a total score of 22). Awareness rates of the specific long-term health impacts of GDM were as follows: impaired glucose tolerance 78.7%, metabolic abnormalities around 60% (like insulin resistance and dyslipidemia) and non-metabolic complications <50% (including cardiovascular, renal, and neurocognitive diseases). Multivariate analysis identified higher knowledge scores in women aged 30-40, with higher education or income, delivery in public hospitals, frequent GDM knowledge acquisition, excellent attitude/practice levels(P<0.05). The poor awareness group had a higher risk of diabetes (HR 1.7, 95% CI: 1.0-2.8) and composite cardiovascular disease (CAC or PAD) (HR 2.6, 95% CI: 1.2-5.6) after excluding participants with pre-existing diabetes and cardiovascular disease. Conclusion: The knowledge of long-term GDM impacts is relatively low in women with prior GDM. The poor awareness is linked to a higher diabetes and cardiovascular disease risk. Hence, strengthening health education is crucial to improve awareness and long-term cardiometabolic health. Disclosure Q. Zhang: None. Z. Zhu: None. Y. Gao: None. Y. Zhang: None.

BACKGROUND:Hashimoto thyroiditis (HT) is a prevalent autoimmune thyroid disease characterized by lymphocytic infiltration and autoantibody production. Our previous findings showed that enhancer of zeste homolog 2 (EZH2) and BACH transcriptional regulator 2 (BACH2) are upregulated in HT thyroid tissues. However, the role of EZH2 in B-cell-mediated autoimmunity remains unclear. OBJECTIVE:To investigate how EZH2 regulates B-cell responses in a spontaneous autoimmune thyroiditis (SAT) mouse model and to explore potential downstream epigenetic mechanisms, including BACH2. METHODS:A NOD.H-2h4 mouse model of SAT was used to assess the effect of the EZH2 catalytic activity inhibitor GSK126 on thyroid inflammation and B-cell responses. The human B-lymphocyte cell line GM12878 underwent EZH2 knockdown or was treated with GSK126 to evaluate BACH2 expression, H3K27me3 levels, and IgG secretion. Chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR) and luciferase assays were employed to examine EZH2-dependent regulation of BACH2, and rescue experiments were conducted using BACH2 overexpression. RESULTS:In SAT mice, GSK126 reduced thyroid lymphocytic infiltration, decreased CD19+ and IgG+ B-cell infiltration, and lowered thyroidal IgG and serum IgG levels. In vitro, pharmacological inhibition of EZH2 catalytic activity or knockdown suppressed BACH2, reduced H3K27me3, and diminished IgG secretion. Luciferase and ChIP-qPCR assays supported EZH2-dependent regulation of BACH2, and BACH2 overexpression partially restored BACH2 expression but did not fully rescue IgG production after EZH2 methyltransferase activity inhibition. CONCLUSION:EZH2 contributes to B-cell-mediated immune responses and IgG production through epigenetic mechanisms in SAT. BACH2 may represent one downstream target of EZH2, but additional pathways are likely involved.

Background Iodine is an essential trace element for pregnant women, and iodine deficiency was still reported in some areas worldwide. Shenzhen is located in southern China where is a coastal city and an iodine sufficient urban area, but there are not large-scale studies related to iodine nutrition status and thyroid function currently. Objectives The aims of our present study were to analyse the iodine nutrition status, and explore the potential associations between UIC and thyroid function during the first trimester of pregnancy in southern China. Methods In this cohort study, 14327 pregnant women during the first trimester were enrolled. Urinary Iodine Concentration (UI), Thyroid-Stimulating Hormone (TSH), Free Thyroxine (fT4), and Thyroid Peroxidase Antibody (TPOAb) were measured. The associations between thyroid function and Iodine nutrition status were estimated. Results The median UIC during the first trimester was 173.5 (118.2-247.5) µg/L, deficiency iodine status was observed in 39.3%. The UIC was negatively associated with TPO ( r= -0.034, P = 0.000). Thyroid dysfunction incidence was 32.97%, Autoimmune Thyroid Disease is the most prevalent one (52.48%). The participants with Thyroid Dysfunction showed higher age ( t= -3.856, P = 0.000) and lower UIC ( χ 2 = 26.079, P = 0.000). ≥35 years old ( β = 0.102, P = 0.041, OR = 1.108,95% CI = 1.004–1.221), severe deficiency Iodine status ( β = 0.224, P = 0.007, OR = 1.251,95% CI = 1.062–1.473) and excess Iodine status ( β=- 0.430, P = 0.000, OR = 0.651,95% CI = 0.524–0.807) were the main determinants of thyroid dysfunction in our study cohort. Conclusions There were 39.3% incidence of deficiency iodine and 32.97% incidence of thyroid dysfunction in first trimester of pregnancy in southern China, where is an iodine sufficient urban area. The UIC was negatively associated with TPO. Higher age, severe deficiency and excess Iodine status were the main determinants of thyroid dysfunction. Additional studies of the Iodine nutrition status and dietary factors that can contribute to the prevention of thyroid dysfunction diseases in pregnant women living in iodine sufficient area are needed.

BackgroundPrimary adrenal natural killer (NK)/T cell lymphoma is extremely rare with rapidly aggressive clinical manifestation and poor prognosis. Here, we report a case of NK/T-cell lymphoma with bilateral adrenal involvement and secondary ectopic adrenocorticotropin syndrome (EAS).Case presentationThis is a 56-year-old woman with main complaint of fatigue and slight weight loss. Bilateral adrenal mass, rapid progress of pancytopenia, and elevated cortisol and ACTH levels were discovered. Cushing’s syndrome was diagnosed when serum cortisol was not suppressed after 1-mg dexamethasone suppression test and low-dose dexamethasone suppression test (LDDST). Morning cortisol and ACTH levels markedly increased after 1 week, whereas the pathology of bone marrow revealed NK/T cell lymphoma, which indicated the diagnosis of EAS. After two cycles of chemotherapy, the patient died 6 months after diagnosis.ConclusionNK/T cell lymphoma should be considered in the differential diagnosis of bilateral enlarged adrenal mass and could induce ectopic ACTH syndrome. For rapid progressing malignancy, the clinical features of Cushing’s syndrome may be absent in patients with EAS.

Endocrine dysfunction is one of the most common immune-related adverse events (irAEs) reported in immune checkpoint inhibitors (ICIs) clinical trials. The aim of this research was to thoroughly assess the clinical features of endocrine irAEs, investigate the risk and predictive variables, and provide guidance for clinical therapy. This study performed a retrospective review of clinical data from 269 patients with malignant malignancies who underwent initial immune checkpoint inhibitor treatment at the First Bethune Hospital of Jilin University between May 2021 and October 2022.The incidence of endocrine irAEs was 31.6% (85/269), while the autoimmune polyendocrinopathy syndrome (APS) was observed in 1.1% (3/269). The median time for the first adverse reaction was 46 (33.5, 100.5) d. The occurrence of ICIs-related thyroid injury events was significant, with the incidence at 27.5% (74/269), whereas the frequency of grade 2 and higher adverse reactions was 33.8% (25/74). Female gender (OR = 2.723, 95 % CI: 1.447-5.125) and a history of chemotherapy (OR = 2.716, 95 % CI: 1.079-6.836) were distinct risk factors for thyroid injury associated with ICIs. In the 106/269 who had baseline antibody testing, the presence of anti-thyroglobulin antibodies (TGAb) (AUC = 0.717) and thyroid peroxidase antibody (TPOAb) (AUC = 0.690) could aid in predicting this injury, with TGAb demonstrating greater reliability. The prevalence of ICIs-related diabetes was 3.7% (10/269), with a higher occurrence in male patients compared to female patients, and the rate of grade 3 and above adverse reactions was 10% (3/10). The occurrence of ICIs-related pituitary inflammation was 1.1% (3/269), primarily involving pituitary hormones such as thyroid stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH). The incidence of ICIs-related adrenocortical hypofunction was 0.4% (1/269), with a grade 3 adverse event. The antibody testing was performed in a nonrandom subset and thus the predictive AUC results might be affected by bias.

ARTICLE HIGHLIGHTS:Previous studies have identified heterogeneity among prediabetes subgroups using clinical characteristics; however, biological and metabolic heterogeneity remains insufficiently captured. This study examined whether data-driven clustering based on metabolomic biomarkers could define distinct prediabetes subtypes with differential type 2 diabetes, cardiovascular disease, and chronic kidney disease risk. Using 16 metabolomic biomarkers, we identify three metabolically distinct clusters showing progressively higher risks of incident type 2 diabetes, cardiovascular disease, and chronic kidney disease. Differential diet-cluster associations across clusters were obtained, and Mendelian randomization supported potential causal roles for several metabolomic biomarkers. Metabolomics-based stratification may improve risk prevention and enable cluster-specific dietary interventions in prediabetes.

ABSTRACT Background Glycated albumin (GA) has already been introduced in clinic for decades. However, it remains unclear whether routine measurement of GA could serve as a practical tool to improve the care of patients with type 2 diabetes (T2DM). Methods This multicenter, randomized controlled trial enrolled 200 patients with newly diagnosed, poorly controlled type 2 diabetes from seven sites in China. Participants were randomly assigned (1:1) to either GA‐guided therapy (treatment intensification if GA > 16% at 4 weeks) or standard therapy, with a 12‐weeks follow‐up. The primary outcome was the proportion of patients achieving HbA1c < 7%; secondary outcomes included HbA1c < 6.5%, glycemic parameters, hypoglycemia, and β‐cell function. Results A total of 200 patients were included in this study. Therapy compliances were 97.4% (SD, 5.3%) and 98.0% (SD, 8.2%) in the GA‐guided therapy group and standard therapy group, respectively. There was no significant difference in the achievement rate of HbA1c (< 7%) between the GA‐guided therapy group (64.3%) and the standard therapy group (64.4%) after the 12‐week follow‐up (p = 0.99). In the secondary outcome, the achievement rate of HbA1c (< 6.5%) was higher in the GA‐guided therapy group than in the standard therapy group (40.5% vs. 25.3%, p = 0.034). Furthermore, the changes in HbA1c, HOMA‐β, HOMA‐IR, body weight reduction were all better in the GA guided therapy group than in standard therapy group. Conclusion GA‐guided therapy did not enhance HbA1c < 7% achievement; however, its potential benefits for more stringent glycemic targets and metabolic parameters in early diabetes management deserve further investigation. Trial Registration: ClinicalTrials.gov: NCT05227677

BACKGROUND:Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) were recognized to cause endocrine adverse reactions (EARs). However, combination therapy-associated EARs are still unclear. METHODS:This was a retrospective study based on the FDA Adverse Event Reporting System. We identified 938 464 cases of all adverse events related to 3 types of treatments. A total of 22 275 cases were EARs and divided into TKIs (n = 9181), ICIs (n = 11 363), and TKIs + ICIs group (n = 1731). RESULTS:The incidence of EARs was the highest in TKIs + ICIs followed by the ICIs and TKIs group. The TKIs + ICIs group had a higher risk of hypothyroidism than the ICIs group [odds ratio (OR) 1.47, 95% confidence interval (CI) 1.28-1.69] and a lower risk compared to the TKIs group (OR 0.68, 95% CI 0.58-0.79). The TKIs + ICIs group presented a higher risk of type 1 diabetes mellitus compared to the TKIs group (OR 26.61, 95% CI 18.60-38.07) but a lower risk compared to the ICIs group (OR 0.63, 95% CI 0.47-0.84). The risk of hypoglycemia was approximately 2.77 times greater in the TKIs + ICIs group than in the ICIs group (OR 2.77, 95% CI 1.95-3.95) and was also higher in the TKIs group compared to the ICIs group (OR 3.44, 95% CI 2.93-4.03). Compared to the ICIs group, the TKIs + ICIs group did not display a higher risk of pituitary dysfunction and primary adrenal insufficiency. The mortality risk of the TKIs + ICIs group was comparable to the ICIs group but was significantly lower than the TKIs group. CONCLUSION:EARs were more common in TKIs + ICIs therapy. The distribution of EARs in different glands varied among combination therapy and monotherapy. Combination therapy-associated EARs did not increase the risk of mortality.