AIM:To explore the association of GLP-1 receptor agonists (GLP-1 RAs) with the risk of psychiatric disorders. METHODS:A systematic search was performed in PubMed, EMBASE, Cochrane Library and Web of Science (inception to June 13, 2025). Randomised clinical trials (RCTs) that compared the use of GLP-1 RAs with either placebo or other non-GLP-1 RAs treatments were included. Psychiatric disorders were collected based on reported treatment-emergent adverse events. Following PRISMA guidelines, two reviewers independently extracted data and evaluated the quality of each study using the Cochrane tool. Evidence quality was assessed using the GRADE framework. RESULTS:A total of 133 378 participants were included across 86 RCTs. No significant statistical difference was found in the incidence of psychiatric disorders between the GLP-1 RAs group and the control group (RR, 0.96; 95% CI, 0.85-1.08; I2 = 0%; ARD, -9 per 10 000 persons/year). GLP-1 RAs treatment was not associated with depression (RR, 0.88; 95% CI, 0.70-1.10), suicide (RR, 0.90; 95% CI, 0.59-1.38), anxiety (RR, 0.92; 95% CI, 0.72-1.19), sleep disorder (RR, 0.98; 95% CI, 0.70-1.37), bipolar disorder (RR, 1.19; 95% CI, 0.56-2.55), delirium (RR, 1.11; 95% CI, 0.74-1.66), addictive disorder (RR, 0.89; 95% CI, 0.45-1.77) or schizophrenia (RR, 1.45; 95% CI, 0.61-3.47). No statistically significant associations were observed for drug type, indication, dose, treatment duration, comparator type, baseline BMI, trial designation, age, inclusion of baseline psychiatric disorders or reporting category. Meta-regression analyses revealed no significant effect of changes in fasting blood glucose, haemoglobin A1c, weight or BMI on the risk of psychiatric disorders. CONCLUSION:GLP-1 RAs use was not associated with the risk of psychiatric disorders, including depression, suicide or anxiety. TRIAL REGISTRATION:PROSPERO Identifier: CRD42024546896.

[This corrects the article DOI: 10.3389/fendo.2025.1700349.].

Purpose:Glucose-dependent insulinotropic polypeptide (GIP) plays a crucial role in lipid metabolism. The effect of GIP on pancreatic lipid and whether it modulates risk of type 2 diabetes (T2D) associated with fatty pancreas remain unknown. The aim of this study was to investigate the interaction between genetically predicted GIP levels and fatty pancreas in the development of T2D. Methods:This is a large-scale cohort study using data from the UK Biobank. Participants of White ethnicity without diabetes at the imaging visit were included in the analysis. The loss-of-function GIPR variant E354Q was used for the prediction of fasting GIP levels, and a polygenic risk score (PRS) of postprandial GIP was used for the prediction of postprandial GIP levels. The presence of fatty pancreas disease (FPD) was determined with magnetic resonance imaging (MRI). Diagnosis of T2D was ascertained based on ICD10-CM diagnosis code E11. During a median follow-up of 51 months, 276 cases of incident T2D were identified. Results:A significant interaction between the carrying status of E354Q and FPD (p for interaction = 0.018) and between 2hGIP PRS and FPD (p for interaction = 0.015) in the development of T2D was found. FPD is associated with a greater increase of risk of T2D in individuals without E354Q [hazard ratio (HR) 2.44, 95% confidence interval (CI) 1.78-3.34] or with higher levels of genetically predicted postprandial GIP (HR 2.64, 95% CI 1.86-3.76). Conclusion:Our findings show that genetically predicted GIP modifies risk of T2D associated with FPD, suggesting that GIP may play a role in linking pancreatic fat accumulation to metabolic dysfunction. These findings are derived from genetically predicted rather than measured GIP.

BACKGROUND:The Lancet Commission redefined obesity by integrating body mass index (BMI) and anthropometric measures, but it remains unclear if they better identify risk for cardiovascular-kidney-metabolic (CKM) syndrome. We aim to compare the CKM risk and all-cause mortality predicted by these new criteria against traditional BMI-based criteria. METHODS:Using Cox models to investigate the associations between different obesity phenotypes, which were normal weight, Anthropometric excess adiposity & Traditionally-defined non-obesity, Traditionally-defined obesity & Non-anthropometric excess adiposity, and excess adiposity by both criteria, with Anthropometric excess adiposity by the anthropometric criteria alone, Traditionally-defined obesity by BMI alone, and CKM syndrome and mortality in the UK Biobank. We further compared whether the anthropometric diagnostic sub-categories were associated with different levels of risk. RESULTS:Among 352 740 participants (mean age 56.8 years; 56% female) with a median follow-up of 13.2 years, compared to normal weight, the "Anthropometric excess adiposity & Traditionally-defined non-obesity" (HR 1.55, 95% CI 1.52-1.59) and "Traditionally-defined obesity & Non-anthropometric excess adiposity" (HR 1.61, 95% CI 1.29-2.02) exhibited similarly elevated risks for CKM syndrome. Those meeting both criteria had the highest risk (HR 2.61, 95% CI 2.56-2.66) for CKM syndrome. Anthropometric excess adiposity had an increased CKM risk (HR 2.00, 95% CI 1.96-2.04), which was lower than that for Traditionally-defined obesity (HR 2.45, 95% CI 2.41-2.49). Among the anthropometric sub-categories, the three BMI-inclusive definitions yielded similar HRs for CKM risk, which were higher than those of Traditionally-defined obesity and the non-BMI sub-categories. CONCLUSION:By incorporating central adiposity, the anthropometric criteria improve CKM risk stratification by identifying high-risk individuals overlooked by traditional standards, especially those with adverse body composition despite lower BMI.

BACKGROUND:Cardiovascular-kidney-metabolic (CKM) syndrome is closely associated with a wide range of adverse health outcomes, yet its relationship with sarcopenia remains poorly defined. This study aimed to investigate the association between CKM syndrome and incident sarcopenia and to further evaluate its impact on sarcopenia state transitions. METHODS:We analyzed UK Biobank data from 47,431 participants without sarcopenia at baseline and with complete CKM risk factor. Kaplan-Meier method and Cox proportional hazards models were applied to evaluate the association between CKM stages and the incidence of sarcopenia, with subgroup and sensitivity analyses conducted. Additionally, 49,905 participants with complete baseline sarcopenia assessments were included in a multi-state Markov model to estimate the impact of CKM stages on transition probabilities and intensities among non-sarcopenia, possible sarcopenia, confirmed sarcopenia, and death. RESULTS:Kaplan-Meier curves demonstrated a gradual increase in the cumulative incidence of sarcopenia with advancing CKM stages (P < 0.0001). In fully adjusted Cox regression models, CKM stage 4 was associated with higher risks of developing probable sarcopenia (HR, 1.22; 95% CI, 1.07-1.39) and confirmed sarcopenia (HR, 1.68; 95% CI, 1.02-2.77). No significant interactions were found in subgroup analyses, and sensitivity analyses supported the robustness of the findings. In the multi-state Markov model, compared with participants in CKM stage 0, those in CKM stages 2-3 and 4 had a lower hazard of recovery from possible sarcopenia to non-sarcopenia (HR 0.55; 95% CI 0.46-0.67 and HR 0.50; 95% CI 0.36-0.68, respectively). Additionally, higher CKM stages were associated with greater probabilities of progression to more severe sarcopenia states. CONCLUSIONS:In this longitudinal cohort study, more advanced CKM stages were associated with a higher risk of incident sarcopenia and with less favorable trajectories of sarcopenia state transitions. Early identification and management of CKM may help prevent the onset of sarcopenia and attenuate its progression to more severe states.

BackgroundType 2 diabetes mellitus (T2DM) is a major global health challenge due to high cardiovascular risk. Sodium-glucose cotransporter 2 (SGLT2) inhibitors can offer glycemic and cardiorenal benefits. Most agents are available in low and high doses, with the assumption that higher doses improve glycemic control. However, previous evidence shows only marginal hemoglobin A1c (HbA1c) reduction (≈0.08–0.18%) with high doses, raising uncertainty about their clinical necessity. Patient factors such as baseline HbA1c and renal function influence SGLT2 efficacy, but whether these factors modify dose response remains unclear. This study evaluates dose-dependent effects across HbA1c and renal function strata.ObjectiveTo assess the glycemic impact of high- versus low-dose SGLT2 inhibitors in T2DM, stratified by HbA1c and renal function.MethodsThis analysis followed PRISMA guidelines (PROSPERO ID: CRD42024605351). PubMed, the Cochrane Library, and EMBASE were systematically searched for randomized controlled trials involving SGLT2 inhibitors in adults with T2DM through November 24, 2024. The primary outcome was change in glycated hemoglobin, stratified by hemoglobin A1c (HbA1c) and glomerular filtration rate (GFR) levels. Subgroup analyses were performed based on different SGLT2 inhibitors and dosages.ResultsA total of 23 studies were included for the meta-analysis. Seventeen studies (n = 7,021) were stratified by HbA1c, and eight (n = 7,998) by GFR. Overall, high-dose SGLT2 inhibitors showed a slightly better glycemic control than low-dose SGLT2 inhibitors, with an additional 0.08% (95%CI: -0.12, -0.04) reduction in HbA1c levels. High-dose vs. low-dose SGLT2 inhibitors showed a 0.06%-0.16% further HbA1c reduction across varying glycemia levels (with HbA1c under or over 8%, 8.5%, 9%) and a change in HbA1c levels ranging from -0.07% to 0.04% across varying GFR levels (with GFR under or over 45, 60, 90 ml/min/1.73m2).ConclusionDose escalation had minimal effect on HbA1c across glycemic and renal strata; higher doses of SGLT2 inhibitors offer limited additional benefit for glycemic control in poorly controlled T2DM.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024605351.

Metabolic dysfunction-associated steatotic liver disease (MASLD), also termed non-alcoholic fatty liver disease (NAFLD), represents the predominant chronic hepatic condition globally, yet remains without successful drug-based interventions. Understanding the molecular mechanisms driving MASLD progression is crucial. DDR2, a recently identified receptor tyrosine kinase, participates in various physiological processes including extracellular matrix remodeling, cell adhesion, and fibrosis. Given that MASLD pathogenesis involves lipid accumulation, inflammation, and progressive fibrotic remodeling of the liver, DDR2 signaling may play a critical role in linking extracellular matrix dynamics to metabolic and inflammatory pathways. However, its precise contribution to MASLD development and progression remains undefined, underscoring the need for mechanistic studies to clarify DDR2's role and potential as a candidate modulator. DDR2 expression was assessed in liver tissues from both hepatic steatosis and genetically obese mice. RT-qPCR, Western blotting, and Oil Red O staining were utilized to examine DDR2's role in lipid synthesis within hepatocytes under both cellular and animal models. The impact of DDR2 on MASLD were examined by utilizing db/db mice alongside C57BL/6J mice fed a high-fat diet (HFD). Hepatic DDR2 expression was markedly diminished in HFD-fed and db/db mice relative to controls. DDR2 overexpression resulted in diminished hepatic triglyceride accumulation and downregulated lipid synthesis-related gene expression in vitro and in vivo, whereas DDR2 knockdown exhibited the opposite effect. Mechanistically, DDR2 overexpression enhanced AMPK/ACC phosphorylation in hepatocytes, while its knockdown suppressed these pathways, findings corroborated by the use of AMPK inhibitors and agonists. DDR2 suppresses hepatocyte lipogenesis via activation of the AMPK/ACC pathway, suggesting its prospective role as a potential regulator in MASLD management.

ObjectiveAlthough an insulin-to-C-peptide molar ratio greater than 1 has traditionally been considered suggestive of insulin autoimmune syndrome (IAS), its diagnostic value remains controversial, and the optimal cutoff is unclear. This study aimed to evaluate the diagnostic performance of the insulin-to-C-peptide molar ratio for distinguishing IAS and exogenous insulin antibody syndrome (EIAS) from insulinoma and to identify the optimal diagnostic cutoff.MethodsWe retrospectively collected clinical and biochemical data from 19 patients with IAS, 33 with EIAS, and 70 control patients with pathologically confirmed insulinoma. Receiver-operating-characteristic (ROC) curve analysis was performed separately for IAS versus insulinoma and EIAS versus insulinoma to assess the diagnostic performance of the insulin-to-C-peptide molar ratio in the fasting state and during hypoglycemic episodes.ResultsThe insulin-to-C-peptide molar ratio was significantly higher in IAS and EIAS than in insulinoma at both fasting and during hypoglycemic episodes. During hypoglycemic episodes, the area under the ROC curve (AUC) was 0.970 for IAS versus insulinoma and 0.944 for EIAS versus insulinoma, with optimal cutoffs of 0.382 and 0.552, respectively. In the fasting state, the corresponding AUCs were 0.916 and 0.961, with optimal cutoffs of 0.309 and 0.386. Compared with the conventionally used cutoff of 1, the optimal cutoffs substantially improved sensitivity while maintaining high specificity, particularly for IAS. Insulin concentration alone also showed good diagnostic performance for distinguishing IAS from insulinoma, with AUCs of 0.985 and 0.943 and optimal cutoffs of 83.1 and 58.86 μIU/mL during hypoglycemic episodes and in the fasting state, respectively, but was less informative for EIAS, with AUCs of 0.853 and 0.729 and optimal cutoffs of 67.85 and 71.94 μIU/mL, respectively.ConclusionThe insulin-to-C-peptide molar ratio, measured either during hypoglycemic episodes or in the fasting state, showed good diagnostic performance for distinguishing IAS and EIAS from insulinoma. The conventionally used cutoff of 1 appears to be too high, and lower cutoffs may provide better sensitivity while preserving specificity. Validation in larger cohorts is needed.

Mitochondrial diabetes mellitus (MDM) is a genetically heterogeneous disorder caused by mitochondrial DNA (mtDNA) or nuclear DNA mutations, characterized by multi-system involvement and diverse clinical phenotypes. We report a pediatric case presenting with growth retardation followed by subsequent development of diabetes mellitus. Systematic evaluation revealed concurrent bilateral sensorineural hearing loss, bilateral basal ganglia calcification, and electroencephalographic abnormalities. A post-exercise lactate test demonstrated significant elevation of serum lactate levels immediately after physical exertion. Genetic analysis identified a large-scale mitochondrial DNA deletion spanning from m.8649 to m.16084. This case report is complemented by a literature review focusing on the pathogenesis, genetic characteristics, and therapeutic approaches of mitochondrial diabetes, with particular emphasis on mitochondrial disorders exhibiting large-scale mtDNA deletions alongside diabetic manifestations. Our comprehensive analysis aims to enhance clinical understanding and inform diagnostic strategies for this complex disease entity.

To evaluate the association of sodium-glucose cotransporter 2 inhibitors (SGLT2i) with diabetic ketoacidosis (DKA) in type 2 diabetes mellitus (T2DM) patients across different subgroups, we searched randomized controlled trials (RCTs) comparing SGLT2i with the control groups among T2DM patients and including DKA as a safety outcome. Pooled risk ratios (RRs) were calculated using random or fixed-effects models, as appropriate. An inverse-variance-weighted Mendelian randomization (MR) analysis was performed to estimate the genetic correlation. Twenty-two trials involving 80,235 patients were included. SGLT2i increased the risk of DKA compared to the control groups (RR 2.32, 95% CI 1.64-3.27). The risk was significantly increased in patients with higher HbA1c levels (> 7.9%) (RR 2.24, 95% CI 1.59-3.14), but not in those with lower HbA1c levels (≤ 7.9%) (RR 1.05, 95% CI 0.49-2.26; interaction P = 0.034). SGLT2i increased DKA risk in chronic kidney disease (CKD) (RR 2.70, 95% CI 1.55-4.71) and high atherosclerotic cardiovascular disease (ASCVD) risk trials (RR 2.46, 95% CI 1.47-4.11) but not significantly in heart failure (HF) trials (RR 1.23, 95% CI 0.51-2.96). Moreover, in the HF trials, SGLT2i consistently did not increase the risk of DKA in any clinical subgroups. Nevertheless, MR analysis still confirmed a genetic association between SGLT2i and the risk of DKA among overall T2DM patients. SGLT2i may increase the risk of DKA in T2DM patients, particularly in patients with higher levels of HbA1c and those with comorbid CKD or at high-risk ASCVD. However, the increased risk was not significant in patients with HF.

BACKGROUND:The aim of this study was to investigate the longitudinal associations between the body size trajectory and the cardio-renal-metabolic (CRM) conditions in adulthood, and evaluate the joint association between body size trajectory and polygenic risk scores (PRS) of CRM conditions. METHODS:This prospective cohort study included 441 470 UK Biobank participants aged 40 to 70 years, recruited between March 2006 and July 2010. CRM conditions were defined as the occurrence of any of cardiovascular disease (CVD), chronic kidney disease (CKD), and type 2 diabetes (T2D). Cox regression models and Fine-Gray sub-distribution hazard models were used to estimate associations and competing risks of mortality. Mediation analysis and group-based trajectory modeling were performed to assess mediation effects and body size change trajectories. Additionally, interaction analyses were conducted to examine the combined effects of between the body size trajectories and PRS on CRM conditions. RESULTS:The incidence density of CRM conditions was 128.9 per 1000 person-years. Adulthood overweight/obesity mediated the association between childhood plumper body size and CRM conditions (mediation proportion = 55.82%, P < 0.0001). Five trajectories of body size from birth to adulthood were identified, and the other four trajectories differing from the "normal-average-normal" trajectory were associated with increased risks of CRM conditions, with hazard ratio (HR) and 95% confidence interval (CI) ranging from 1.20 (1.15, 1.26) to 1.32 (1.28, 1.37). Intermediate and high genetic risk groups demonstrated elevated risks of CVD, CKD, and T2D, and the additive interactions were found between body size trajectories and PRS on CKD and T2D. CONCLUSIONS:Maintaining a normal body size across the life cycle, even with intermediate or high genetic risk, may help mitigate the impact of genetic risk. Early monitoring and interventions aimed at sustaining a normal body size throughout life could provide life-course benefits in preventing CRM conditions, particularly for individuals with elevated genetic risk. GRAPHICAL ABSTRACT:

Background Limited data exist on the association of glucagon‐like peptide 1 receptor agonists (GLP‐1RAs) with the risk of venous thromboembolism. This meta‐analysis aimed to investigate the association between GLP‐1RAs and the risk of venous thromboembolism including deep vein thrombosis (DVT) and pulmonary embolism. Methods and Results A systematic search of PubMed, Web of Science, EMBASE, and Cochrane library was conducted from inception until July 3, 2024, to identify randomized controlled trials comparing GLP‐1RAs with placebo or other anti‐iabetic drugs, with reported data on DVT and pulmonary embolism. The primary outcome was venous thromboembolism, and secondary outcomes included DVT and pulmonary embolism. Pooled odds ratios (ORs) were calculated using fixed‐effects models with Mantel–Haenszel method and treatment arm continuity correction for zero‐event trials. A total of 39 randomized controlled trials involving 70 499 participants were included. A nonsignificant upward trend in the risk of venous thromboembolism was observed among participants using GLP‐1RAs (OR, 1.19 [95% CI, 0.94–1.50]). GLP‐1RAs were significantly associated with an increased risk of DVT (OR, 1.64 [95% CI, 1.14–2.36]); risk difference 25 (5–52) more events per 10 000 person‐years). Subgroup analyses revealed that increased risk of DVT was particularly prominent in randomized controlled trials with treatment duration >1.5 years (OR, 2.32 [95% CI, 1.49–3.60]) and in cardiovascular outcome trials (OR, 2.18 [95% CI, 1.36–3.49]). No significant association was observed between GLP‐1RAs and risk of pulmonary embolism. Conclusions GLP‐1RAs might increase the risk of DVT, especially for long‐term use of GLP‐1RAs. Clinicians should be aware of this potential risk when prescribing GLP‐1RAs.

Disclosure: R. Xiong: None. Y. Yang: None. Y. Li: None. H. Zhang: None. Aims: The study aimed to evaluate the glycemic-lowering efficacy of sodium glucose transporter 2 (SGLT2) inhibitors with high and low dose in patients with T2DM stratified by HbA1C and renal function. Materials and methods: This study followed the PRISMA guidelines (PROSPERO ID: 605351). PubMed, Cochrane Library, and EMBASE were searched for RCTs on SGLT2 inhibitors in adult type 2 diabetes patients up to June 16, 2024. Key outcomes of the studies were changes in glycated hemoglobin, stratified by hemoglobin A1c (HbA1c) and glomerular filtration rate (GFR) levels. Subgroup analyses were performed based on different SGLT2 inhibitors and dosages. Results: A total of 24 studies were included for the meta-analysis. 18 studies involving 9818 participants were used for HbA1c stratification, while 8 studies with 6839 participants were used for GFR stratification. Overall, high-dose SGLT2 inhibitors showed a slightly better glycemic control than low-dose SGLT2 inhibitors, with an additional 0.10% reduction in HbA1c levels. High-dose vs. low-dose SGLT2 inhibitors showed a 0.10%-0.13% further HbA1c reduction across varying glycemia levels (with HbA1c under or over 8%, 8.5%, 9%) and a change in HbA1c levels ranging from -0.06% to 0.09% across varying GFR levels (with GFR under or over 45, 60, 90 ml/min/1.73m²). Conclusions: Our study suggested that dosage alterations had little clinically meaningful impact on reduction in glycation levels in patients with different glucose levels or renal function statuses. Therefore, high-dose SGLT2 inhibitors are not necessary for glycemic control in patients with poorly controlled T2DM. Presentation: Sunday, July 13, 2025

Aims: This cross-sectional study is aimed at determining whether systemic inflammation, diabetic autoantibodies, and islet β cell dysfunction play a role in the progression of macrovascular complications in patients with autoimmune diabetes. Methods: 202 patients with autoimmune diabetes aged ≥ 35 years and hospitalized in Peking Union Medical College Hospital were enrolled in this study. The patients were divided into three groups based on the severity of peripheral atherosclerosis. Biomarkers of systemic inflammation, diabetes autoantibodies, islet β cell function, and other covariates validated to be associated with macrovascular complications were collected. Correlations between the severity of peripheral atherosclerosis and systemic inflammation, diabetic autoantibodies, and islet β cell function were examined using an ordinal logistic regression model. Results: Of the enrolled patients, 39.1% were male, with a median age of 53 (43, 60) years and a diabetes duration of 96 (36, 216) months. 58 patients had no lesions in the peripheral arteries, 72 had atherosclerosis in the carotid or lower extremity arteries, and the rest had lesions in both arteries. In the multifactor ordinal logistic regression test, positive islet cell cytoplasmic antibody (ICA) and long-term use of lipid-lowering agents were independently associated with peripheral atherosclerosis after adjusting for age and diabetes duration. Conclusions: The correlation between positive ICA and atherosclerosis suggests inflammation at an early stage plays a role in macrovascular complications in autoimmune diabetes. The association between long-term use of lipid-lowering agents and atherosclerosis suggests the need for early screening and intervention for dyslipidemia in patients with autoimmune diabetes.

Rationale: The association between Barrier to Autointegration Factor 1 (BANF1) and various human diseases has been recently reported. However, its role and mechanism in colorectal cancer (CRC) initiation and progression remain unexplored. Methods: This study examined BANF1 expression in CRC tissues and cells using bioinformatics databases, PCR, Western Blot (WB), and immunohistochemistry (IHC). The role of BANF1 in the initiation and progression of CRC was evaluated through both in vitro and in vivo experiments. RNA sequencing was employed to explore potential mechanisms, which were subsequently validated experimentally. Furthermore, a database-driven approach predicted an upstream protein interacting with BANF1, and its role in CRC was validated. Results: BANF1 expression was found to be elevated in both CRC cell lines and tissues, establishing BANF1 as an independent prognostic factor for CRC patients. Experiments conducted both in vitro and in vivo revealed that BANF1 influences CRC phenotypes through the regulation of GLI1 expression. Bioinformatics analyses predicted an interaction between BANF1 and vaccinia-related kinase 1 (VRK1), which was confirmed through functional validation. VRK1 was identified as an upstream regulator of BANF1, interacting with it at the protein level to influence CRC phenotypes. Conclusion: The study offers insights into CRC's molecular mechanisms and proposes targeting the VRK1/BANF1/GLI1 axis as a potential therapeutic strategy. This method could result in more effective treatments for advanced CRC.

Insulin autoimmune syndrome (IAS) is a rare autoimmune disorder characterized by spontaneous hypoglycemia. The incidence of IAS is higher in East Asian populations compared to other populations. Delayed diagnosis and treatment can lead to recurrent hypoglycemia, significant glucose fluctuations, and adverse clinical outcomes, including life-threatening situations. Currently, no standardized guidelines exist for the diagnosis and treatment of IAS. This consensus aims to provide a systematic summary of the epidemiology, triggers, pathogenesis, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of IAS, with the objective of standardizing its clinical management.

BackgroundRemnant cholesterol (RC) has been implicated in cardiovascular and metabolic disorders, but its direct associations with biological aging remain unclear. We aimed to examine the relationship between RC and two established aging biomarkers, leukocyte telomere length (LTL) and serum α−Klotho, and to evaluate the potential mediating roles of inflammation and oxidative stress.MethodsThis cross-sectional analysis included 1052 adults from a rural cohort in northern China. Linear regressions and restricted cubic splines (RCS) assessed linear and nonlinear relationships. Mediation models explored the mediating effect of inflammation (TNFα, IL-6, IL-1β) and oxidative stress markers (SOD, 8-OHdG).ResultsParticipants with higher RC levels had lower LTL and α-Klotho levels, along with higher levels of TNFα, IL-6, IL-1β, and SOD. In adjusted linear regression, RC showed negative associations with both LTL and α-Klotho (β[95%CI]: -0.177[-0.262, -0.091] and -0.045[-0.066, -0.024]), independent of conventional lipid profiles. Both relationships were nonlinear (P for nonlinear = 0.001 for LTL; 0.019 for α-Klotho). For LTL, the inverse association was confined to 0.65-1.42 mmol/L (no significant associations outside this range), while for α-Klotho it was observed only below 1.37 mmol/L (no associations above it). TNFα and IL-6 partially mediated the relationship between RC and LTL (17.78% and 14.12%, respectively); while SOD partially mediated the association between RC and α-Klotho (58.18%).ConclusionsRC is inversely and nonlinearly associated with both LTL and α-Klotho, independent of traditional lipid profiles, with inflammation and oxidative stress as partial mediators. From an aging perspective, these cross-sectional findings support increased attention to early RC management alongside traditional lipids.

OBJECTIVE:To investigate the relation of glycemic and lipid metabolism with brain structure and cognitive function in people with diabetes, so as to improve cognitive function in these individuals. METHODS:Based on the UK Biobank, 26,394 patients, who were diagnosed with diabetes by doctors between 2006 and 2010, were included in the study. The demographic information, clinical data of glycemic and lipid metabolism and cognitive function (brain MRI and cognitive function scores) were collected. Multiple linear regression and non-restricted cubic spline analyses were used to investigate the relations of glycemic and lipid metabolism with brain structure and cognitive function. RESULTS:In this study, the mean age of people with diabetes (containing 39 % females) was 59.58 ± 7.21 years. Higher random blood glucose (β = -0.116, p < 0.001) and glycosylated hemoglobin (HbA1c) (β = -0.062, p = 0.051) were associated with a smaller brain volume. Higher HbA1c (β = 0.036, p < 0.001; β = 0.023, p = 0.021) was related with worse cognitive function. Further analysis showed that HbA1c < 6.5 % had a protective effect on cognitive function, and HbA1c = 6.5 %∼8.5 % and >8.5 % was unrelated and negatively related with cognitive function, respectively. Different types of lipids had varying effects on cognitive function. Higher total cholesterol (TC) (β = 0.125, p = 0.008), low density lipoprotein-cholesterol (LDL-C) (β = 0.086, p = 0.025), and ApoB (β = 0.092, p = 0.026) were associated with more significant brain structural abnormalities. Conversely, triglyceride (TG) = 0.75∼8.0 mmol/L was positively correlated with cognitive function (β = -0.036, p < 0.001; β = -0.044, p < 0.001; β = 0.058, p = 0.001), and higher ApoA (β = -0.032, p < 0.001; β = -0.033, p < 0.001; β = 0.047, p = 0.004) was associated with better cognitive function. The age-stratified analysis revealed that the impact of lipids on cognitive function was age-dependent. TC and LDL-C were related to brain structural abnormalities in the 55-60 age group, while TG had a stronger protective effect on cognitive function in older adults, particularly those aged 65-70 years. CONCLUSION:In people with diabetes, higher HbA1c (>8.5 %), as well as elevated TC, LDL-C, and ApoB, are associated with worse brain structure and cognitive function. Conversely, HbA1c < 6.5 % and elevated TG within the range of 0.75∼8.0 mmol/L have a protective effect on cognitive function, and the later exhibited more evident impact in older adults. To prevent or delay the onset of dementia in people with diabetes, it may be necessary to intensify glycemic control, targeting an HbA1c level of <6.5 %. Additionally, the age-specific lipid-lowering strategies shall be considered, with more flexible triglyceride-lowering goals for elderly patients.

Micronutrient intake can modulate aging biology. α‑Klotho, a circulating anti-aging protein, exerts protective effects against age-related decline and disease. However, links between specific micronutrients and serum α‑Klotho remain poorly explored. In this cross-sectional study, we analyzed 898 participants aged 18–84 years from rural communities in Changping, Beijing, China, to assess associations between energy-adjusted micronutrient intakes (per 100 kcal) and serum α-Klotho (modeled as log-transformed). Using a single 24-hour recall, intakes of 15 micronutrients were quantified, including total vitamin A, thiamine, riboflavin, vitamin C, vitamin E, phosphorus, potassium, calcium, magnesium, zinc, sodium, iron, selenium, copper, and manganese. Multivariable linear regression showed no significant associations between any micronutrients and serum α-Klotho in the overall population (all P > 0.05). In contrast, restrictive cubic spline analysis identified an inverted U-shaped association between iron intake and serum α-Klotho (P for nonlinear = 0.002), with a turning point at 1.863 mg/100 kcal. Below this threshold, iron intake was positively associated with α-Klotho (β: 0.045; P = 0.011), whereas above it the association was negative (β: -0.018; P = 0.035). The nonlinear pattern was evident in women and in participants aged < 60 years (P for nonlinear = 0.024 and 0.007, respectively), with similar turning points (1.908 and 1.906 mg/100 kcal, respectively). Inadequate iron intake was more prevalent in these subgroups than overall (60.8