Objectives:This randomised controlled trial assessed the effectiveness and safety of weekly 56.5 μg teriparatide (SAL056) compared to alendronate in postmenopausal women in China with osteoporosis at high risk of fractures over 48 weeks. Methods:This phase 3, multicentre, randomised, open-label, active-controlled, parallel-group, non-inferiority trial enrolled postmenopausal women aged 45-80 years with osteoporosis at 37 centres in China. Participants were randomised (1:1) to receive either subcutaneous teriparatide 56.5 μg weekly or 70 mg oral alendronate weekly for 48 weeks, with the primary efficacy assessment at Week 48. Results:Between November 2021 and September 2023, 493 patients were enrolled (243 in the teriparatide group and 250 in the alendronate group). The primary endpoint, lumbar spine bone mineral density (BMD) at L1-L4, showed a significantly greater increase in the teriparatide group compared to the alendronate group at Week 48 (5.01% vs. 4.20%, mean difference 0.80%, P = 0.025). Sensitivity analysis confirmed these results. At Weeks 24 and 48, teriparatide also resulted in higher hip BMD than alendronate (1.50% vs. 1.46%, P > 0.05 and 3.27% vs. 1.67%, P < 0.001). Procollagen type 1 N-terminal propeptide (P1NP) levels in the teriparatide group increased transiently at Week 12, then declined toward baseline by Weeks 24 and 48, and a decrease in serum cross-linked c-terminal telopeptide of type I collagen (S-CTX) levels from baseline to the end of treatment. Meanwhile, in the alendronate (a typical bone resorption inhibitor) group, CTX level remained continuously suppressed from the baseline. Clinical fracture rates were lower in the teriparatide group than in the alendronate group at Weeks 24 (1.2% vs. 2.8%, P > 0.05) and 48 (1.7% vs. 4.0%, P > 0.05). Teriparatide was generally safe and well tolerated. Conclusions:Teriparatide (56.5 μg once weekly) was more effective than alendronate in treating postmenopausal osteoporosis with a high fracture risk, significantly increasing L1-L4 BMD over 48 weeks. It was safe, well tolerated, and had a safety profile similar to that of Teribone®. The translational potential of this article:This study demonstrates that once-weekly teriparatide significantly improves bone mineral density and reduces fracture risk in postmenopausal osteoporosis patients. As a patient-friendly alternative to daily injections, it may enhance adherence and inform clinical guidelines, representing a promising strategy for patients and healthcare systems.

Aims The purpose of this study was to explore the molecular mechanism of circRNA mediated colonic hypersensitivity in rats with diabetes.Methods Intraperitoneal injection of streptozocin female rats was used to induce Type 1 Diabetes Mellitus. A combination of molecular biology and behavioral approaches was used to investigate the role of circRbfox1 in the pathogenesis of colonic hypersensitivity in diabetic rats.Results A new circular RNA-Rbfox1, derived from the host gene encoding RNA-Binding Protein Fox1, as a mechanism of visceral pain is identified. We confirmed that circRbfox1 remarkably upregulated in T13-L2 dorsal root ganglions in rats with diabetes, and could interact with the RNA-binding protein HuC to promote its transition from the cytosol into the nucleus to promote the translation level of RBFOX1. In addition, the increased expression of Rbfox1 could further promote colonic hypersensitivity in diabetic rats by regulating the expression of Cav1.3.Conclusions We conclude that circRbfox1 serves as pain regulator in diabetic colonic hypersensitivity and provides a potential therapeutic target in clinic.

Diabetic encephalopathy (DE), a severe complication of diabetes, is characterized by cognitive decline and neuroinflammation, in which astrocytes play a critical role. YTHDF2, an m6A reader protein, has been implicated in regulating inflammatory processes. This study investigated the role of astrocytic YTHDF2 in DE pathogenesis. In a mouse model of high-fat diet-induced DE, we observed significant cognitive impairment and hippocampal inflammation. Astrocyte-specific overexpression of YTHDF2 alleviated these deficits, reducing cognitive dysfunction and the levels of pro-inflammatory cytokines IL-1β and IL-6. Both in vivo and in vitro high-glucose models confirmed that YTHDF2 overexpression suppressed astrocyte activation. YTHDF2 negatively regulated SIGMAR1 expression by promoting SIGMAR1 mRNA degradation, which inhibited astrocyte activation and inflammation. Mechanismly, SRAMP, a sequence-based predictor of m6A modification sites, identified four high-confidence m6A sites (P828, P916, P938 and P979) in SIGMAR1 mRNA. Mutation of P916 m6A site could inhibit SIGMAR1 mRNA degradation induced by YTHDF2 overexpression. Our findings demonstrate that astrocytic YTHDF2 attenuates astrocyte activation and neuroinflammation by promoting SIGMAR1 mRNA degradation in DE progression, which may provide a novel treatment strategy for neuroinflammation and cognitive dysfunction in DE.

BackgroundGait impairment is common in older adults with type 2 diabetes mellitus (T2DM). This complication increases risk of falls, disability, and mortality. Although gait disorders are often associated with peripheral deficits, emerging evidence suggests that central mechanisms may play an important role. The relative contributions of central and peripheral factors across gait parameters remain unclear.MethodsIn this cross-sectional study, gait parameters were assessed using wearable inertial sensors in 41 older adults with T2DM and 55 age-matched controls. Central factors included medial temporal atrophy (MTA) on magnetic resonance imaging (MRI) and global cognition (MoCA/MMSE). Grip strength was used as the index of peripheral function. Hierarchical regression quantified the incremental variance explained by central versus peripheral factors after adjusting for demographic and vascular confounders.ResultsCompared with the control group, the T2DM group showed significantly worse gait performance, including a reduction in gait speed of about 35% (p < 0.001). For gait speed, central factors (MTA and cognition) explained most of the model’s explained variance, whereas grip strength explained little and was not an independent predictor. Both central and peripheral factors contributed independently to cadence.ConclusionHippocampal atrophy and cognitive dysfunction are independently associated with slowed gait speed in the elderly with T2DM. Cadence reflects combined effects of central and peripheral influences. These findings suggest that future intervention research should explore a shift toward from traditional peripherally focused approaches to brain-centered strategies for maintaining motor ability in the future. These findings are cross-sectional and associative; causal inferences require longitudinal validation.

Type 1 diabetes (T1D) is a T cell‑mediated autoimmune disorder characterized by the destruction of insulin‑producing β‑cells. Sialic acid‑binding Ig‑like lectin 15 (Siglec‑15) could inhibit T‑cell activation and suppress immune responses. However, the association between Siglec‑15 expression levels and T1D is largely unknown. Serum concentrations of soluble Siglec‑15 were quantified in a cohort comprising 34 individuals newly diagnosed with T1D and 21 healthy control subjects. A murine mesenchymal stem cell (MSC) line, C3H10 T1/2, was genetically engineered to stably express SIGLEC15 through lentiviral transduction. Non‑obese diabetic (NOD) mice were administered treatments with Siglec15‑expressing MSCs, control MSCs, or phosphate‑buffered saline. The present study evaluated diabetes incidence, blood glucose concentrations, the severity of insulitis and the composition of immune cell populations in the pancreatic lymph nodes and spleens. In the present study, measurement of human serum specimens by ELISA revealed a positive association between new‑onset T1D and soluble Siglec‑15 levels. In NOD mice, treatment with Siglec15‑MSCs resulted in a significant reduction in diabetes incidence, preservation of insulin‑positive islets and mitigation of insulitis. Flow cytometric analysis demonstrated an increase in CD4+effector memory T cells within the pancreatic‑draining lymph nodes of mice treated with Siglec15‑MSCs, while no significant alterations were observed in splenic T cell populations or the frequencies of regulatory T cells. The findings of this study underscore the potential of Siglec‑15‑overexpressing MSCs as a promising cell‑based therapeutic approach for T1D, primarily through the localized modulation of memory T cells within the pancreatic lymph nodes.

Background: Elderly patients with type 2 diabetes mellitus (T2DM) often experience cognitive decline and physical function degradation. However, whether cognitive function mediates the association between T2DM and physical performance in older adults has not been previously examined. This study aimed to explore whether cognitive function was statistically associated with the relationship between T2DM and physical performance in older adults using mediation analysis. Methods: We conducted a cross-sectional study, and a total of 102 participants aged ≥60 were included (46 patients with T2DM and 56 non-diabetes controls). Cognition was assessed using standardized neuropsychological tests (global cognition, as assessed by the MoCA total score; and domain-specific measures). Physical performance was quantified by walking speed and handgrip strength. Mediation analyses were performed to test whether the cognitive function statistically accounted for part of the association between the T2DM state and the physical performance. Results: Participants with T2DM had poorer cognitive performance and lower physical performance than controls. In mediation models, the MoCA total score statistically accounted for approximately 18% of the association between T2DM and gait speed (ACME -5.19 cm/s, 95% CI -8.73 to -2.32; proportion mediated 0.18, 95% CI 0.08-0.32). For grip strength, the corresponding proportion was estimated at 60% (ACME -2.16 kg, 95% CI -3.78 to -0.81; proportion mediated 0.60, 95% CI 0.23-1.81), although this estimate should be interpreted cautiously because of the wide confidence interval. Conclusions: This study suggests that poorer cognitive performance may partially account for the observed relationship between T2DM and the decline in physical performance of the elderly. The results support the presence of concurrent cognitive and physical impairment among older adults with T2DM. Given the cross-sectional design, these findings should be regarded as exploratory and hypothesis-generating, and longitudinal studies are required to establish temporal relationships.

BackgroundDiabetes-related gait disorders are important drivers of falls and functional decline in older adults. Gait variability, as an indicator highly sensitive to fluctuations between steps, remains underexplored in diabetic populations. Compared with the average gait parameters, gait variability may better reflect impaired neuromuscular control and the risk of falling. This study aimed to evaluate the diagnostic accuracy of gait variability parameters, and test whether cognitive function plays an intermediary role between type 2 diabetes mellitus (T2DM) and gait variability.MethodsA total of 56 non-diabetic older participants and 37 T2DM patients (aged 60 years or older) were enrolled in this study. We used wearable inertial sensors to evaluate the gait parameters (including the variability in stance time, gait speed, stride length and turn duration) during straight walking and turning tasks. Standardized tools were used to evaluate cognitive functions, including the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) and other verified measures.ResultsOur results showed that T2DM patients exhibited significantly higher gait variability across all indicators. All gait variability indices were significantly negatively correlated with cognitive function (r = −0.20 to −0.53, P < 0.05). After adjusting for demographic characteristics and cognitive functions, the T2DM status was still an independent predictor of gait variability. The receiver operating characteristic (ROC) curve analysis showed that the stance time variability had good diagnostic accuracy (area under the curve [AUC] = 0.813, 95% CI 0.727–0.898, p < 0.001, sensitivity 94.6%), and gait speed variability also demonstrated good diagnostic performance (AUC = 0.801, 95% CI 0.705–0.897, p < 0.001). Mediation analysis showed that cognitive function mediated the effect of T2DM on stance time variability, and the mediated effect accounted for 31.9% of the total effect.ConclusionThis study showed that T2DM patients demonstrated a significant increase in gait variability. This variation was closely associated with cognitive decline. Stance time and gait speed variability could be used as a sensitive and non-invasive screening method to identify gait dysfunction related to diabetes. T2DM may affect gait stability through dual pathways, involving both cognitive decline and non-cognitive mechanisms. Comprehensive intervention strategies (including blood sugar control, neuropathy management and cognitive training) could improve the gait stability of T2DM elderly people and mitigate the risk of falling.

OBJECTIVE:Cardiovascular-kidney-metabolic (CKM) syndrome links metabolic, kidney, and cardiovascular disorders, but its burden among women of reproductive age (WRA) remains poorly understood. We quantified the global burden and trends of key CKM-related conditions and high body mass index (BMI)-attributable burden among WRA. METHODS:Using global burden of disease data from 1990 to 2021, we quantified six CKM-related disease outcomes and the burden attributable to high BMI. Trends were assessed using estimated annual percentage changes (EAPCs), and burden was projected to 2050 using Bayesian age-period-cohort models. RESULTS:In 2021, diabetes mellitus had the highest incidence rate (273.37 per 100,000 population; 95% uncertainty interval [UI], 204.50-353.52), ischemic heart disease the highest death rate (8.48 per 100,000 population; 95% UI: 7.68-9.35), high BMI the highest attributable disability-adjusted life-year (DALY) rate (641.53 per 100,000 population; 95% UI: 283.14-998.09), and chronic kidney disease the highest prevalence rate (6805.22; 95% UI: 5319.94-8575.90). From 1990 to 2021, the age-standardized death rate attributable to high BMI increased (EAPC, 0.43%; 95% confidence interval [CI]: 0.37%-0.50%), whereas the age-standardized DALY rate (ASDALYR) for stroke declined (-1.93%; 95% CI: -2.01% to -1.86%). Low-middle sociodemographic index regions had the highest ASDALYR in 2021 (2757.18; 95% UI: 2056.45-3505.64). Under historical-trend assumptions, high-BMI-attributable DALYs were projected to remain dominant through 2050 (1051.49; 95% UI: 235.36-1868.06), with the fastest projected increase in lower extremity peripheral arterial disease (3.39%; 95% CI: 3.13%-3.66%). CONCLUSIONS:Among WRA, CKM-related burden was substantial and varied across sociodemographic index quintiles. These findings support intensified adiposity control and context-specific prevention to reduce future burden through 2050.

Diabetic peripheral neuropathy (DPN) is a chronic complication resulting from diabetes that leads to pain and sensory abnormalities, significantly impacting the quality of life for affected patients. This study aims to investigate the role of glutamatergic neurons in the paraventricular thalamus (PVT) and the prelimbic cortex (PrL) in diabetes-induced nociceptive hypersensitivity. We established a diabetic mouse model through a single intraperitoneal injection of streptozotocin (STZ) and employed fiber photometry, optogenetics, and chemogenetics to examine the responses of glutamatergic neurons in the PVT and PrL to nociceptive stimuli. The results demonstrated that diabetic mice exhibited significant mechanical allodynia in response to von Frey filament (VFF) stimulation, accompanied by a marked increase in glutamatergic neuronal activity in the PVT. Manipulation of PVT glutamatergic neurons through optogenetics altered mechanical thresholds in the mice, indicating the critical role of the PVT to PrL projection in pain perception. Furthermore, chemogenetic modulation of the activity of glutamatergic neurons in both the PVT and PrL similarly affected nociceptive thresholds, further emphasizing the regulatory role of the PVT-PrL glutamatergic pathway in pain processing. Our findings highlight the significance of the PVT-PrL glutamatergic projection in painful diabetic neuropathy-like phenotypes, emphasizing the critical role of central brain circuits in diabetic neuropathy, which has traditionally been characterized primarily as a peripheral condition.

Rheumatoid arthritis (RA) has long been observed to co-occur with Hashimoto’s thyroiditis, a condition characterized by the presence of thyroid peroxidase antibody (TPOAb); however, the specific contribution of TPOAb to RA pathogenesis remains unclear. Therefore, we aimed to investigate the association between TPOAb and RA. We performed a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary data from East Asian and European population. This analysis was complemented by functional enrichment analyses and validation using cross-sectional data from 12,014 and 5,270 participants in the National Health and Nutrition Examination Survey (NHANES). In East Asian populations, both TPOAb concentration and TPOAb positivity were significantly associated with RA (OR = 1.447, P < 0.001; OR = 1.198, P < 0.001) and seropositive RA (OR = 1.349, P < 0.001; OR = 1.166, P = 0.002). In European populations, TPOAb concentration was significantly associated with RA, seropositive RA, and seronegative RA, while TPOAb positivity was significantly associated with RA and seropositive RA (all P < 0.05), but not seronegative RA. In the NHANES III dataset, TPOAb positivity remained significantly associated with RA and seropositive RA (OR = 1.358, P = 0.045; OR = 1.95, P = 0.046). Functional annotation further revealed enrichment of genes involved in immune regulation, immune cell differentiation, and activation. Collectively, these findings provide genetic and observational evidence supporting an association between TPOAb and RA. However, the potential role of TPOAb in rheumatoid arthritis risk prediction requires further investigation.

BACKGROUND AND AIMS:We aimed to explore whether saxagliptin, a dipeptidyl peptidase-IV inhibitor, could ameliorate glucose fluctuations and maintain β-cell function in T1DM. METHODS AND RESULTS:A multicentre, open-label, randomised trial was performed, including 184 T1DM patients from six medical centres. These patients received insulin with or without saxagliptin at 5 mg per day for 24 weeks. The primary endpoint was the change from the baseline value of the MAGE, as measured by a CGMS after 24 weeks. The secondary endpoints included the change from baseline value of islet function during the 3-hour BMTT, HbA1c, and insulin dosage. The exploratory analysis was the influence of SNPs in the incretin-related genes on saxagliptin treatment outcomes. No differences were observed between the two groups in MAGE after treatment for 24 weeks. The change of C-peptidemax levels from baseline to 24 weeks in SAXA group (insulin plus saxagliptin) was higher than in CONT group (insulin only) [p = 0.040]. No difference were observed between the groups in HbA1c, insulin dosage after 24 weeks. In SAXA group, rs10305439, rs10305441 of GLP1R and rs6233 of PCSK1/3 were associated with HbA1c response (p = 0.026, 0.019, and 0.048 respectively); the G allele of rs2143734 of GLP1R were associated with lower change of fasting C-peptide from baseline (p = 0.029) CONCLUSIONS: The saxagliptin did not ameliorate glucose fluctuations; however, it appeared to maintain β-cell function to some extent, and SNPs in the incretin-related gene may indicate responsiveness to DPP-IV inhibitors in T1DM. CLINICALTRIALS:Gov number, NCT02307695.

AimThe aim of this study was to explore the clinical characteristics and associated factors of constipation in patients with type 2 diabetes (T2DM). Here, we focus on the correlation between time in range (TIR) and coefficient of variation (CV) of glucose and constipation in patients with T2DM.MethodsIn the exploratory, cross-sectional study, a total of 120 patients diagnosed with T2DM in the department of Endocrinology and Gastroenterology of Liqun hospital from 2023 to 2024 were recruited. Patients with concurrent constipation were included in the constipation group, and those without concurrent constipation were included in the non-constipation group. Fasting blood indicators of patients were detected, including fasting blood glucose (FBG), 2 hours postgrandial blood glucose (2hPBG), glycosylated hemoglobin type A1C (HbA1c), fasting C-peptide (FCP), homeostasismodel assessment-insulin resistance (HOMA-IR), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Blood Glucose was monitored by a silicon-based dynamic system for 14 days, and TIR and CV were calculated by a continuous glucose monitoring system (CGM). In addition, the symptoms of constipation, gastroparesis cardinal symptom index (GCSI), patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) and patient assessment of quality-of-life index (PAGI-QOL) were evaluated by questionnaires. The impact of TIR and CV for constipation risk was evaluated using receiver operating characteristic (ROC) curves.Results1. More serious condition in constipation symptoms, GCSI, VSI, PAGI-SYM and PAGI-QOL scores in the constipation group. 2. Compared with the non-constipation group, the constipation group had longer courses, and higher probabilites of complications of autonomic neuropathy, diabetic nephropathy and hyperlipidemia; 3. Compared with the non-constipated group, FCP was significantly decreased, and HbA1c, TC and LDL-C were significantly increased in the constipation group. 4. TIR and CV were significantly correlated with constipation in patients with T2DM.ConclusionsLower TIR and higher CV were associated with constipation in T2DM patients. These findings suggest that CGM-derived metrics may be useful markers of constipation risk and warrant investigation in prospective studies to determine whether improving these parameters can prevent constipation development.

Mounting evidence indicates that renal tubular ferroptosis plays a crucial role in the progression of diabetic kidney disease (DKD). Caffeic acid phenethyl ester (CAPE), derived from propolis, a precious resinous substance synthesized by various bee species, has garnered broad attention in biomedical research. This study aims to explore the mechanism by which CAPE protects renal tubular epithelial cells (TECs) against ferroptosis in DKD. DBA/2J mice were administered streptozotocin (STZ) by intraperitoneal injection, fed a high-fat diet (HFD) and treated with CAPE. The findings revealed significant changes in ferroptosis markers. In diabetic mice and TECs under high-glucose (HG) conditions, levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) decreased, while transferrin receptor 1 (TFR1) increased. These changes were accompanied by a reduction in antioxidant capability and the accumulation of malondialdehyde (MDA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the intersection targets of CAPE and ferroptosis were mainly located in the mitochondria and exhibited high enrichment values in mitophagy. Further investigations revealed that HG induced a depolarization of mitochondrial membrane potential and an excessive level of mitochondrial reactive oxygen species (ROS), accompanied by defective mitophagy. The administration of CAPE inhibited exacerbated ferroptosis and rescued defective mitophagy induced by DKD. In addition, CAPE restored PTEN-induced putative kinase 1 (PINK1) levels, which were markedly diminished in the kidneys of DKD mice and TECs subjected to HG. Molecular docking simulation experiments suggested that CAPE is steadily bound to the PINK1 active pocket. Cellular Thermal Shift Assay (CETSA) and Drug Affinity Responsive Target Stability assay (DARTS) showed that CAPE enhances the thermal stability of the PINK1 protein within a specific temperature range and protects the PINK1 protein from degradation by proteolytic enzymes. These results confirm that CAPE interacts with PINK1 as its specific target. However, the positive outcomes of CAPE treatment on ferroptosis were nullified by the PINK1 siRNA. This research indicates that CAPE has potential therapeutic benefits for DKD by protecting renal TECs against ferroptosis via rescuing PINK1-mediated mitophagy. These findings suggest that CAPE shows potential as a therapeutic agent to prevent tubular injury in DKD.

Gallbladder carcinoma (GBC) is the most aggressive biliary tract cancer and is associated with a high mortality rate. Treatment of GBC faces therapeutic challenges owing to the elusive nature of in situ drivers within the local tumor microenvironment that drive its progression. Here, we created a single-cell atlas of 1,117,245 cells and a mutational landscape from 102 patients, which unveiled spatial-temporal characterizations of cellular constitutions, spatial interplays and molecular functions, and generalized five local ecosystems stratifying clinical outcomes. An integrated epithelial program, AI-EPI, combined with spatial transcriptome analysis, revealed the concurrent localization of a highly malignant tumor subtype (GM16) and AREG+ T cell, B cell, dendritic cell and macrophage subtypes within the pro-metastatic niche of primary adenocarcinomas. In vitro and in vivo experiments suggest that in addition to promoting metastasis, AREG facilitates CXCL5 expression in tumor cells through EGFR-pERK-EGR1 signaling, leading to increased neutrophil infiltration and impeding the effectiveness of immunotherapy. Our study provides a spatial-temporal landscape of the GBC microenvironment and sheds light on potential strategies for preventing immunotherapy resistance.

To explore the relationship between the triglyceride-glucose (TyG) index and diabetic chronic complications 922 patients with type 2 diabetes mellitus (T2DM) hospitalized in the Affiliated Suqian Hospital of Xuzhou Medical University from November 2023 to July 2024 and the Second Affiliated Hospital of Soochow University from January 2019 to December 2020 were enrolled. We divided the patients into different complications groups and corresponding non-compication groups. Clinical and biochemical parameters were compared between the two groups.The TyG index was determined by the following formula: Ln [TG(mg/dl)×FBG(mg/dl)/2], where TG is triglycerides and FBG is fasting blood glucose. (1) The TyG index showed significant positive correlation with diabetic retinopathy (DR) and carotid plaque (CP), while demonstrating inverse correlations with high density lipoprotein cholesterol (HDL-c) and 25-hydroxyvitamin D [25(OH)D] levels. (2) Among patients with DR, duration, TyG index and the prevalence of diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) were significantly higher. (3) Among patients with CP, age and TyG index were significantly higher. 922 patients with type 2 diabetes mellitus (T2DM) hospitalized in the Affiliated Suqian Hospital of Xuzhou Medical University from November 2023 to July 2024 and the Second Affiliated Hospital of Soochow University from January 2019 to December 2020 were enrolled. We divided the patients into different complications groups and corresponding non-compication groups. Clinical and biochemical parameters were compared between the two groups.The TyG index was determined by the following formula: Ln [TG(mg/dl)×FBG(mg/dl)/2], where TG is triglycerides and FBG is fasting blood glucose. (1) The TyG index showed significant positive correlation with diabetic retinopathy (DR) and carotid plaque (CP), while demonstrating inverse correlations with high density lipoprotein cholesterol (HDL-c) and 25-hydroxyvitamin D [25(OH)D] levels. (2) Among patients with DR, duration, TyG index and the prevalence of diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) were significantly higher. (3) Among patients with CP, age and TyG index were significantly higher. High TyG index is a relative specific risk factor of diabetic retinopathy and carotid plaque in patients with type 2 diabetes and not a contributing factor to the other chronic complications of diabetes. Not applicable.

Autoreactive memory T cells are considered to be a primary contributor to chronic islet inflammation in individuals with type 1 diabetes (T1D). OX40-expressing T cells not only facilitate and sustain the presence of CD4+ memory T cells but also promote the generation of CD8+ memory T cells. We aimed to investigate the role of OX40+CD4+/CD8+ memory T lymphocytes in the pathogenesis of T1D. A total of 35 patients diagnosed with Type 1 diabetes and 40 healthy control individuals were enrolled in this study. Peripheral Blood Mononuclear Cells (PBMCs) were isolated from the study participants and analyzed by flow cytometry. Inflammatory cytokines in the plasma were quantitatively measured. The pancreatic islet autoantibodies as well as islet function were also evaluated. The frequencies and the mean fluorescence intensity (MFI) of OX40 on CD4+ effector memory T (Tem) cells significantly increased in patients with T1D compared to healthy controls. Importantly, the expression of OX40 on CD8+ Tem and central memory T (Tcm) cells was also significantly higher in T1D compared with healthy controls. However, the expression of OX40 on CD4+ Tem cells was not significantly higher in T1D with two or more autoantibodies than control group. Furthermore, the frequencies of OX40+CD8+ Tem cells significantly increased in T1D patients with two or more autoantibodies but not in those with one autoantibody, compared with control groups. Meanwhile, the frequencies of OX40+CD8+ Tcm cells were consistently higher across all three subgroups of T1D patients (AAb−, 1AAb, ≥2AAb) compared to the control group. Notably, both the frequencies of OX40+CD4+ and OX40+CD8+ Tem cells exhibited significant negative correlations with the serum C-peptide levels in T1D patients. Additionally, the expression levels of OX40 on peripheral CD4+/CD8+ memory T cells were positively correlated with the levels of plasma inflammatory cytokines in patients with T1D. The elevated expression of OX40 on CD4+/CD8+ memory T cells was associated with the autoimmune-mediated destruction of islet beta cells in T1D. Our findings indicate that the expression levels of OX40 on peripheral CD4+ and CD8+ memory T lymphocytes may serve as potential predictive biomarkers for the severity of T1D. Additionally, OX40 expression on memory T cells may serve as a potential biomarker for assessing the efficacy of immunotherapy in T1D patients.

Phase I study showed comparable pharmacodynamic, safety and pharmacokinetic profiles of denosumab biosimilar CMAB807 and reference product Prolia® in healthy males. However, the efficacy and safety of CMAB807 in postmenopausal women with osteoporosis were unknown. To compare the efficacy and safety of CMAB807 and Prolia® in Chinese postmenopausal women with osteoporosis. This randomized, double-blind, active-controlled study enrolled Chinese postmenopausal women with osteoporosis. Participants received either CMAB807 or Prolia® 60 mg every 6 months for 12 months. The primary endpoint was the percentage change in BMD at lumbar spine (LS) from baseline to month 12. Secondary endpoints included BMD changes at LS at month 6, total hip (TH) and femoral neck (FN) at month 6 and 12. Additionally, bone turnover markers (BTMs) and incidence of new fragility fractures were evaluated. Safety assessments were also included. A total of 284 women were enrolled, with 276 (97.2

BACKGROUND:Diabetic gastrointestinal autonomic neuropathy (DGAN) often affects the patients' quality of life. Thus, research on influencing factors of DGAN may promote DGAN prevention and decrease the incidence rate. This study used electrogastrogram (EGG) to assess the relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and DGAN. AIM:To analyze the changes of EGG in patients with MASLD and type 2 diabetes mellitus (T2DM), and to elucidate whether ultrasound-diagnosed MASLD is an independent risk factor for diabetic gastric motility disorders (DGMD). METHODS:A total of 272 patients with T2DM hospitalized at the Second Affiliated Hospital of Soochow University from December 2020 to December 2021 and the Affiliated Suqian Hospital of Xuzhou Medical University from November 2023 to June 2024 were included in the cross-sectional study. General information, clinical data, and medical history of all study subjects, including name, age, gender, body mass index, and duration of diabetes were collected. Laboratory tests included biochemical parameters, glycosylated hemoglobin (HbA1c), fasting C-peptide, 2h postprandial C-peptide and 25-hydroxyvitamin D [25(OH)D]. EGG, fundus examination and carotid artery ultrasonography were performed and results were recorded. According to the results of EGG, the subjects were divided into the DGMD group and non-DGMD group. RESULTS:The duration of diabetes, fasting blood glucose (FBG), HbA1c, 25(OH)D and the prevalence of MASLD were significantly higher in the DGMD group (P < 0.05). Multiple logistic regression analysis showed that the duration, FBG, 25(OH)D and the presence of MASLD were independent influencing factors. CONCLUSION:MASLD is strongly associated with an increased incidence of DGMD. Timely treatment of MASLD is effective to prevent diabetic gastroparesis.

Liver metastasis (LM) is a cancer hallmark linked to poor prognosis and high mortality. Immune and metabolic shifts play critical roles in LM progression. This study aims to explore the prognostic value of immune- and metabolism-associated genes for LM and investigate their potential mechanisms. Here, we established a prognostic model based on Consensus Clustering-derived Metabolism- and Immune-associated genes (CCMI). Both the CCMI model and each hub gene demonstrated predictive value for LM patients at RNA and protein levels. Moreover, patients with high CCMI scores showed worse prognosis, elevated mutation frequency and heterogeneity, enrichment of cancer-promoting pathways, and increased neutrophil infiltration. Mechanistically, functional studies showed that CKB and ARG2 enhanced the proliferation, self-renewal, migration and invasion of cancer cells via activating MAPK or PI3K-AKT signaling pathways. MAFF was validated to play a key role in inducing neutrophil recruitment and infiltration through upregulating expression of CXCL1, thereby accelerating LM progression. In conclusion, this study presented a practical prognostic CCMI model for LM patients and investigated associated molecular and immune signatures. Our results uncovered the regulatory mechanisms of CCMI hub genes that promote LM progression, highlighting their potential as biomarkers for precision diagnosis and treatment of LM.

Lymphedema is an important, and often underdiagnosed complication of obesity and is likely due to acquired defects in the lymphatic vasculature. Study of diet-induced obesity animal models have indicated defective lymphatic vasculatures might extend to other anatomical sites, especially visceral depots. Excess mechanical pressure, metabolites, pro-inflammatory cytokines, and adipokines released during adipose tissue expansion can predispose lymphocytes to overactivation and apoptosis; compromising collecting lymphatic vessels; and triggering lymph node hypoplasia, fibrosis, and apoptosis. Consequently, the defective lymphatic vasculature may disrupt local and systemic immune-metabolic homeostasis, contributing to various adverse outcomes including inflammation and immune dysfunction, abnormal transport dynamics of lipids, vitamin D, and possibly incretin in obesity. Weight reduction is the definitive management to restore lymphatic function and should be instituted before permanent vasculature impairment develops. Besides lymphatic regeneration, future research aimed at elucidating the pathophysiological mechanisms between adipose tissue and lymphatic vasculature should be considered to help the development of potential adjunctive therapies that might repair the lymphatic vasculature, improve immune-metabolic outcomes, and even combat obesity.