INTRODUCTION:Diabetes mellitus (DM) increases susceptibility to lower respiratory tract infections (LRTIs) and is associated with higher rates of complications and mortality. Although poor glycemic control is known to increase infection risk, it is unclear whether long-term glycemic status influences outcomes once an LRTI occurs. This study examined whether hemoglobin A1c (HbA1c) predicts clinical outcomes in adults with DM hospitalized for LRTI. METHODS:This retrospective, single-center observational study was conducted at Kantonsspital Baselland, Switzerland, and included adult patients with Type 1 and Type 2 DM hospitalized for LRTI between January 2023 and December 2024. Data were extracted from the hospital's electronic medical records system. Long-term glycemic control was assessed by HbA1c values. Outcomes included length of hospital stay (LOHS), readmission, and mortality at 30 and 180 days. Associations were evaluated using multivariable regression models adjusted for age, sex, and number of chronic comorbidities. RESULTS:A total of 389 patients were included, with a median age of 79 years (IQR 72-84) and 41.1% female. Multimorbidity was highly prevalent, with 76.9% of patients having ≥ 5 chronic conditions. The median HbA1c was 7.2%. The most frequent LRTI admission diagnosis was pneumonia (53.5%), followed by COVID-19 (25.2%) and COPD exacerbation (17.0%). The median LOHS was 8 days (IQR 5-12). Mortality was 5.7% in hospital, 7.5% at 30 days, and 18.2% at 180 days after admission. Rehospitalization occurred in 13.4% of patients within 30 days and 36.7% within 180 days after discharge. Higher HbA1c was modestly associated with longer LOHS (IRR 1.058, p = 0.004) but not with readmission or mortality at any time point. CONCLUSION:Patients with DM hospitalized for LRTI are typically elderly, multimorbid, and experience high readmission and mortality rates. Long-term glycemic control showed an association with slightly prolonged hospital stay but no association with mortality or readmission. These findings indicate limited prognostic value of HbA1c in the acute LRTI setting and highlight the dominant role of age, sex, and multimorbidity. These findings are primarily applicable to frail, elderly patients with multimorbidity and should be interpreted cautiously in other populations. Prospective studies should investigate the impact of short-term glycemic control and structured inpatient diabetes management on outcomes.
OBJECTIVE:Gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP) are two of the most prevalent pregnancy complications affecting both singleton and twin pregnancies worldwide. This study specifically investigates the combined effect of concurrent GDM and HDP on maternal and perinatal outcomes among twin gestation populations. METHODS:This retrospective single-center study enrolled 132,314 pregnant people who delivered at ≥ 20 weeks of gestation as the eligible study population, including 918 stillbirth cases, 2803 live twin births, and 128,593 live singleton births. All included cases met core inclusion and exclusion criteria. The total population was categorized into four subgroups according to the presence of HDP and/or GDM: non-HDP-GDM, HDP only, GDM only, and concurrent HDP-GDM. The primary analysis focused on comparing perinatal outcomes between twin and singleton pregnancies within each of the four subgroups to evaluate the effect of HDP, GDM, and their co-occurrence on perinatal outcomes across different pregnancy types. RESULTS:Among the 132,314 pregnant people included in this study, the stillbirth rate in twin pregnancies was higher than that in singleton pregnancies (1.79% vs. 0.67%, p < 0.001). Distinct differences in maternal and neonatal complication profiles were observed between singleton and twin pregnancies, and this discrepancy persisted across both term and preterm subgroups. The incidence of HDP and GDM in twin pregnancies was 23.0% and 21.0%, respectively. Across all subgroups, twin pregnancies were associated with preterm birth (PTB), cesarean section (CS), and anemia. Interestingly, the number of complications showing comparable occurrence patterns between singleton and twin pregnancies was 3 in the non-HDP-GDM group, 6 in the HDP group, 8 in the GDM group, and 15 in the HDP-GDM group. Notably, the positive association between HDP/GDM and adverse outcomes observed in singleton pregnancies was not equivalently present in twin pregnancies. In singleton pregnancies, the combined effect of HDP and GDM on adverse outcomes could either synergistically amplify or counteract (attenuate) their individual impacts, depending on whether their individual effects were congruent-a pattern with synergistic amplification when individual risks were congruent. In contrast, the combined influence of HDP and GDM showed limited association with adverse outcomes in twin pregnancies. CONCLUSIONS:Although the individual incidence of HDP and GDM is higher in twin pregnancies, their combined effect on adverse perinatal outcomes is attenuated in twin populations. This retrospective single-center finding offers reference for individualized risk assessment of twin pregnancies.
OBJECTIVE:This study sought to investigate the correlation between serum uric acid (SUA) levels and bone mineral density (BMD) among patients with Type 2 diabetes mellitus (T2DM). METHODS:A single-center retrospective cross-sectional analysis was performed. A total of 249 hospitalized patients with T2DM (147 men and 102 postmenopausal women) were recruited from Zhongshan Hospital (Xiamen), Fudan University, between June 2024 and June 2025. Baseline clinical characteristics were first compared between patients with normal BMD and those with osteopenia or osteoporosis. All participants were subsequently stratified into a normal uric acid (NUA) group and a hyperuricemia (HUA) group based on SUA concentrations. BMD measurements at the femoral neck, total hip, and lumbar spine were compared across the two groups. Multivariate logistic regression analysis was applied to determine independent factors associated with the risk of osteopenia and osteoporosis. RESULTS:Of the 249 enrolled participants, 178 (71.5%) were diagnosed with osteopenia or osteoporosis. Relative to patients with normal BMD, individuals with osteopenia/osteoporosis were older, had a higher proportion of female cases, exhibited elevated osteocalcin (OCN) levels and increased fracture risk, and presented significantly lower body mass index (BMI), estradiol (E2), and SUA levels. In the overall cohort, as well as in male and postmenopausal female subgroups, higher SUA levels were significantly and positively correlated with higher BMD at all three skeletal sites (all p < 0.05). Multivariate logistic regression demonstrated that OCN served as an independent risk factor for osteopenia and osteoporosis, whereas BMI, E2, and SUA served as independent protective factors against these bone disorders (all p < 0.05). CONCLUSION:Elevated SUA levels are correlated with higher BMD and a reduced risk of osteopenia and osteoporosis in T2DM patients. BMI, E2, OCN, and SUA act as independent predictors of bone status in this patient population. Routine SUA testing may facilitate the identification of T2DM patients at high risk of osteopenia and osteoporosis.
BACKGROUND:Diabetic nephropathy (DN) is a serious microvascular complication of diabetes that urgently requires effective treatments with low toxicity. The traditional Chinese medicine formula Yiqi Yangyin Qingre decoction (YQYYQR) has demonstrated potential in alleviating DN, yet its pharmacological mechanism remains unclear. METHODS:UPLC-MS/MS combined with network pharmacology was utilized to qualitatively analyze YQYYQR's bioactive components and predict therapeutic targets. Integrating public databases and GEO-derived DN-related genes, core targets were identified via intersection and subjected to pathway enrichment. Molecular docking validated key component-core target interactions, with in vivo DN mouse experiments and transcriptome sequencing performed for verification. RESULTS:This study identified 376 bioactive components from YQYYQR, corresponding to 1284 potential therapeutic targets. Cross-analysis between these targets and DN-related genes yielded 57 overlapping targets, among which GSK3β and NFKB1 were screened as core hub genes. Network pharmacology and transcriptomic pathway enrichment analyses indicated that the mechanism of YQYYQR in intervening DN involves biological processes such as autophagy and inflammatory response. In vivo, YQYYQR significantly improved mouse proteinuria and renal function and alleviated pathological kidney damage. Mechanistically, YQYYQR enhanced the inhibitory phosphorylation of GSK3β at Ser9, thereby facilitating TFEB nuclear translocation and activating the autophagy-lysosomal pathway. Simultaneously, it suppresses the NLRP3/ASC/caspase-1/GSDMD-N-mediated pyroptosis pathway, ultimately reducing renal inflammation. CONCLUSION:YQYYQR exerts a protective effect against DN progression by targeting core genes including GSK3β, regulating the GSK3β-TFEB axis to restore autophagic flux via the autophagy-lysosomal pathway, and inhibiting NLRP3-mediated pyroptosis to mitigate excessive renal inflammation.
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, and current therapies often fail to adequately address oxidative stress-induced podocyte injury. Huangqi Tujian Decoction (HTD), a traditional Chinese herbal formula, has shown promise in the clinical management of DN, yet its molecular mechanisms remain incompletely understood. This study aimed to elucidate the protective role of HTD and its interplay with glutathione S-transferase P1 (GSTP1) and the Rac1-mineralocorticoid receptor (MR) signaling pathway. Integrated bioinformatic analysis of human DN transcriptomes identified GSTP1 as a central hub gene. In vivo studies using db/db mice and streptozotocin-induced GSTP1-knockout models revealed that HTD significantly improved renal function; reduced albuminuria, serum creatinine, and blood urea nitrogen levels; and restored podocyte integrity markers (ZO-1 and Nephrin). HTD treatment also suppressed Rac1-MR activation and downregulated NADPH oxidase subunits, thereby alleviating oxidative stress and apoptosis. Importantly, GSTP1 deficiency completely abolished these protective effects. Coimmunoprecipitation assays demonstrated direct binding between GSTP1 and both Rac1 and MR, suggesting that GSTP1 disrupts the pathogenic Rac1-MR complex. In summary, HTD ameliorates DN by normalizing GSTP1 expression toward physiological levels, thereby disrupting the pathogenic Rac1-MR complex and attenuating oxidative damage and podocyte injury. These findings reveal a novel molecular pathway for HTD and highlight GSTP1 as a promising therapeutic target and potential biomarker for DN.
BACKGROUND:Diabetic peripheral neuropathy (DPN) is a common and disabling complication of Type 2 diabetes mellitus (T2DM). Emerging evidence suggests that elevated serum uric acid (SUA) may associate with microvascular complications; however, data from sub-Saharan Africa remain limited. We examined the association between hyperuricemia and DPN among adults with T2DM in northern Tanzania. METHODS:We conducted a hospital-based cross-sectional analytical study at a tertiary diabetes clinic from November 2024 to April 2025. Adults aged ≥ 18 years with established T2DM were consecutively recruited. DPN was assessed using the Toronto Clinical Scoring System (TCSS), with DPN defined as TCSS ≥ 6. Fasting SUA was classified as elevated at ≥ 340 μmol/L in women and ≥ 420 μmol/L in men. Multivariable logistic regression estimated adjusted odds ratios (aORs). Receiver operating characteristic (ROC) analysis assessed discriminatory performance. RESULTS:Of 321 clinic attendees, 220 participants met eligibility criteria and were analyzed (mean age < 65 years: 69.1%; male: 53.2%). DPN prevalence was 51.8% (114/220). Elevated SUA was present in 52.7% and was strongly associated with DPN (aOR 5.89, 95% CI 3.01-11.51, p < 0.001). Diabetes duration ≥ 5 years (aOR 3.81, p = 0.016), overweight status (aOR 2.18, p = 0.034), elevated fasting glucose (aOR 2.20, p = 0.022), and low HDL (aOR 2.10, p = 0.040) were independently associated with DPN. Elevated total cholesterol was inversely associated (aOR 0.36, p = 0.003). SUA demonstrated moderate discrimination for DPN (AUC 0.773). CONCLUSIONS:Hyperuricemia was independently associated with prevalent DPN in this Tanzanian study. SUA may represent a clinically accessible marker for neuropathy risk stratification in resource-limited settings.
BACKGROUND:Little is known about the prevalence and experiences of intermittent caloric restriction (ICR) among individuals with Type 1 diabetes mellitus (T1DM), despite its growing popularity. METHODS AND RESULTS:From September to October 2023, patients diagnosed with T1DM aged 18-89 in Minnesota were invited via the M Health Fairview's electronic health record (EHR) to complete a 10-min online survey. The survey gathered patient-provided data on demographics, clinical data, and questions centered on weight and use of ICR. Out of 124 respondents, 39 reported participating in ICR and completed the survey. These participants, with a mean age of 42.8 years (SD = 12.0) and a mean BMI of 28.2 kg/m2 (SD = 5.5), included 22 females and 17 males. Among them, 34 reported practicing time-restricted eating (TRE), whereas 5 reported practicing intermittent fasting (IF). TRE participants reported an average weight loss of 6.0 kg, whereas IF participants reported an average weight loss of 3.5 kg. Hypoglycemia was reported by five TRE participants and one IF participant, with no episodes of diabetic ketoacidosis (DKA) reported. Only six participants reported that their healthcare providers were aware of their fasting program. CONCLUSIONS:Individuals with T1DM do engage in ICR, mainly TRE, with rare hypoglycemia and no DKA. Further research is needed on long-term ICR safety in T1DM patients.
BACKGROUND:Atherosclerosis (AS), which causes chronic inflammation, aberrant lipid metabolism and vascular endothelial damage, is the main cause of cardiovascular disease. The Ce-Bai-Si-Wei decoction (CSD) may reduce AS, although its molecular mechanisms are unknown. This study investigates core molecular pathways using multi-omics integration and experimental validation. METHOD:Network pharmacology prediction: Construct a 'drug-component-target-disease' interaction network using databases like TCMSP, HIT and ETCM to identify active components and targets of CSD. AS regulatory targets and signalling pathways can be identified by integrating microarray data and single-cell transcriptomics data. In vitro validation: Utilise the OX-LDL-induced model of macrophage foam cells to test CSD's effects on lipid accumulation utilising CCK-8, Oil Red O and TC/TG quantification. Validate CSD's regulatory effects on core targets using molecular docking, molecular dynamics simulation, RT-qPCR and Western blot. RESULTS:Four core genes, HMOX1, SELE, CD4 and FLT1, were identified as key regulators of inflammation and oxidative stress in AS, and they bind stably to the active components of CSD. Single-cell data analysis suggested that CSD may improve AS by targeting macrophages and endothelial cells. In vitro, CSD reduced ox-LDL-induced lipid accumulation in macrophages and downregulated TNF-α and IL-1β. Mechanistically, the anti-AS effect of CSD depends on the NRF2/HMOX1 pathway. CSD also downregulated FLT1 and SELE in damaged endothelial cells. CONCLUSION:This study investigated the mechanism of CSD in treating AS. CSD acts on the core targets HMOX1, SELE, FLT1 and CD4, with macrophages and endothelial cells as key effector cells. It exerts anti-AS effects by inhibiting inflammation, reducing lipid accumulation and protecting endothelial function.
OBJECTIVE:Individuals with both diabetes and hypertension face a heightened risk of all-cause death. We aimed to validate the DHAM score's performance in predicting 5-year overall mortality in two prospective cohorts. METHODS:The internal validation cohort comprised 3291 patients with diabetes and hypertension drawn from the 1999-2014 cycles of the National Health and Nutrition Examination Survey database. The external validation cohort comprised 2478 patients from the 2008-2015 China Kailuan cohort. The DHAM score was constructed from eight predictors (age, sex, education, marriage, smoking, cardiovascular disease, serum albumin, and urea nitrogen). Renal dysfunction was determined by an estimated glomerular filtration rate < 60 mL/min/1.73 m2 computed via the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS:The C-index was 0.758 (95% CI: 0.743-0.833) in the NHANES database and 0.741 (95% CI: 0.731-0.790) in the Kailuan cohort. A DHAM score > 148 independently predicted 5-year all-cause death in NHANES (adjusted-HR 10.03, 95% CI: 3.37-18.83, p < 0.001); after recalibration, a score > 152 independently predicted mortality in Kailuan (adjusted-HR 9.24, 95% CI: 4.71-16.84, p < 0.001). The patients were further stratified by DHAM score and renal function into three risk groups. Intermediate- and high-risk categories showed higher 5-year all-cause death rates than low-risk categories across both cohorts (log-rank p < 0.001). CONCLUSION:The DHAM score had a robust prognostic value for 5-year all-cause death among individuals with both diabetes and hypertension. Higher DHAM score combined with renal dysfunction could identify patients at highest risk of all-cause death. TRIAL REGISTRATION:Chinese Registry of Clinical Trials: ChiCTR2000029767.
Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine that has recently been identified as a key regulator of appetite homeostasis. Although GDF15 was previously regarded as only a biomarker of disease burden, the discovery of its exclusive receptor, GFRAL, repositioned it as a key mediator of sickness-associated anorexia. The clinical significance of GDF15 and its receptor, GFRAL, is supported by evidence that established weight-loss agents influence circulating GDF15 levels and that GDF15 agonists induce marked weight loss in both preclinical and early-phase clinical studies. This review integrates recent advances in GDF15 biology from evolutionary, mechanistic and translational perspectives, with particular emphasis on its emerging therapeutic potential in obesity.
BACKGROUND:Prior studies have suggested that serum total bilirubin (TBil) may be linked to diabetic nephropathy (DN); however, its potential relationship with structural renal injury in histopathology has not been well defined. OBJECTIVE:The objective of the study is to explore whether physiological levels of TBil are associated with the severity of renal pathological changes in individuals with Type 2 diabetes mellitus (T2DM) and biopsy-confirmed DN. METHODS:A cross-sectional cohort of 401 individuals with T2DM and biopsy-confirmed DN was included. DN severity was determined according to the Renal Pathology Society classification and categorized as early-stage DN (Classes I-II) or advanced DN (Classes III-IV). Multivariable logistic regression was used to evaluate the association between TBil and advanced DN. TBil quartiles, restricted cubic spline modeling, subgroup and sensitivity analyses, and receiver operating characteristic curve analysis were also performed. RESULTS:Among 401 biopsy-confirmed DN patients, 258 (64.3%) were classified as having advanced DN. In multivariable models, higher TBil levels were independently associated with lower odds of advanced DN after full adjustment (OR = 0.882, 95% CI 0.827-0.941; p < 0.001). When TBil was analyzed by quartiles, individuals in the highest quartile exhibited significantly lower odds of advanced-stage disease relative to those in the lowest quartile in the fully adjusted model (OR = 0.331, 95% CI 0.153-0.718; p = 0.005), with a notable dose-response pattern across quartiles (p for trend = 0.003). Restricted cubic spline analyses confirmed an inverse association between TBil levels and advanced DN. Receiver operating characteristic curve analysis identified a TBil cutoff of 9.9 μmol/L for discriminating advanced DN, with an area under the curve of 0.684. The results were broadly consistent across subgroup and sensitivity analyses. CONCLUSION:Higher physiological TBil levels were linked to lower histopathological severity of DN in patients with Type 2 diabetes.
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and remains one of the leading causes of end-stage renal disease, significantly affecting patients' survival rates and quality of life. Currently, commonly used clinical assessment indicators include proteinuria and estimated glomerular filtration rate (eGFR); however, these indicators have limited sensitivity, making it difficult to detect early kidney damage in a timely manner and to accurately monitor disease progression. This review provides a comprehensive overview of recent progress in identifying various urinary biomarkers that reflect renal tubular injury, oxidative stress, inflammatory responses, fibrotic remodeling, metabolic dysregulation, and exosomal components. Furthermore, we discuss the potential clinical applications of these biomarkers in DKD early diagnosis, disease stratification, and prognostic evaluation. Looking ahead to the future and the ongoing development of multiomics integration and artificial intelligence-assisted modeling, urinary biomarkers are expected to drive DKD diagnosis and management toward a future characterized by early detection, precision, dynamic monitoring, and noninvasive assessment.
BACKGROUND:Diabetic foot ulcers (DFU) impose a healthcare burden due to prolonged hospitalization, high amputation rates, and increased mortality. This study evaluated healing outcomes and explored factors associated with adverse outcomes among patients managed within a structured multidisciplinary DFU care setting at a specialized diabetes care center in Kerala. METHODS:A retrospective analysis was conducted among 1057 patients with DFUs managed between January and November 2022. Care included wound culture-directed antibiotics, glycemic optimization, offloading, daily debridement and dressing, and vascular assessment when indicated. Healing outcomes were assessed, and factors associated with poor outcomes and delayed healing were evaluated using multivariable logistic regression. RESULTS:In the full cohort, 74.7% of patients achieved complete healing, whereas the major amputation rate was 2.6%. After excluding referrals, deaths, and loss to follow-up, 887 patients comprised the complete follow-up cohort, of whom 790 (89.1%) achieved favorable outcomes, and 97 (10.9%) experienced poor outcomes (nonhealing ulcer or major amputation). Coronary artery disease (OR 2.08, 95% CI 1.23-3.51; p = 0.006) and prior ulcer history (OR 2.41, 95% CI 1.55-3.74; p < 0.001) were independently associated with poor outcomes. Among patients with healing-time data (n = 766), chronic kidney disease was independently associated with delayed healing (> 5 months) (OR 1.96, 95% CI 1.26-3.06; p = 0.003). CONCLUSION:High rates of favorable outcomes and low rates of major amputation were observed in this cohort managed within a multidisciplinary DFU care model. These findings support the need for prospective multicenter evaluations of multidisciplinary DFU care models.
OBJECTIVE:Obesity, impaired glucose tolerance, and diabetes significantly increase hypertension risk. Previous studies across various populations have linked the weight-adjusted waist index (WWI)-a key indicator for assessing obesity-to hypertension. However, this relationship remains unclear specifically in non-diabetic populations, particularly normoglycemic individuals. Focusing on normoglycemic Japanese adults, the present study explored the correlation of WWI with prehypertension or hypertension. METHODS:Data sourced from the program for medical screening at Murakami Memorial Hospital (Japan) were subjected to secondary analysis, which included 15,464 participants. To quantify the relationship of the WWI with prehypertension (pre-HTN) or hypertension (HTN), multivariable logistic regression analyses were applied. Restricted cubic spline (RCS) models were further applied to evaluate the dose-response relationship of WWI with the two outcomes. Subgroup analyses were also conducted. RESULTS:Among 15,453 normoglycemic Japanese adults, the mean WWI increased progressively across blood pressure categories (normal < prehypertension < hypertension). Following adjustment for key confounding variables, WWI was independently correlated with prehypertension (OR = 1.50, 95% CI: 1.39-1.61, p < 0.001) and hypertension (OR = 1.74, 95% CI: 1.51-2.00, p < 0.001). Curve Fitting confirmed a linear, monotonic positive correlation of WWI with both outcomes (all p values for non-linearity tests > 0.05). Subgroup analyses revealed a stronger association between WWI and prehypertension in females, individuals without fatty liver disease, and current smokers. CONCLUSIONS:Our study demonstrated a positive linear correlation of WWI with both prehypertension and hypertension risk in normoglycemic Japanese individuals.
Worldwide, diabetic retinopathy (DR) stands as a leading cause of vision loss. However, the involvement of PANoptosis-a form of inflammatory cell death that combines features of apoptosis, pyroptosis, and necroptosis-in the development of DR has not been fully elucidated. This study investigated the molecular mechanisms underlying high glucose (HG)-induced PANoptosis in human retinal microvascular endothelial cells (hRMECs), focusing on the scavenger receptor CD36 and NOTCH/MAML signaling. HG specifically induced PANoptosis in hRMECs, evidenced by concurrent activation of apoptotic, pyroptotic, and necroptotic markers, along with PANoptosome complex formation and morphological validation via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. HG significantly upregulated CD36 expression and activated the NOTCH/MAML pathway. CD36 overexpression exacerbated PANoptosis by enhancing cell death, inflammatory responses, and oxidative stress, whereas CD36 knockdown conferred protection. Mechanistically, CD36 promoted PANoptosome assembly through NOTCH/MAML pathway activation, as demonstrated by increased NICD-MAML1 nuclear colocalization and enhanced NOTCH component expression. We further verified that the CD36-NOTCH axis regulates PANoptosis through the modulation of NLRP3, a core component of the PANoptosome. Pharmacological NOTCH inhibition using DAPT ameliorated HG-induced PANoptosis, whereas NOTCH activation mimicked CD36 overexpression effects. These results establish a novel CD36-NOTCH/MAML-NLRP3-PANoptosis regulatory pathway in diabetic retinal endothelial cells. This discovery provides crucial insights into DR pathogenesis and pinpoints potential targets for therapeutic intervention.
BACKGROUND:Prediabetes is a heterogeneous condition encompassing three glucose-defined phenotypes (isolated impaired fasting glucose [i-IFG], isolated impaired glucose tolerance [i-IGT], and IFG + IGT), with distinct pathophysiological mechanisms. This study assessed the associations of weight status (body mass index [BMI]), general adiposity (fat mass index [FMI]), total lean mass (lean mass index [LMI]), and body fat distribution (waist circumference [WC] and DEXA-derived appendicular, gynoid, abdominal and visceral adiposity) with prediabetes phenotypes. METHODS:This cross-sectional study included 3225 adults without diabetes who had complete data on fasting and 2-h plasma glucose, anthropometric measures (BMI and WC), and DEXA-derived measures (FMI, LMI, and percentages of total fat in appendicular, gynoid, abdominal and visceral regions) from the National Health and Nutrition Examination Survey 2011-2016. BMI and WC were classified according to WHO criteria. DEXA-derived measures were classified using sex-specific tertiles. Glycemic status was classified as normoglycemia, i-IFG, i-IGT, or IFG + IGT based on ADA criteria. Logistic regression and restricted cubic spline analyses were performed. RESULTS:The weighted mean (SD) age was 37.16 (12.15) years, and 49.5% of participants were male. Overall, 59.6%, 29.1%, 4.2%, and 7.0% had normoglycemia, i-IFG, i-IGT, and IFG + IGT, respectively. Compared with individuals with normal BMI, those with overweight or obesity had higher odds of i-IFG (overweight: OR = 1.56 [1.19, 2.03]; obesity: OR = 2.73 [2.09, 3.56]) and IFG + IGT (overweight: OR = 2.81 [1.61, 4.91]; obesity: OR = 6.72 [4.03, 11.22]), whereas both underweight (OR = 3.22 [1.21, 8.58]) and obesity (OR = 2.57 [1.64, 4.04]) were associated with higher odds of i-IGT, indicating a U-shaped relationship between BMI and i-IGT (pnon-linearity = 0.006). Higher FMI and LMI were associated with higher odds of all three phenotypes (all pT3vs.T1 < 0.05). Compared with normal WC, very-high-risk central obesity was associated with higher odds of all three phenotypes (all p < 0.05). Higher proportions of abdominal or visceral fat and lower proportions of appendicular or gynoid fat were associated with higher odds of i-IFG and IFG + IGT (all pT3vs.T1 < 0.001). For i-IGT, only gynoid fat showed an inverse association (pT3vs.T1 = 0.002). CONCLUSION:Adiposity patterns differed across prediabetes phenotypes. These findings provide insights for tailoring intervention strategies by prediabetes phenotype to optimize diabetes prevention.
AIMS:The aim of the study is to integrate targeted transcriptomic analyses of previously identified biomarker proteins (proteomic findings) to better understand vascular complications (Cx) in Type 2 diabetes (T2D). METHODS:Total RNA was extracted from baseline citrate plasma samples of 543 individuals with T2D from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. Among these, 224 participants had microvascular Cx, 142 had macrovascular Cx (51 had both types of Cx) and 228 had no Cx (control group). mRNA expression was quantified using the OpenArray platform and group differences were analysed using ΔΔct values. Neutrophil elastase (NE) protein levels were measured in baseline plasma by ELISA. RESULTS:Eleven genes were retained for focused analysis. For microCx, the largest gene expression differences were observed for clusterin (~2-fold upregulation) and integrin alpha-IIb (~50% downregulation), compared with the control group. For macroCx, clusterin exhibited the strongest upregulation (~2.5-fold), whereas apolipoprotein F showed the greatest downregulation (~20%). Comparative analysis of proteomic and transcriptomic data across study groups revealed that only 32% of gene expression differences were mirrored at the protein level. NE levels were highest in the microCx group and were significantly elevated versus control only in that group; NE levels also correlated inversely with circulating actin protein expression (R2 = 0.92). CONCLUSION:Combining proteomic and targeted plasma transcriptomic data provides exploratory insights into biological processes associated with vascular complications in T2D and highlights NE as a candidate component of a proteolytic pathway for further investigation.
INTRODUCTION:We previously found that urinary n-terminal osteopontin (ntOPN) performed well for predicting diabetic kidney disease (DKD). This study is aimed at screening potential biomarkers for improving ntOPN-based models in DKD detection and prediction. METHODS:We performed a cross-sectional and then prospective cohort study. The novel biomarkers for DKD development were selected by the SOMAscan platform. The selected biomarkers were further validated by the SHapley Additive exPlanations (SHAP) algorithm, Pearson correlation, and logistic regression. The ntOPN-based models for DKD prediction were established, evaluated, and utilized by machine learning. RESULTS:The baseline growth differentiation factor 15 (GDF15) was selected by SOMAscan assays, and urinary GDF15 was validated as an independent predictor for DKD occurrence (adjusted OR 1.43, 95% CI 1.20-1.75) and progression (adjusted OR 1.39, 95% CI 1.15-1.75) by multivariate logistic regression. The receiver operating characteristic (ROC) analysis showed that the multibiomarker panel consisting of urinary ntOPN-to-creatinine ratio (UntOCR) and urinary GDF15-to-creatinine ratio (UGCR) had stronger abilities in forecasting the 2-year risk of DKD occurrence (AUC 0.838 vs. 0.818) and DKD progression (AUC 0.867 vs. 0.834) than the combination of estimated glomerular filtration rate (eGFRcr-cys) and urinary albumin-to-creatinine ratio (UACR). A nomogram was further built with a high C-index (0.8433). CONCLUSIONS:Compared with eGFRcr-cys combined with UACR, the models based on urinary ntOPN and GDF15 could provide more accurate tools for DKD prediction. Our attempt might provide a feasible approach for searching promising biomarkers for clinical applications.
BackgroundLactylation is a posttranslational modification involved in cellular metabolic and immune processes. Although dysregulated lactate metabolism has been implicated in type 1 diabetes (T1D), the genetic relevance of lactylation-related molecular traits remains poorly defined.MethodsSummary-data-based Mendelian randomization (SMR) was applied to integrate blood-derived methylation/expression/protein quantitative trait loci (mQTLs/eQTLs/pQTLs) for 353 lactylation-related genes with a T1D genome-wide association study (7467 cases and 10,218 controls). The HEIDI test evaluated heterogeneity. Shared genetic signals were assessed by Bayesian colocalization. Associations identified in the discovery analysis were replicated in the FinnGen_R12_T1D and FinnGen_R9_E4_DM1NEU cohorts. mQTL-eQTL SMR analysis evaluated methylation-expression regulatory relationships. Steiger directionality testing and GTEx tissue eQTL analyses were performed for prioritized genes.ResultsSMR prioritized PDAP1, PNKD, and HMGB1 as candidate genes associated with T1D. At the DNA methylation level, methylation at cg05715492 (PDAP1) was positively associated with T1D risk (OR = 1.29, 95% CI: 1.09-1.53), whereas cg05991184 (PNKD) showed an inverse association (OR = 0.73, 95% CI: 0.59-0.90). cg22712983, cg26786924, and cg04880052 in PNKD exhibited positive associations. cg25251738 (HMGB1) methylation was inversely associated with risk (OR = 0.85, 95% CI: 0.75-0.97). At the expression level, genetically predicted PDAP1 (OR = 0.26, 95% CI: 0.10-0.66) and HMGB1 (OR = 0.45, 95% CI: 0.22-0.91) expressions were inversely associated with T1D risk, whereas PNKD expression was positively associated (OR = 1.13, 95% CI: 1.04-1.23). mQTL-eQTL SMR analyses demonstrated significant methylation-expression associations at PDAP1, PNKD, and HMGB1 loci. Steiger directionality testing supported the observed associations. In GTEx datasets, higher PNKD expression was associated with increased T1D risk in both whole blood and spleen.ConclusionPNKD, PDAP1, and HMGB1 were prioritized as lactylation-related candidate genes associated with T1D risk through integrated genetic analyses. This finding generates hypothesis for future investigations into the potential involvement of lactylation-related pathways in T1D pathogenesis.
BACKGROUND:This study is aimed at examining the associations between insulin resistance (IR) surrogate indices, including TyG, TyG-BMI, TG/HDL-C, and METS-IR, and hyperuricemia (HUA) in young and middle-aged patients with Type 2 diabetes mellitus (T2DM). METHODS:A total of 1005 patients with T2DM were included in this cross-sectional study. Participants were classified into HUA and nonhyperuricemia (NHUA) groups according to serum uric acid concentrations and further stratified by age into young (18-44 years) and middle-aged (45-59 years) subgroups. Multivariable logistic regression analyses were performed to assess the associations between IR surrogate indices and HUA. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the discriminatory ability of these indices for HUA across sex- and age-specific subgroups. RESULTS:All IR surrogate indices were significantly higher in the HUA group than in the NHUA group. TyG and TG/HDL-C showed stable associations with HUA across the regression models, while the association for TyG-BMI was attenuated after additional adjustment when modeled continuously, although individuals in the highest quartile remained associated with higher odds of HUA. METS-IR was associated with HUA only in unadjusted models. Age-stratified analyses showed that none of the IR surrogate indices remained significantly associated with HUA after multivariable adjustment in younger patients, whereas TyG and TG/HDL-C remained associated with higher odds of HUA in middle-aged patients. ROC analyses indicated limited to moderate discriminatory performance (AUC < 0.75). TyG-BMI showed the highest AUC in younger patients (AUC = 0.715), while TG/HDL-C demonstrated relatively higher specificity in middle-aged patients. Sex-stratified analyses showed slightly higher AUC values in males than in females, although overall discrimination remained modest. CONCLUSION:IR surrogate indices showed varying associations with HUA in young and middle-aged patients with Type 2 diabetes. TyG and TG/HDL-C showed relatively stable associations with HUA across the regression models, whereas the associations for TyG-BMI and METS-IR were attenuated after additional adjustment. Overall, these indices demonstrated limited discriminatory performance and are not suitable as standalone diagnostic tools but may serve as adjunctive markers for preliminary risk stratification.
