Type 2 diabetes (T2D) and obesity are established risk factors for Alzheimer's disease and related dementias, yet the cerebrovascular mechanisms linking metabolic dysfunction to cognitive decline remain poorly understood. This study aims to assess BBB water permeability-surface area product in older adults with T2D and obesity using non-contrast WEPCAST MRI, and to evaluate associations between BBB integrity, metabolic markers, and cognitive function.

Twenty-eight older adults - 12 with T2D and obesity (BMI ≥ 30 kg/m²) and 16 age- and sex- matched controls - underwent WEPCAST MRI to quantify the BBB water permeability measures: permeability-surface area product (PS), water extraction fraction (E) and global cerebral blood flow (CBF), along with T1-Weighted structural MRI acquisition. Cognitive function and fasting blood biomarkers were assessed in all participants. Associations between PS versus metabolic and cognitive function were examined using linear regression adjusted for age and sex. An additional adjustment for statin use was made for hemoglobin A1c (HbA1c) and lipid markers.

T2D participants exhibited significantly elevated BBB water permeability-surface area product (PS: P = 0.001, Hedges' g = 1.10). Specifically, higher PS was associated with HbA1c (f² = 0.28, P = 0.016) and lower circulating cholesterol (total cholesterol: f² = 0.49, P = 0.003; LDL: f² = 0.45, P = 0.004; HDL: f² = 0.18, P = 0.053). The T2D group demonstrated lower scores across multiple domains including memory, attention, learning, executive function, and processing speed (g = 0.80-1.42). Higher PS was associated with poorer measures of executive function (P-values < 0.05).

Older adults with T2D and obesity exhibit elevated PS, detectable by non-contrast WEPCAST MRI. Higher PS was associated with higher glycemic burden and lower executive function, providing preliminary evidence that PS may serve as a novel imaging biomarker linking metabolic dysregulation to early cognitive vulnerability in T2D that follows a traditional "frontal-subcortical" pattern.

Cardiometabolic diseases often cluster as multimorbidity, yet current risk prediction models typically focus on a single disease and rarely incorporate social determinants. This study aims to develop a Bayesian risk prediction model for cardiometabolic multimorbidity in middle-aged Swedish adults. This prospective cohort included 11,964 adults without prior cardiometabolic disease from the Swedish CArdioPulmonary bioImage Study (SCAPIS; enrolment 2013-2016). Cardiometabolic disease was defined as incident type 2 diabetes (T2D), ischaemic heart disease/heart failure, or stroke. Regularised Bayesian logistic regression models were developed to predict any cardiometabolic disease (≥ 1 condition) and cardiometabolic multimorbidity (≥ 2 conditions) within 2-5 years. Twenty-two social and cardiometabolic risk predictors were considered. During follow-up, 6.0% of participants developed cardiometabolic disease(s) (5.7% with a single cardiometabolic disease and 0.3% with multimorbidity). The prediction model showed fair discrimination for any cardiometabolic disease (AUC 0.76, 95% CI 0.74-0.78) and good discrimination for multimorbidity (AUC 0.89, 95% CI 0.86-0.93). The highest predicted risks were observed among older foreign-born males with hypertension, low HDL-C, high waist circumference, and current/ex-smoker, with predicted risks of 34.7% (95% CrI 30.3%-39.5%) for any cardiometabolic disease and 4.4% (95% CrI 2.0%-7.9%) for multimorbidity. These findings suggest that social determinants and uncertainty estimates may provide useful information for cardiometabolic disease prediction, though further validation is needed before use in clinical practice.

Osteocalcin (OC), a bone protein, is evaluated by its proteoforms, which are implicated in various illnesses. Rapid, clinically used immunoassays are well-established. Epitope dependence, fragment cross-reactivity, uneven identification across carboxylation states, and lack of standardization restrict their efficacy. This study aims to characterize various OC proteoforms in patients with type 2 diabetes mellitus (T2DM) and vitamin D insufficiency and to develop a mass spectrometric immunoassay (MSIA) for their detection. The first MRM-MSIA test to specifically detect OC proteoforms in plasma with vitamin D deficiency-induced alterations in T2DM patients was developed and validated. A precise and selective MRM-MSIA was developed to assess OC fragments in plasma from T2DM patients with normal (DN) or deficient (DD) vitamin D levels. The approach examined OC-1 (aa64-71), OC-2 (aa64-70), and OC-3 (aa72-93) proteoforms. It met international linearity, precision, and accuracy criteria with variability <15% and intra/inter-day accuracy of 88.8% to 110.1%. The DD group had significantly higher OC-1 levels than the DN group. The receiver operating characteristic (ROC) curve for OC-1 produced an AUC of 0.8263 (95% confidence interval [CI], p = 0.0004). The developed MRM-MSIA measures plasma OC proteoforms with good specificity and sensitivity, making it a promising clinical diagnostic tool.

Background/Objectives: Gestational diabetes mellitus (GDM) is one of the most common metabolic disorders during pregnancy and is associated with adverse maternal and neonatal outcomes. Xenopsin-Related Peptide-1 (XRP-1) has recently emerged as a potential regulator of glucose metabolism and insulin homeostasis. This study evaluated serum XRP-1 levels and assessed their diagnostic performance in women with GDM. Methods: In this prospective observational study, 120 pregnant women between 24 and 28 weeks of gestation were enrolled, including 60 women with GDM and 60 healthy controls. Serum XRP-1 concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). Clinical, biochemical, and obstetric characteristics were compared between groups. Receiver operating characteristic (ROC) curve analysis and multivariable logistic regression were performed to evaluate the diagnostic performance and independent association of XRP-1 with GDM. Results: Serum XRP-1 levels were significantly higher in women with GDM than in healthy controls (3.45 ± 0.47 vs. 2.87 ± 0.46 ng/mL, p = 0.003). ROC analysis demonstrated moderate discriminatory performance for XRP-1 in identifying GDM (AUC = 0.658, 95% CI: 0.560-0.750), with an optimal cut-off value of 3.12 ng/mL, corresponding to 63.3% sensitivity and 61.7% specificity. Multivariable logistic regression demonstrated that serum XRP-1 remained independently associated with GDM after adjustment for maternal age, pre-pregnancy body mass index, gestational weight gain, and parity (adjusted OR 2.74, 95% CI 1.31-5.73; p = 0.007). HbA1c and C-reactive protein levels were also significantly higher in the GDM group. Conclusions: Serum XRP-1 concentrations were independently associated with GDM and demonstrated moderate diagnostic accuracy. Although XRP-1 cannot replace established diagnostic methods, it may represent a complementary biomarker for identifying gestational dysglycemia. Larger multicenter studies are required to validate its clinical utility.

Background/Objectives: Human islet amyloid polypeptide (IAPP) aggregation plays a critical role in the pathogenesis of type 2 diabetes mellitus (T2DM). Although metabolic alterations are a hallmark of T2DM, the functional roles of differential metabolites in regulating disease-associated molecular processes remain largely unexplored. This study aimed to establish a metabolomics-guided strategy for identifying endogenous metabolites with anti-amyloid activity and to investigate their underlying chemical interactions with IAPP. Methods: Untargeted metabolomic profiling of clinical samples from T2DM patients, obesity patients and healthy controls was performed to identify differential metabolites. Candidate metabolites were subsequently screened for their ability to modulate IAPP aggregation. Transmission electron microscopy (TEM), thioflavin T (ThT) fluorescence assays, and cell viability measurements were employed to evaluate their effects on fibril formation and cytotoxicity. Mass spectrometry was further used to characterize metabolite-IAPP interactions. Results: Metabolomic analysis identified 3-hydroxypyruvic acid (also known as β-hydroxypyruvic acid, hereafter referred to as HPA) as a significantly altered endogenous metabolite associated with T2DM and a candidate regulator of IAPP aggregation. Functional assays demonstrated that HPA effectively inhibited amyloid fibril formation, as evidenced by the absence of typical fibrillar structures and a prolonged lag phase during aggregation. HPA also significantly alleviated IAPP-induced cytotoxicity. Mass spectrometric analysis revealed the formation of HPA-IAPP oligomer complexes (n < 4), suggesting that HPA directly interacts with early oligomeric intermediates and interferes with their progression toward mature fibrils. Conclusions: This work demonstrates that untargeted metabolomics of clinical samples can serve as an effective strategy for discovering bioactive endogenous metabolites involved in disease-related molecular processes. The identification of HPA as a potential endogenous inhibitor of IAPP aggregation provides new chemical insight into the relationship between metabolic dysregulation and amyloidogenesis and highlights endogenous metabolites as a valuable source of potential therapeutic lead compounds.

Background: Imeglimin is a novel oral antidiabetic agent that improves mitochondrial function and glucose metabolism in patients with type 2 diabetes mellitus (T2DM). Its effects on liver enzymes remain unclear. We investigated the effects of imeglimin on hepatic biomarkers, particularly γ-glutamyl transpeptidase (γ-GTP), and the reversibility of these changes after treatment discontinuation. Methods: This post hoc analysis of the prospective INFINITY Study included 25 patients with T2DM who completed 6 months of imeglimin treatment followed by a 3-month withdrawal period. Clinical parameters were averaged within predefined 3-month study phases. Changes during treatment and after discontinuation were analyzed. Results: Imeglimin significantly improved glycemic control. The geometric mean γ-GTP decreased from 36.2 (27.1-48.4) U/L during the Baseline Phase to 31.1 (23.5-41.1) U/L during the Late Treatment Phase (p < 0.05). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) also showed downward trends, although these changes were not statistically significant. During the Withdrawal Phase, γ-GTP returned to 35.6 (26.4-48.5) U/L (p < 0.05 vs. Late Treatment Phase). Patients with baseline γ-GTP >50 U/L showed larger but non-significant changes. Changes during treatment and after discontinuation were inversely correlated (r = -0.480, p = 0.015). Only total cholesterol correlated with γ-GTP during both treatment (r = 0.554, p = 0.005) and withdrawal (r = 0.450, p = 0.024). Conclusions: γ-GTP levels showed a significant decrease during imeglimin treatment and increased during the post-treatment observation period in patients with T2DM. Exploratory analyses identified an association between changes in γ-GTP and total cholesterol; however, these findings should be interpreted cautiously and require confirmation in prospective studies with prespecified endpoints.

Artificial sweeteners are commonly used as sugar substitutes because they provide sweetness with little or no caloric content. However, the relationship between artificial sweetener consumption and type 2 diabetes (T2D) remains controversial. This meta-analysis was conducted to investigate the longitudinal association between artificial sweetener intake and T2D among adults.

Electronic databases in English and Chinese were searched for prospective studies published from inception to March 2025. Using a random-effects model, the pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to investigate the longitudinal association between artificial sweetener intake and T2D among adults aged 18 years and older. Between-study heterogeneity was assessed using the I ² statistic, while the robustness of the findings was examined using a leave-one-out sensitivity analysis. Publication bias was evaluated by inspection of funnel plots and Egger's regression test.

A total of six cohort studies including 721,003 participants were analyzed in this meta-analysis. Compared with those with low or no consumption of artificial sweeteners, participants with higher artificial sweetener intake were more likely to develop T2D (pooled HR = 1.31, 95% CI = 1.16-1.49). Substantial heterogeneity was observed across studies (I ² = 86.02%), while the overall estimate remained stable in sensitivity analysis. No significant publication bias was observed among the studies included in this meta-analysis.

A longitudinal association was observed between artificial sweetener intake and the risk of developing T2D among adults. This study has important public health implications. The findings of this study highlight that artificial sweeteners may not be a completely risk-free alternative to sugar in dietary interventions aimed at reducing high-energy sugar intake and suggest that their potential adverse metabolic effects should be considered in public health policy-making and clinical dietary recommendations regarding artificial sweetener intake.

Peripheral arterial disease (PAD) is a common comorbidity in patients undergoing coronary artery bypass grafting (CABG) and is associated with increased morbidity. Early identification of PAD in this population is clinically important; however, the relationship between coronary disease complexity and peripheral arterial involvement remains unclear.This study aimed to evaluate the association of the SYNTAX score, ankle-brachial index (ABI), and toe-brachial index (TBI) with the development of peripheral arterial disease following CABG.

In this retrospective study, 87 patients who underwent CABG were evaluated four years after surgery for the presence of PAD. Baseline SYNTAX score, ABI, and TBI were measured prior to CABG. PAD was diagnosed based on clinical symptoms in combination with abnormal ABI and/or TBI findings and was confirmed by Doppler ultrasonography when indicated. Associations between SYNTAX score, ABI, TBI, and PAD were analyzed using appropriate statistical tests.

During the follow-up period, 7 patients (8.0%) developed PAD. Diabetes mellitus was significantly more prevalent among patients with PAD compared to those without PAD (85.7% vs. 45.0%, P = 0.039). Right ABI (P = 0.005), left TBI (P = 0.008), and right TBI (P = 0.010) were significantly associated with PAD, whereas left ABI was not. Although the SYNTAX score was not directly associated with PAD incidence, higher SYNTAX scores were significantly correlated with greater reductions in both left ABI (r = -0.296, P = 0.005) and right ABI (r = -0.220, P = 0.040) 4 years after CABG.

Peripheral arterial disease following CABG was significantly associated with diabetes mellitus and with lower ABI and TBI values, particularly in the right lower extremity. While the SYNTAX score was not directly associated with PAD occurrence, it was correlated with longitudinal declines in ABI, suggesting an association between coronary disease complexity and systemic vascular dysfunction.

Despite growing recognition of the mental health consequences of type 2 diabetes (T2D), the prevalence, overlap and associated factors of psychological burden-encompassing diabetes distress (DD), depression and anxiety remain underexplored in the Indian population. This study aimed to examine these dimensions among Indian adults with T2D.

This cross-sectional study included 1925 adults (≥18 years) with T2D enrolled in an online diabetes management programme at the Freedom from Diabetes Clinic, Pune, India (December 2023 to December 2024). Socio-demographic, anthropometric, clinical and biochemical data were recorded. DD, depression and anxiety were measured using the Type 2 Diabetes Distress Assessment System, Patient Health Questionnaire-9 and Generalised Anxiety Disorder-7, respectively. Multivariable logistic regression identified factors independently associated with each outcome; results were interpreted using effect size (Cohen's d) to prioritise clinical significance.

DD was the most prevalent condition (53.1%), followed by depression (20.3%) and anxiety (17.3%). Substantial comorbidity was observed: 7.5% experienced all three conditions simultaneously, while 42.3% remained symptom-free. Depression and anxiety showed a strong intercorrelation (ρ=0.692), with moderate correlations between DD and both conditions (ρ=0.460-0.466). Absence of prior depression history was the strongest factor associated with psychological burden across all outcomes (adjusted OR (AOR)/Firth OR: DD=50.44, depression=2.11, anxiety=2.24; all p<0.001), though the large AOR for DD reflects quasi-complete separation; Firth's penalised regression yielded a consistent estimate (OR=42.67, p<0.001). The anxiety model required Firth's penalised regression as the primary method due to non-convergence in standard logistic regression caused by quasi-complete separation. Both DD and anxiety findings are presented as hypothesis-generating. Depression and anxiety were strongly co-associated (AORs >13.0). Additional factors associated with burden included younger age (<45 years), female sex, poor glycaemic control and insulin use.

Indian adults with T2D experience substantial, overlapping psychological burden. These findings support the integration of routine, comprehensive mental health screening using validated tools into diabetes care, with particular attention to individuals without prior mental health history.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) and Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) are effective antidiabetic therapies in patients with type 2 diabetes mellitus (T2DM). However, real-world evidence regarding the combined effectiveness and safety of these agents in this population remains limited. This study aimed to evaluate the effectiveness and safety of GLP-1RA/SGLT2-i therapy (GLP-1RAs and/or SGLT2-i) in patients with T2DM, in comparison with standard treatment approaches.

This retrospective cohort study reviewed medical records of patients with T2DM attending the diabetes clinic at the University Hospital of Sharjah. Patients on anti-diabetic medications for at least 6 months were included, while those with irregular follow-up, a T2DM diagnosis within the past year, or non-diabetic obesity were excluded. Data were collected at baseline, 3, 6, 12, and 18 months and compared the effectiveness (HbA1c, blood pressure, weight) and safety (gastrointestinal and genitourinary symptoms) of GLP-1RA/SGLT2-i therapy (GLP-1 RA and/or SGLT2-I) with standard treatment.

A total of 199 patients were included in the analysis, of whom 50% were female, with a median age of 61 years (interquartile range [IQR] = 19). Patients receiving the GLP-1RA/SGLT2-i therapy demonstrated a statistically significant reduction in body weight (p = 0.002), whereas no significant weight change was observed in the standard treatment group over the 18-month follow-up period.Glycaemic outcomes showed greater improvement in the GLP-1RA/SGLT2-i therapy (median change:-2% VS -1%; p=0.001) in 18 months. Both groups demonstrated modest improvements in blood pressure, with no clear superiority observed between the treatment arms.Regarding safety, hypoglycaemia was the most commonly reported adverse event in the standard treatment group (5.5%, n=11). Within the GLP-1RA/SGLT2-i therapy group, GLP-1 RA were associated with gastrointestinal side effects in 0.5% of patients, leading to treatment discontinuation, while SGLT2 inhibitors were associated with genitourinary symptoms in 2.5% of patients.

GLP-1RA/SGLT2-i therapy with SGLT2-i and/or GLP-1RA showed clinically significant weight loss and HbA1c, with a low percentage of patients experiencing side effects that led to discontinuation and improvement in blood pressure.