BACKGROUND: Thrombosis of varicocele veins is extremely rare and may mimic other causes of acute scrotal pain. Spontaneous thrombosis occurring in adults without trauma, surgery, or known coagulation disorders is seldom reported. CASE PRESENTATION: A 54-year-old male with type 2 diabetes mellitus presented with acute left testicular pain radiating to the left inguinal region. Physical examination revealed a soft left testis with a palpable left scrotal sac cord-like swelling, while the right testis and scrotum were normal. Color Doppler ultrasonography, performed in supine and erect positions using a SonoAce X8 (Medison, Korea) ultrasound system with a 5-12 MHz superficial probe, demonstrated a grade III left varicocele with dilated refluxing veins and echogenic intraluminal thrombus within some scrotal veins. There was no history of trauma, heavy activity, surgery, or coagulation disorder. A diagnosis of spontaneous thrombosis of a left-sided varicocele was established. CONCLUSIONS: This case highlights the importance of differentiating primary from secondary varicoceles, excluding tumor thrombus, and recognizing the role of diabetes-induced endothelial dysfunction as a potential risk factor. Awareness of this rare entity can guide accurate diagnosis and management, preventing unnecessary intervention.

BACKGROUND: Meteorin-like protein (Metrnl) is a novel secreted protein produced by multiple tissues, which is involved in metabolic regulation, immune homeostasis, and tissue repair. In recent years, research on the role of Metrnl in diabetes has advanced significantly. However, substantial controversies persist regarding its expression dynamics, protective roles, and underlying molecular mechanisms in diabetes and its complications. MAIN BODY: This review synthesizes current evidence to systematically analyze the complex roles of Metrnl in diabetes. Preclinical studies have demonstrated that Metrnl primarily improves insulin resistance, protects pancreatic β-cells, and mitigates diabetes related damage to kidney, heart, and skin through multiple pathways, including the KIT receptor, AMPK and Wnt/β-catenin signaling pathways.In contrast, clinical data exhibit significant heterogeneity. Reports on circulating Metrnl levels in patients with type 2 diabetes are highly inconsistent, with findings of decreased, increased, or no significant changes. Such discrepancies are largely attributed to methodological inconsistencies and clinical confounders. Similar inconsistencies are observed in studies on gestational diabetes. Importantly, Metrnl also displays markedly different or even opposing expression patterns across various diabetic complications, highlighting its tissue-specific regulatory characteristics. CONCLUSIONS: In summary, Metrnl is a pleiotropic molecule involved in the pathophysiological processes of diabetes and its complications, and it holds potential as a candidate biomarker or therapeutic target. However, its clinical translation faces key challenges, including insufficient standardization of detection methods, unclear characterization of receptor systems, and undefined pharmacological properties. Therefore, although Metrnl shows promise in preclinical models, its clinical utility requires rigorous validation, and its roles should be interpreted cautiously based on the current body of evidence.

BACKGROUND: Trial teams frequently make language-related, non-clinical eligibility decisions during recruitment. They need to ensure that patients understand the conditions and implications of trial participation and either have the necessary language skills to participate, or receive appropriate accommodations (e.g. translation or interpreting). Fair and consistent assessments are necessary to avoid unduly excluding patients, which could limit external validity and exacerbate inequalities. This study examines how trial teams make language-related eligibility decisions. METHODS: We conducted a systematic review of National Institute for Health and Care Research (NIHR) research reports (2010-2022) for UK-based randomised controlled trials (RCTs) recruiting adults for two conditions that disproportionately affect ethnic minority populations: clinical depression and type 2 diabetes mellitus (T2DM). Two researchers independently screened titles and abstracts and extracted data. We analysed the communication demands of the interventions and primary outcome measures in relation to how language screening was reported, including procedures or instruments used as proxies for language-related gatekeeping. RESULTS: We assessed 185 titles and abstracts from NIHR monographs. Thirty-two RCTs (23 depression, 9 T2DM) ultimately met our inclusion criteria. Ethnic diversity was minimal, particularly in the depression RCTs, where the median proportion of White participants was 97%. Language screening practices were inconsistent across studies and were often poorly aligned with the actual linguistic demands of the trial. Half of the included RCTs explicitly reported a language-based eligibility criterion, including 63% of trials evaluating talking therapies for depression compared to 27% of trials assessing pharmacological, device-based, or surgical interventions. Explicit and implicit language-related gatekeeping measures included the ability to complete research assessments involving language (sometimes to a prespecified score cut-point), provide informed consent, and engage in the intervention as judged by recruiters. Translation and interpreting support were mentioned in one depression study. CONCLUSIONS: This review exposes methodological practices that may impede diverse patients' participation. Linguistic demands of the interventions and outcomes need to be considered in justifying language-related screening and accommodations. Participants' language variables need to be disentangled from ethnicity through routine data collection. A purpose-built screening tool that is universally applied to all participants could lead to fairer, more consistent assessments. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42021267905. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=267905. Registered on October 21 2021.

BACKGROUND: Research on gestational diabetes mellitus has mainly focused on glucose metabolism, but improving glycemic control has not eliminated the complication rate in these pregnancies. The aim of this study was therefore to investigate how other metabolic and cardiovascular risk factors in women with gestational diabetes mellitus contribute to adverse pregnancy outcomes, thereby giving a more nuanced characterization of maternal metabolic status and the effects on fetal outcome. METHODS: This cohort study included mother-infant pairs with maternal gestational diabetes mellitus (n = 722) in the Central Region of Denmark from 2019 to 2022. Anthropometric and metabolic data were collected during a pregnancy visit at week 34-38. Offspring data were collected from an audit of the participants' medical records. Large for gestational age (LGA) was defined as birth weight above the 90th centile for gestational age and sex. Logistic and linear regression were performed to determine the association between maternal metabolic cardiovascular risk factors and adverse pregnancy outcomes. Analyses were adjusted for age, ethnicity, and parity. Exposures unrelated to weight were adjusted for pregestational body mass index. Furthermore, outcome rates were stratified by treatment (insulin vs. diet-only). RESULTS: This study found increased odds for LGA with pre-pregnancy body mass index ≥ 30 kg/m (adjusted odds ratio (aOR)) = 2.26 [1.37;3.73]), increasing diagnostic oral glucose tolerance test 2-h glucose value (aOR = 1.20 [1.05;1.38]), 3rd trimester total cholesterol (aOR = 1.25 [1.05;1.49]), 3rd trimester triglycerides (aOR = 1.28 [1.07;1.53]), 3rd trimester HbA1c (aOR = 1.13 [1.07;1.18]), high gestational weight gain (aOR = 1.76 [1.07;2.87]), and insulin-treatment compared to diet-only treatment (risk ratio = 2.51[1.89;3.33]). CONCLUSION: Strong associations between pre-pregnancy body mass index, glycemic measures, and lipid profiles with adverse neonatal outcomes, particularly large for gestational age, underscore the importance of a broader risk assessment in women with gestational diabetes mellitus, not only based on glycemic parameters but also including weight prior to and during pregnancy and lipid status.

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome stages 0-3 represent a critical window for preventing progression to overt cardiovascular disease (CVD). Insulin resistance (IR) is central to CKM pathophysiology, yet the comparative utility of longitudinal IR patterns (cumulative burden and longitudinal pattern groups) across multiple surrogates, and the mediating role of biological ageing, remain unexamined in this preclinical population. METHODS: We included 3948 participants with CKM stages 0-3 from the CHARLS 2011-2020. Twelve IR surrogates (TyG and derivatives, METS-IR, CTI, eGDR, TG/HDL-C) were assessed via cumulative exposure and K-means-derived pattern groups. Associations with incident CVD were evaluated using Fine-Gray competing risk models, spline regression, receiver operating characteristic analyses, and quantile-based models. Mediation analyses quantified the contribution of biological age acceleration. RESULTS: 756 (19.1%) of 3948 participants with CKM stages 0-3 developed incident CVD. Higher cumulative levels and the least favorable pattern groups of TyG-based indices, METS-IR, CTI, and TG/HDL-C were consistently associated with increased CVD risk, whereas elevated cumulative eGDR was protective. Cumulative eGDR demonstrated superior predictive performance for CVD risk (AUC: 0.613; all DeLong P < 0.05 vs. other indices) and was consistently identified as the top contributor by both WQS and Qgcomp analyses. Both KDM- and Light-BioAgeAccel partially mediated several IR-CVD associations (up to 45.8% and 25.9%, respectively). CONCLUSIONS: Sustained IR burden and unfavorable longitudinal IR patterns are linked to higher CVD risk in CKM stages 0-3, partly through accelerated biological aging. Integrating longitudinal IR profiling with aging metrics may sharpen early risk stratification and support scalable prevention targeting upstream metabolic drivers.

BACKGROUND: This study aimed to characterize comorbidity distribution patterns and assess their clinical impact on therapeutic effectiveness in elderly pulmonary tuberculosis (PTB) patients, establishing an evidence base for risk-stratified clinical decision-making. METHODS: A retrospective cohort study was conducted among 1,340 hospitalized PTB patients (aged ≥ 60 years) from January 2020 to January 2024. Demographic characteristics, comorbidity data, and treatment outcomes were extracted from electronic medical records. Patients were categorized into treatment success (n = 1,105) and adverse outcome (n = 235) groups according to WHO criteria. Propensity score matching (PSM) was employed to balance baseline confounders, followed by multivariate logistic regression to evaluate associations between comorbidities and adverse outcomes. RESULTS: Comorbidities were prevalent in 81.64% (1,094/1,340) of patients, with stratification as follows: single comorbidity (30.67%, 411), dyad (26.64%, 357), triad (18.13%, 243), and complex multimorbidity (≥4 conditions: 6.19%, 83). The most frequent comorbidities were chronic heart diseases (31.12%), chronic lung diseases (27.84%), and hypertension (26.49%), followed by diabetes mellitus(20.30%) and psychiatric disorders (15.07%). The adverse outcome rate was 17.54% (235/1,340), comprising 98 treatment failures (7.31%), 89 deaths (6.64%), and 48 treatment terminations (3.58%).Multivariate analysis identified the following independent risk factors: diabetes mellitus(adjusted odds ratio [aOR]=2.73, 95% confidence interval [CI]:1.91-3.90), chronic kidney diseases (aOR = 6.31, 95% CI:4.00-9.96), active malignancy (aOR = 3.27, 95% CI:2.07-5.14), and multimorbidity (≥3 comorbidities; aOR = 1.71, 95% CI:1.20-2.46) (all p < 0.05). CONCLUSIONS: Elderly PTB patients exhibit a high comorbidity burden. Diabetes mellitus, chronic kidney diseases, active malignancy, and multimorbidity significantly increase the risk of adverse treatment outcomes. These findings underscore the necessity for multidisciplinary collaborative management models and early comorbidity screening to optimize clinical interventions. CLINICAL TRIAL NUMBER: Not applicable.

BACKGROUND: Prediabetes is an early stage of type 2 diabetes mellitus (T2DM) that is prevalent around the world. A combination of genetic and lifestyle factors is contributed in conversion of prediabetes to T2DM. The present study aimed to investigate the association of the ITLN1 gene Val109Asp polymorphism with dietary patterns, glycemic factors, and anthropometric indices in women with prediabetes. METHODS: This cross-sectional study was carried out on 202 women with prediabetes aged 18-65 years who were selected from the healthcare center using the convenience sampling method. Fasting blood samples, anthropometric measurements, and information about the dietary intake of the participants were collected. The ITLN1 gene Val109Asp polymorphism genotypes were recognized by the high-resolution melting-polymerase chain reaction (HRM-PCR) method. Dietary patterns were obtained by exploratory factor analysis and JASP software. Data analyses were conducted by analysis of covariance and ordinal regression using IBM SPSS Statistics software. RESULTS: AA, AT, and TT genotypes of the ITLN1 polymorphism were found in 15.8%, 52.0%, and 32.2% of participants, and three dietary patterns, including vegetarian, high-fat, and mixed dietary patterns, were extracted. According to the ordinal regression, participants in the AT genotype had a lower chance of having a high-fat dietary pattern compared to the AA genotype (Adjusted odds ratio (AOR) (CI 95%): 0.466 (0.219, 0.989), p = 0.047). The ANCOVA test also indicated that participants with the AT (Mean difference (MD) (CI 95%): -3.073 (-5.245, -0.901), p = 0.007) and TT (MD (CI 95%): -3.188 (-5.513, -0.862), p = 0.006) genotypes had a decreased body weight compared to the AA genotype. Moreover, women in the TT genotype group had higher waist circumference compared to the AA genotype (MD (CI 95%): 2.557 (0.060, 5.055), p = 0.045). Individuals with genotypes AT (MD (CI 95%): 0.028 (0.011, 0.044), p = 0.001) and TT (MD (CI 95%): 0.022 (0.005, 0.040), p = 0.013) also have higher WHthR compared to the AA genotype. There was no significant association between the ITLN1 polymorphism genotypes and glycemic parameters in the adjusted model. CONCLUSION: The findings revealed a link between the ITLN1 Val109Asp polymorphism and dietary pattern 2 and general and central obesity in women with prediabetes. Further well-designed studies are required to confirm these findings and clarify the association of the ITLN1 polymorphism with glycemic factors.

BACKGROUND: Regulation of body weight and glucose homeostasis includes the coordinated activity of hypothalamic neurons and adipocytes within a neuroendocrine network whose dysfunctions underlie obesity, insulin resistance, and type 2 diabetes (T2D). The neuronal surface P antigen (NSPA) is a plasma membrane protein with characteristics of an E3 ubiquitin ligase encoded by the unique gene Zzef1, which has been linked to T2D. NSPA's original discovery in neurons, as a cell-surface cross-reacting autoantigen of anti-P antibodies that associate with cognitive dysfunctions in patients with systemic lupus erythematosus, focused its study on hippocampal-mediated memory processes. Anti-P effects and NSPA-KO mice revealed that NSPA contributes to glutamatergic transmission and synaptic plasticity through mechanisms involving ubiquitylation processes coupled to the stability of NMDAR at the synaptic density. However, NSPA is also expressed in hypothalamic neurons, where glutamatergic synapses and NMDAR function are pivotal to the neuroendocrine control of metabolic and energy balance. Transcriptomics suggests an extended expression of NSPA in metabolically relevant peripheral tissues, including the adipose tissue. Here, we investigated whether body weight regulation and energy homeostasis involve NSPA. METHODS: We characterized the phenotype of NSPA-KO mice under standard chow and high-fat/high-sugar (HFHS) obesogenic diet conditions, monitoring metabolic parameters and WAT's expression of enzymes and transporters of the glucose metabolism and lipolysis. RESULTS: NSPA-KO mice exhibit: (i) Increased body weight gain, despite similar food intake and higher horizontal locomotion activity; (ii) A shift towards a glycolytic metabolism reflected in an increased RER, accompanied by an increased WAT mass indicating higher lipogenesis; (iii) Improved early glycemic response to glucose challenge, attenuating the acute glycemic rise induced by HFHS feeding; (iv) Reduced insulin sensitivity at 20 weeks of age; (v) Elevated Glut1 and LDH, with decreased Glut4, and HSL S563 phosphorylation in WAT, indicating altered glucose uptake, glycolysis and lipolysis; (vi) Decreased levels of phosphorylated STAT3 in the hypothalamus, suggesting attenuated leptin signaling. CONCLUSIONS: This study identifies NSPA as a novel regulator of energy homeostasis, body weight, glucose metabolism, insulin sensitivity, and adipose tissue accumulation, presumably acting at both the hypothalamus and WAT, with potential implications for obesity and metabolic disorders.

INTRODUCTION: Metabolic syndrome (MetS) is a series of health conditions, including insulin resistance, abdominal obesity, hypertension, and dyslipidemia. In diabetic patients, MetS elevates the risks of cardiovascular disease, stroke, and cardiovascular mortality. Its predictors are context-dependent, varying by diagnostic criteria and population characteristics, thus requiring localized studies to identify specific determinant factors. OBJECTIVE: To assess predictors of MetS among type II diabetic patients (T2DM) visiting public hospitals in Sidama Region, Ethiopia, from January 25- March 25, 2025. METHODS: An institutional unmatched case control study design was employed among 132 cases and 268 controls. Data were collected using a structured, interviewer-administered questionnaire adapted from the World Health Organization (WHO) STEPS instrument, complemented by laboratory investigations and standardized anthropometric measurements. MetS was diagnosed using the International Diabetes Federation (IDF) criteria. Bivariable and multivariable logistic regression models were fitted to determine predictors of MetS. Results were presented using adjusted odds ratios (AOR) with 95% confidence intervals (CI). RESULT: The mean age (± standard deviation) of the cases and controls was 56.9 (± 8.2) and 49.5 (± 8.1) years, respectively. MetS was found to be higher in female (61.4%) study participants than in male (38.6%). The identified predictors of MetS with 95% CI (AOR) were older age: 5.74 (2.56, 12.88), female sex: 2.91 (1.61, 5.26), urban residence: 2.59 (1.41, 4.75), monthly income > 3500 Ethiopian Birr: 4.30 (2.23, 8.28), family history of hypertension: 2.79 (1.47, 5.29), duration with DM: 5-9 years: 3.06 (1.57, 5.99) and ≥ 10 years: 3.61 (1.54, 8.48), and poor glycemic control: 3.93 (2.17, 7.13). CONCLUSION: The findings call for prioritizing targeted screening, lifestyle interventions, health education, and community-based programs to enhance the prevention, early detection, and management of MetS among T2DM patients.

Diabetes-related blindness creates a major challenge for the healthcare system due to its high treatment cost. The presence of type 2 diabetes has been associated with an increased risk of hypertension, and vice versa, and their coexistence increases the risk of diabetic retinopathy. Despite this fact, to date, most of the research on diabetic retinopathy in Northwestern Ethiopia has been limited and has not considered the diabetic patient comorbid with hypertension. The study aims to determine the incidence and its predictors among patients with type-2 diabetes and hypertension at Debre Markos comprehensive and specialized hospitals. An institution-based retrospective follow-up study was conducted among 600 patients with type 2 diabetes and hypertension between June 30/2014, and July 01/2023. Data were entered using Epidata version 4.6 and analyzed using STATA version 17. All variables with P-values less than 0.25 in the bi-variable analysis were considered for multivariable analysis. Parametric survival models were fitted, and the Weibull model was selected based on its lowest AIC and BIC. Multicollinearity was checked using VIF. Statistical significance was declared at 95% CI with a P-value less than 0.05. Patients were followed for different follow-up times: with a median follow-up period of 85.2 months (IQR: 25.1). The overall incidence density of diabetic retinopathy was 5.16 per 1,000 person-months (95% CI 4.33-6.14). Injection medication (AHR = 0.24, 95% CI [0.18, 0.31]) and treatment duration ≥ 6 years (AHR = 0.30, 95% CI [0.15, 0.65]) decreased the hazard of developing the event. Whereas, poor glycemic control (AHR = 1.87, 95% CI [1.66, 2.31]), age ≥ 60 years (AHR = 1.51, 95% CI [1.09, 2.12]), obesity (AHR = 2.04, 95% CI [1.63, 2.71]), glycated hemoglobin (AHR = 1.88, 95% CI [1.42, 2.71]), and family history of diabetes (AHR = 2.12, 95% CI [1.16, 4.11]) had increased the hazard of developing diabetic retinopathy. The findings indicate a substantial burden and earlier occurrence of diabetic retinopathy. Therefore, early and regular screening could be prioritized, particularly for high-risk groups such as older patients, those with poor glycemic control, obesity, and a family history of diabetes. Clinically, targeting HbA1c reduction, blood pressure control, and weight reduction interventions should be recommended at all follow-up visits.

Epidemiological studies have linked type 2 diabetes to Parkinson's disease (PD), but causality and mechanisms remain unclear. Here, using Mendelian randomization, we identify genetically elevated 2‑hour post‑load glucose as a causal risk factor for PD. To investigate the underlying biology, we developed a mouse model combining glucose intolerance with MPTP‑induced dopaminergic injury. Glucose intolerance markedly exacerbated motor and cognitive deficits, dopaminergic neuron loss, and α‑synuclein accumulation. Mechanistically, hyperglycemia synergized with MPTP to impair mitochondrial respiration, collapse membrane potential, and disrupt cristae architecture. These changes were accompanied by iron overload, glutathione depletion, lipid peroxidation, downregulation of the ferroptosis suppressor GPX4, and upregulation of the pro‑ferroptosis enzyme ACSL4-a signature of ferroptosis. The same pathway was activated in human dopaminergic neurons exposed to high glucose and MPP⁺. Our findings establish that glucose intolerance directly aggravates PD pathology via mitochondrial dysfunction and ferroptosis, suggesting that targeting this cell death pathway or improving glycemic control could offer therapeutic opportunities for PD, especially in patients with metabolic comorbidities.

OBJECTIVES: To assess longterm weight and comorbidity outcomes following bariatric surgery at a publicly funded obesity service. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Cohort of 203 individuals who underwent bariatric surgery between 1 October 2009 and 1 June 2024 were followed for 1-10 years postoperatively. Major obesity-related comorbidities assessed included type 2 diabetes mellitus (T2DM), dyslipidaemia, hypertension, obstructive sleep apnoea (OSA), arthritis and arthralgia, and depression and anxiety. MAIN OUTCOME MEASURES: Percentage change in weight over time and change in prevalence of obesity-related comorbidities. RESULTS: At baseline the mean age was 50.4 years (SD, 11 years), mean weight 134.6 kg (SD, 30.3 kg), mean BMI 49.3 kg/m (SD, 9.5 kg/m) and 59.6% (n = 121) of the cohort had ≥ three of the six comorbidities. Maximal weight loss occurred at 18-months post-surgery with a mean 26.6% (SD, 9.8%) weight reduction. Data were available for 45% (n = 73/162) at 5 years and 38% (n = 19/50) of the cohort at 10 years, with mean weight loss of 23% and 21.9%, respectively. Compared to baseline, at 5 years there was a significant reduction in the proportion of the cohort with T2DM (-13.2%, p < 0.001), OSA (-11.4%, p < 0.001), hypertension (-10.4%, p < 0.002) and dyslipidaemia (-9.2%, p < 0.003), but there was no change in the proportion with anxiety, depression, arthritis or arthralgia. CONCLUSIONS: Bariatric surgery in a publicly funded service was shown to have long-term efficacy, with weight loss maintained to 10 years follow-up and a reduction in the incidence of four major obesity-related comorbidities after 5 years.

OBJECTIVE: This study aimed to assess whether visceral fat area (VFA) enhances prediction of diabetic microvascular disease (DMV) beyond the triglyceride-glucose (TyG) index in a county-level population of individuals with type 2 diabetes mellitus. METHODS: A cross-sectional study was conducted among 1042 adults with type 2 diabetes between 2022 and 2025. DMV was defined as the presence of diabetic retinopathy, chronic kidney disease, or diabetic peripheral neuropathy. Multivariable logistic regression analysis, receiver operating characteristic curve analysis, decision curve analysis, and calibration plots were applied to evaluate model performance. The predictive value of the TyG index was first assessed, after which the incremental contribution of VFA was quantified using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: After adjustment for established risk factors, each 1-unit increase in TyG was associated with 31% higher odds of DMV (OR 1.31, 95% CI 1.04-1.65). VFA was not independently associated with DMV (OR 1.00, 95% CI 0.99-1.00). The area under the receiver operating characteristic curve (AUC) was 0.740 for the TyG-plus-covariates model and 0.741 for the TyG-plus-VFA-plus-covariates model. The categorical NRI was 0.8% (p = 0.310), and the IDI was 0.04% (p = 0.258). Subgroup analyses for diabetic retinopathy, chronic kidney disease, and diabetic peripheral neuropathy Subgroup analyses for diabetic retinopathy, chronic kidney disease, and diabetic peripheral neuropathy yielded consistent results: categorical NRI, IDI, and ΔAUC 95% CIs all crossed zero. Sensitivity analyses supported the primary findings. CONCLUSIONS: The TyG index was independently associated with diabetic microvascular disease, whereas the addition of visceral fat area provided negligible incremental predictive value beyond established risk factors.

Ultra-processed foods (UPFs) are industrial products formulated largely from extracted or refined food constituents, such as sugars, starches, oils, and protein isolates, and typically contain additives (e.g., flavorings, colorants, emulsifiers, sweeteners, and preservatives) to improve taste, appearance, and shelf stability. UPFs are often energy-dense, high in added sugars, unhealthy fats, and sodium, and low in dietary fiber and essential micronutrients. High intake has been consistently linked to increased risks of obesity, cardiovascular disease (CVD), type 2 diabetes, and all-cause mortality. The cardiovascular health implications of UPF consumption remain incompletely understood. This position review aims to synthesise current evidence on associations between UPF intake and CVD and to survey the positions of major scientific organisations regarding UPF and cardiovascular health. Given substantial heterogeneity in UPF definitions, exposure assessment, cardiovascular outcomes, and study designs, a position review approach is appropriate to characterise how this relationship has been examined to date.

PURPOSE/OBJECTIVES: To characterize the long-term endoscopic natural history of chronic radiation proctitis (CRP) and identify predictors of severe lesions in patients with locally advanced rectal cancer (LARC) from the STELLAR study. METHODS: This secondary analysis included 74 patients with locally advanced rectal cancer undergoing anal-preserving surgery after neoadjuvant therapy (39: short-course radiotherapy/TNT; 35: long-course chemoradiotherapy/CRT). Systematic endoscopic follow-up (>2 years) was performed, with mucosal damage graded by the Vienna Rectoscopy Score (VRS). Multivariate analyses identified factors for severe (VRS≥3) and persistent severe CRP. RESULTS: The incidence of VRS≥3 CRP was 33.3% (TNT) versus 20.0% (CRT) (P=0.197). Endoscopic severity peaked at 2 years post-radiation. A distinct recovery trend was observed in the TNT group, but not in the CRT group. Diabetes mellitus was an independent risk factor for both severe CRP (HR 5.46, 95% CI 1.25-23.89, P=0.024) and persistent severe CRP (HR 6.09, 95% CI 1.23-30.23, P=0.027). ECOG performance status 1 predicted persistent severe CRP (HR 8.81, 95% CI 1.50-51.68, P=0.016). CONCLUSION: Hypofractionated radiotherapy (TNT) did not increase severe CRP risk and showed a favorable recovery pattern. Diabetes and reduced performance status are strong, independent predictors of severe and persistent endoscopic injury, enabling risk-stratified patient management. These findings support tailored surveillance and preventive strategies for high-risk individuals.

BACKGROUND: Metabolic syndrome (MetS) promotes skeletal muscle complications, which can impair glucose uptake and contribute to the development of diabetes. In contrast, powder bergamot juice (PBJ) possesses bioactive compounds with potential therapeutic applications. OBJECTIVE: To evaluate the effects of PBJ on skeletal muscle complications in an experimental model of metabolic syndrome. METHODS: Male Wistar rats were fed a control diet (n=20) or a high-sugar fat diet (n=20) with 25% sucrose in drinking water (w/v) for 20 weeks to induce MetS. After this period, animals were then redistributed into two groups (n=7 each): MetS and MetS + PBJ. PBJ was administered by gavage at 250 mg/kg daily for 10 weeks. Systemic metabolic parameters were measured, and lipid content, fatty acid profile, inflammatory and oxidative stress biomarkers, insulin signaling proteins, and histological outcomes were evaluated in the quadriceps. RESULTS: PBJ treatment significantly attenuated systemic adiposity and dyslipidemia. In the quadriceps, PBJ markedly reduced triglyceride accumulation and modulated the fatty acid composition, lowering saturated fatty acid (SFA) levels and increasing the desaturation index. Oxidative stress markers, including malondialdehyde, advanced oxidation protein products, and protein carbonylation, were reduced, while antioxidant defenses were enhanced by upregulating nuclear factor erythroid 2-related factor 2 (NRF-2) signaling. Pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), were significantly decreased and interstitial collagen deposition was also attenuated. Crucially, PBJ modulated the endocrine response and increased total protein expression of glucose transporter type 4 (GLUT-4) without altering IRS-1 phosphorylation. CONCLUSION: PBJ attenuated skeletal muscle complications resulting from MetS. However, due to the absence of a healthy control group, these findings demonstrate an improvement relative to the diseased condition, but cannot confirm a return to a normal physiological baseline.

Rho GTPases, a family of small GTPases, are important players in many physiological processes such as cytoskeleton remodeling. Emerging experimental results have indicated them as pivotal regulators of lipid metabolism, which has profound implications for metabolic health. This review aims to summarize the roles of key Rho GTPases, RhoA, RAC1, and CDC42 in adipocyte differentiation, insulin signaling, and lipid droplet dynamics. Relevant research articles were retrieved via searches in available public databases such as PubMed and reviewed here. For adipocyte differentiation, RhoA predominantly acts as a negative regulator during the early commitment phase, while RAC1 and CDC42 typically promote differentiation. Furthermore, Rho GTPases are integral to insulin signaling pathways, where their dysregulation can contribute to insulin resistance. The role of Rho GTPases in lipid droplet dynamics appears to be involved in the stabilization of lipid droplets through the regulation of the formation of actin stress fibers, whereas RAC1 facilitates droplet mobilization and degradation. The therapeutic potential of Rho GTPase pharmacological inhibitors and their efficacies in reducing lipid accumulation and improving insulin sensitivity in preclinical models are discussed. Nevertheless, challenges such as the specificity of these inhibitors and the complexity of the underlying mechanisms still remain. The development of highly specific modulators and full elucidation of signaling cascades are imperative to fully exploit Rho GTPases as promising therapeutic targets for combating obesity, type 2 diabetes, and related metabolic disorders.

BACKGROUND: Excess body weight is associated with chronic low-grade inflammation and metabolic abnormalities, such as insulin resistance, and dyslipidemia. OBJECTIVE: This study aimed to assess the impact of a soy protein-yogurt-honey powdered meal replacement (PMR) on inflammation, gut microbiota, and metabolism in individuals with excess body weight and in weight-stable conditions. METHODS: The Premium Study was a 12-week, parallel-arm, randomized controlled trial. Participants (body mass index 25-37 kg/m) were randomized into either control (CON; usual diet, n=34) or PMR (two daily doses added to usual diet, n=29) groups, maintaining a stable body weight. Assessments occurred at baseline, week 6, and week 12, and included inflammation markers (primary outcome: interleukin-6 [IL-6]), gut microbiota diversity and composition (secondary outcome), metabolic blood markers (glucose and lipid profile), body composition (via dual-energy X-ray absorptiometry), and dietary intake. Data of completers was analyzed by two-way repeated measures analysis of variance or generalized estimating equations with Bonferroni-corrected post-hoc tests. Between-group differences in changes over time are expressed as mean and 95% confidence intervals. RESULTS: Adherence to PMR was 98% of total doses, which increased protein intake (6.53 [5.04, 8.02]%, p<0.001) and decreased fat intake (-5.23 [-7.10, -3.35]%, p<0.001) compared to CON. By design, body weight remained stable. There were no changes in IL-6 (0.01 [-0.47, 0.45] pg/mL, p=0.412, with a low statistical power of 13.7%). Minor changes in gut microbiota composition included an increase in relative abundance of Subdoligranulum (0.72 Log fold-change, q=0.002). In exploratory outcomes, PMR increased lean soft tissue (LST; 0.57 [0.12, 1.02] kg, p=0.014) and reduced total cholesterol (-0.33 [-0.58, -0.08] mmol/L, p=0.01) and low-density lipoprotein cholesterol (-0.28 [-0.46, -0.10] mmol/L, p=0.003). CONCLUSIONS: In this population, PMR intake did not improve chronic low-grade inflammation and had limited effects on gut microbiota. Improvements in LST and lipid profile warrant further exploration. CLINICAL TRIAL REGISTRY: Number NCT03235804 registered on August 1, 2017: https://clinicaltrials.gov/study/NCT03235804.

OBJECTIVE: This study aimed to investigate the molecular mechanisms by which human umbilical cord-derived mesenchymal stem cell exosomes (hUC-MSC-Exo) promote diabetic wound healing by focusing on the delivery of specific microRNAs (miRNAs) that regulate downstream target genes and subsequently activate the autophagy pathway. METHODS: A skin defect model was established in mice with type 2 diabetes mellitus (DM) using a high-fat diet combined with streptozotocin injection. The therapeutic effect of locally administered hUC-MSC-Exo was evaluated. Wound healing quality, collagen deposition, autophagic activity, and oxidative stress levels were analyzed using histological staining (hematoxylin-eosin (HE) and Masson), immunofluorescence (IF), and Western blotting. Human immortalized keratinocytes (HaCaTs) were treated with high glucose (HG) to mimic a diabetic microenvironment. The effects of MSC-Exo on cell function, reactive oxygen species (ROS) levels, and autophagy were assessed. Bioinformatics screening, gene knockdown/overexpression, dual-luciferase reporter assay, and quantitative PCR were employed to identify and validate the key target gene, Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1), and its upstream regulatory miRNA, miR-2467-3p. RESULTS: Mice treated with hUC-MSC-Exo showed significantly accelerated wound closure, manifested by increased collagen deposition and enhanced autophagy activity. In vitro, MSC-Exo were internalized by HaCaT cells, which further promoted cell growth by activating autophagy. These effects were reversed by the autophagy inhibitor, 3-MA. CYP1A1 expression was significantly upregulated both in vivo and in vitro, whereas MSC-Exo treatment reduced its expression levels. Functionally, CYP1A1 knockdown mimicked the effects of MSC-Exo, whereas CYP1A1 overexpression produced opposite effects, antagonizing the benefits of MSC-Exo. The dual-luciferase reporter assay confirmed that miR-2467-3p directly binds to the 3'UTR of CYP1A1 and inhibits its expression. miR-2467-3p was enriched in MSC-Exo and delivered to recipient cells. Inhibition of miR-2467-3p markedly attenuated the ability of MSC-Exo to downregulate CYP1A1, subsequently reducing autophagy and suppressing cell growth. CONCLUSION: This study demonstrates that hUC-MSC-Exo promotes diabetic wound healing by delivering miR-2467-3p, which further inhibits CYP1A1 expression and activates autophagy. Our findings revealed a novel MSC-Exo/miR-2467-3p/CYP1A1/Autophagy regulatory axis, providing a potential therapeutic target for wound healing in DM.

Down syndrome (DS) or trisomy 21 is a genetic condition presenting with intellectual disabilities, distinctive phenotypic features, and multisystem involvement. As life expectancy in individuals with DS increases, obesity has emerged as a significant and growing clinical concern. Although obesity is highly prevalent among DS patients, its contribution in shaping cardiovascular risk has not been comprehensively synthesized in the existing literature. Studies published between January 2000 and March 2026 were identified through searches of PubMed and ScienceDirect, supplemented by manual screening of reference lists. In total, 65 studies met the inclusion criteria. Evidence indicates that individuals with DS commonly exhibit increased central adiposity, altered metabolic and adipokine profiles, adverse lipid abnormalities, sedentary behavior, and a higher prevalence of sleep apnea, all of which may contribute to downstream cardiometabolic and cardiovascular strain. However, findings on insulin resistance remain varied, and much of the available evidence is cross-sectional and based on intermediate risk markers rather than on longitudinal cardiovascular outcomes. Overall, the current literature supports obesity in DS as a clinically relevant and probable amplifier of cardiovascular risk. Early, targeted strategies centred on nutrition, physical activity, and caregiver-supported interventions may help mitigate long-term burden. Although DS-specific longitudinal and interventional studies remain needed.

AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are widely used for type 2 diabetes mellitus (T2DM). The long-term impact on cancer risk remains uncertain. This study aimed to evaluate the association between GLP-1RA and the risk of cancer, including site-specific malignancies. METHODS: This retrospective cohort study utilized the TriNetX database. Adults with T2DM between 2015 and 2023 were identified. After 1:1 propensity score matching, 144,410 GLP-1RA users were compared with non-users. Primary outcomes were all-cause mortality and incident malignant neoplasms. Secondary outcomes included site-specific cancers. RESULTS: GLP-1RA use was associated with lower all-cause mortality (HR 0.693) and a reduced overall incidence of cancer (HR 0.905). Regarding non-endocrine malignancies, significant risk reductions were observed for digestive cancers (HR 0.710) and respiratory cancers (HR 0.691), as well as for other sites including oral, female genital, and central nervous system cancers. In contrast, GLP-1RA was linked to an increased risk of thyroid gland cancer (HR 1.411). Active-comparator analyses against DPP-4i and SGLT2i yielded broadly consistent findings. Landmark analyses at 3 years showed attenuation of the thyroid cancer signal to non-significance, suggesting surveillance bias rather than a true carcinogenic effect. CONCLUSION: This real-world analysis demonstrates divergent oncologic risks associated with GLP-1RA use while the therapy offers potential protective effects against non-endocrine malignancies (particularly digestive and respiratory). The initially elevated thyroid cancer risk was no longer significant at 3 years, suggesting surveillance bias. These findings support the overall oncologic safety of GLP-1 RA in T2DM management, while warranting further long-term studies to confirm these associations.

This review highlight the function of insulin in the central nervous system in addition to its role in the periphery. The cerebral distribution and mechanisms of insulin and its receptor isoforms are reviewed in detail. We emphasize the essential roles of insulin in the maintenance of cerebral glucose homeostasis, modulation of cognitive performance, regulation of appetite, promotion of cerebrovascular angiogenesis, and exertion of neuroprotective effects. We demonstrate how insulin resistance exacerbates characteristic neuropathological features in Alzheimer's disease (AD) and Parkinson's disease (PD), while insulin-based interventions ameliorate these pathologies through multiple mechanisms including increasing the activity of insulin-degrading enzyme, suppressing Aβ neurotoxicity, and reducing α-synuclein deposition. The review also systematically examines the neuroprotective effects of insulin sensitizers and their potential to reduce the risk of AD, while noting the complexity of their bidirectional regulatory role in PD, which warrants further investigation. Notably, intranasal insulin administration emerges as a promising non-invasive therapeutic approach that bypasses the blood-brain barrier via olfactory and trigeminal pathways, suggesting significant potential for cognitive enhancement and neuropathological mitigation. Nonetheless, it must be noted that the optimal dosage, long-term safety, and sustained efficacy of insulin therapy remain unclear, and the current evidence is derived primarily from preclinical studies or small-scale clinical trials. In summary, this review paper underscores the critical physiological roles of insulin in the brain and outlines novel therapeutic strategies for using insulin in the treatment of AD and PD.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynomorium songaricum is a traditional medicinal herb commonly used in Chinese medicine for metabolic disorders, including diabetes. Its triterpenoid-rich fractions contain pentacyclic triterpenoids with potential metabolic regulatory activity, but the underlying mechanisms remain insufficiently understood. AIM OF THE STUDY: This study aimed to evaluate the metabolic improvement effects of the triterpenoid-enriched fraction of C. songaricum (CST), while comparatively assessing its two major constituents, oleanolic acid (OA) and ursolic acid (UA); and to explore their molecular mechanisms using integrated multi-omics analysis and experimental methods. MATERIALS AND METHODS: Insulin-resistant 3T3-L1 cells and HFD-induced obese mice were used to evaluate metabolic effects. Glucose uptake, lipid accumulation, adipokine secretion, and insulin signaling were assessed. Integrated transcriptomics and lipidomics analyses were applied to explore the underlying molecular pathways. RESULTS: CST, OA, and UA significantly increased glucose uptake and reduced lipid accumulation in 3T3-L1 cells. Adiponectin secretion increased from 36.74 ± 3.78 pg/ml in the model group to 79.83 ± 3.39 pg/ml (CST 25 μg/ml), accompanied by reductions in leptin, resistin, and TNF-α. In vivo, OA, UA, and CST reduced body-weight gain (14.3 % decrease in CST high dose group), improved glucose tolerance (15.6 % decrease in OGTT (AUC) of CST high dose group) and insulin sensitivity, and decreased plasma triglycerides. Multi-omics analyses revealed suppression of inflammatory chemokine signaling and normalization of dysregulated lipids. CONCLUSIONS: CST and its principal triterpenoids OA and UA alleviated insulin resistance and obesity, possibly through coordinated modulation of metabolic, inflammatory, and mitochondrial pathways, suggesting C. songaricum as a potential source of anti-diabetic agents.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a foundational therapeutic option for type 2 diabetes mellitus (T2DM), offering glycemic control and cardiovascular benefits. This systematic review and meta-analysis evaluates the impact of GLP-1RAs on cardiovascular outcomes in patients with T2DM. METHODS: We conducted a comprehensive search of PubMed, Embase, and Cochrane Library up to March 31, 2025, for randomized controlled trials (RCTs) comparing GLP-1RAs with placebo in T2DM patients. Risk ratios (RR) with 95% confidence intervals (CIs) were pooled using a random-effects model. RESULTS: Twenty RCTs involving 83,004 patients were included. GLP-1RAs significantly reduced the risk of major adverse cardiovascular events (RR 0.87, 95% CI 0.83-0.92), all-cause death (RR 0.89, 95% CI 0.84-0.93), cardiovascular death (RR 0.88, 95% CI 0.81-0.94), myocardial infarction (RR 0.87, 95% CI 0.79-0.96), stroke (RR 0.88, 95% CI 0.81-0.96) and composite renal outcome (RR 0.80, 95% CI 0.73-0.88) compared to placebo. In addition, a trend of reduction in heart failure hospitalizations (RR 0.93, 95% CI 0.85-1.01), and coronary revascularization (RR = 0.87, 95% CI 0.74 to 1.01) was observed with GLP-1 RAs without reaching statistical significance. CONCLUSION: GLP-1RAs are associated with improved cardiovascular outcomes in patients with T2DM. These findings support current guideline recommendations and highlight their cardioprotective benefits beyond glycemic control in patients with T2DM.

Diabetic foot ulcers (DFUs) represent a severe complication of diabetes mellitus, characterized by impaired wound healing and persistent inflammation. Despite advances in understanding the molecular mechanisms underlying DFU pathogenesis, effective therapeutic targets remain limited. This study aimed to identify novel biomarkers and therapeutic targets for diabetic wound healing through integrative bioinformatics analysis and experimental validation. We performed comprehensive transcriptomic analysis of DFU samples (n = 6) compared to normal skin controls (n = 6) from the GEO database (GSE80178). Differential expression analysis, functional enrichment, gene set enrichment analysis (GSEA), and protein-protein interaction network analysis were conducted to identify hub genes. Key findings were validated through in vitro experiments using keratinocyte cell lines cultured under normal glucose (NG), low glucose (LG), and high glucose (HG) conditions, with functional assays including colony formation and scratch wound healing assays. We identified 8,269 differentially expressed genes (DEGs), including 1,852 upregulated and 6,417 downregulated genes in DFU samples. Functional enrichment analysis revealed significant alterations in skin development, keratinocyte differentiation, inflammatory responses, and IL-17 signaling pathways. Hub gene analysis identified interleukin-1 alpha (IL1A) as a central hub gene and a key inflammatory mediator (log2FC = 5.18, adjusted p < 0.001), participating in seven distinct biological pathways. Experimental validation demonstrated that high glucose conditions impaired keratinocyte colony formation and wound closure capacity, accompanied by dysregulated inflammatory responses, consistent with the bioinformatics predictions. Through integrative computational and experimental approaches, we identified IL1A as a critical therapeutic target in diabetic wound healing. Our findings provide mechanistic insights into DFU pathogenesis and establish IL1A as a promising biomarker for developing targeted interventions to improve diabetic wound healing outcomes.