Diabetes mellitus (DM) induces skeletal muscle atrophy and mitochondrial dysfunction. Although antioxidant supplementation has exhibited beneficial effects on diabetic skeletal muscle, the effects of astaxanthin (AST), a potent antioxidant that protects mitochondrial function, remain unclear. We investigated whether AST supplementation attenuates DM-induced skeletal muscle alterations in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were assigned to control, DM, and DM + AST groups. DM was induced via STZ injection, and AST (100 mg/kg/day) was administered orally for 6 weeks. The plantaris muscle was analyzed for morphology, mitochondrial function, oxidative stress, inflammatory status, and signaling pathways related to protein metabolism and atrophy. Diabetic rats exhibited reductions in muscle mass and fiber cross-sectional area, decreases in mitochondrial enzyme activity and mitochondrial protein content, and increased oxidative stress. The expression of pro-inflammatory cytokines was elevated, along with markers associated with ubiquitin-proteasome system-, autophagy-, and apoptosis-related signaling. AST supplementation improved muscle mass and fiber cross-sectional area, partially restored mitochondrial enzyme activity and related protein expression, reduced oxidative stress, and attenuated inflammatory and atrophy-related signaling, without improving hyperglycemia. These findings indicate that AST attenuates DM-induced skeletal muscle atrophy and mitochondrial dysfunction in fast-twitch plantaris muscle. The protective effects of AST appear to be associated with reduced oxidative stress, attenuated inflammation, and attenuation of atrophy-related signaling rather than the restoration of anabolic signaling.

BACKGROUND AND OBJECTIVE: Patients with chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) are at increased risk of sepsis, yet the comparative infection-related outcomes of newer antihyperglycemic agents remain unclear. We evaluated the associations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus sodium-glucose cotransporter 2 inhibitors (SGLT2is) with infection outcomes in this population. METHODS: In this retrospective cohort study using the TriNetX global federated database, individuals aged 40-100 years with coexisting COPD and T2DM who initiated a GLP-1RA or SGLT2i between 2021 and 2024 were identified. A new-user, active-comparator design with 1:1 propensity score matching was applied. Sepsis was the primary outcome; all-cause mortality and components of the primary outcome were secondary. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: After matching, 45,491 pairs were included. Compared with SGLT2is, GLP-1RAs showed lower risks of sepsis (adjusted HR, 0.832; 95% CI, 0.781-0.887), all-cause mortality (0.642; 0.598-0.689), and severe sepsis (0.841; 0.774-0.914). CONCLUSION: In patients with COPD and T2DM, GLP-1RAs were associated with significantly lower risks of sepsis and all-cause mortality compared with SGLT2is.

Diabetes mellitus (DM) is a chronic metabolic condition characterized by persistently high blood glucose levels. The emergence of drug resistance in DM therapy presents significant clinical challenges, highlighting the need for the development of new and effective therapeutic agents. The primary objective of this study is to investigate the potential anti-diabetic activity of a newly designed Schiff base molecule, 2-[(2,4-dichloro-benzylidene)-amino]-4-methyl-phenol [compound (I)]. Compound (I) was synthesized, and its structure was confirmed using spectroscopic methods such as UV-Vis, FT-IR, and NMR spectroscopy. Single-crystal X-ray diffraction (SC-XRD) revealed that compound (I) crystallizes in the orthorhombic 222 space group and is stabilized by a combination of intra- and intermolecular hydrogen bonds (O-H···N, O-H···O, C-H···O, and C-H···Cl), forming a robust 3D supramolecular framework. The compound (I) was evaluated for its anti-diabetic potential using α-amylase inhibition assays. The compound's cytocompatibility was assessed using the MTT assay. The interaction pattern and binding orientation of compound (I) within the catalytic site of human pancreatic α-amylase (HPA) was explored through molecular docking studies, supporting the biological results. Furthermore, the stability of the docked complex was evaluated through 100 ns molecular dynamics (MD) simulations. In addition, the quantum computational analysis was investigated using Density Functional Theory (DFT) at the B3LYP/6-31++G(d,p) level were conducted to explore the electronic properties of compound (I), including electrophilicity, nucleophilicity, hardness, and softness. Moreover, the binding thermodynamics of compound (I) with α-amylase were examined by Isothermal Titration Calorimetry (ITC), which elucidated the thermodynamic parameters and interaction mechanisms.

Albuminuria is one of the most important biomarkers of chronic kidney disease and also a target that can be influenced by treatment. The amount of albumin excreted in the urine is an independent predictor of declining kidney function, cardiovascular events, and all-cause mortality. It is most easily determined based on the albumin-to-creatinine ratio (ACR) measured in the first morning urine sample; in the vast majority of cases, 24-hour urine collection is not required. The pathophysiology of albuminuria centers on damage to the glomerular filtration barrier - particularly podocytes - hemodynamic hyperfiltration, inflammation associated with tubular protein reabsorption, and activation of the renin-angiotensin-aldosterone system (RAAS). Modern four-pillar pharmacotherapy - RAS inhibitors (ACE inhibitors/ARBs), SGLT2 inhibitors, non-steroidal mineralocorticoid receptor antagonists (finerenone), and GLP1 receptor agonists in type 2 diabetes - acts on these processes through complementary mechanisms. When tailored to the degree of albuminuria and eGFR, this treatment significantly slows the progression of chronic kidney disease and reduces cardiovascular risk. Measuring and monitoring albuminuria must therefore be an essential part of daily clinical practice. Orv Hetil. 2026; 167(31): 1231-1237.

BACKGROUND: As a critical preclinical stage of type 2 diabetes (T2D), prediabetes necessitates urgent lifestyle interventions to halt disease progression. Despite robust evidence supporting the efficacy of exercise in improving glycemic control, exercise adherence remains suboptimal among individuals with prediabetes. OBJECTIVES: This review aimed to identify barriers and facilitators to exercise adherence in individuals with prediabetes while also extracting evidence-based behavior change techniques (BCTs) that may enhance physical activity maintenance. DESIGN: Mixed-methods systematic review. DATA SOURCES AND METHODS: A comprehensive literature search was performed in 10 databases from inception to November 2024. Guided by the JBI Manual for Evidence Synthesis, a convergent integrated approach was used to map barriers and facilitators to the Behavior Change Wheel (BCW) and Theoretical Domains Framework (TDF). TDF domains were ranked by frequency across studies, while adherence-promoting interventions were mapped to BCW intervention functions and BCTs. Barriers were systematically linked to BCW intervention functions and BCTs to guide implementation design. RESULTS: A total of 36 studies were included, consisting of 9 qualitative studies, 24 quantitative studies (15 randomized controlled trials, 5 cross-sectional studies, and 4 quasi-experimental studies), and 3 mixed-methods studies. The synthesis identified "lack of time," "lack of appropriate exercise equipment or venues," and "health-related physical limitations" as predominant barriers. Conversely, "perceived health benefits," "social support," and "tools or methods to help with exercise adherence" emerged as key facilitators. These factors were mapped to five primary TDF domains: reinforcement, environmental context and resources, behavioral regulation, social influences, and skills. Furthermore, seven intervention functions derived from the BCW were linked to 21 BCTs. CONCLUSION: This review highlights multifaceted determinants of exercise adherence in individuals with prediabetes and identifies theory-informed strategies to address barriers to adherence. Determinants supported more consistently across studies may provide a stronger basis for intervention development, whereas less frequently reported findings should be interpreted more cautiously. TRIAL REGISTRATION: PROSPERO CRD42024605588.

PURPOSE: Quality of life (QoL) in type 2 diabetes mellitus (T2DM) is frequently impaired by disease-related complications and symptoms. Aromatherapy has been proposed as a non-pharmacological means of improving QoL. This review evaluates randomized controlled trials (RCTs) of aromatherapy and QoL in adults with T2DM experiencing diabetes-related complications. METHODS: The review was prospectively registered in PROSPERO (CRD42024625423) and reported according to PRISMA. Web of Science, PubMed, Scopus, CINAHL, Google Scholar and the Cochrane Library were searched between December 2024 and January 2025. Eligibility criteria followed the PICOS framework, and full database-specific search strings are reported. Two reviewers independently performed study selection, data extraction and quality appraisal using the Joanna Briggs Institute (JBI) checklist for RCTs. Owing to heterogeneity, the data were synthesized narratively. RESULTS: Four RCTs comprising 293 randomized participants were included; three enrolled patients with diabetic peripheral neuropathic pain and one patients with insomnia. Aromatherapy was delivered by massage in three trials and by inhalation in one. JBI scores ranged from 9 to 12 of 13 (three high, one moderate quality). Randomization, baseline comparability and analysis were adequate throughout, whereas allocation concealment was unclear in three trials and blinding was incomplete in the massage trials. All four trials reported significant QoL improvement. CONCLUSION: Aromatherapy may improve QoL in complicated T2DM, but the evidence is limited by few small trials and by susceptibility to performance and detection bias. Adequately powered, registered, placebo-controlled RCTs with concealed allocation and blinded outcome assessment are needed. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-026-02033-z.

BACKGROUND: Cognitive impairment is a common complication among older adults with type 2 diabetes mellitus (T2DM). Reduced muscle strength has been associated with adverse health outcomes; however, the relationship between relative knee extension strength and cognitive function in older adults with T2DM remains unclear. This study aimed to examine the association between relative knee extension strength and cognitive function in older adults with T2DM. METHODS: This cross-sectional study included 42 older adults with T2DM (mean age 72.8 ± 7.4 years; 35% male). Relative knee extension strength was calculated by normalizing knee extension strength to body weight. Cognitive function was assessed using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Hierarchical regression analyses were performed using sequentially adjusted models culminating in a fully adjusted model including age, relative knee extension strength, HbA1c, and visceral fat area. RESULTS: In the crude model, relative knee extension strength showed a positive association with cognitive function (B = 8.18, 95% CI - 0.57 to 16.93,  = 0.066; adjusted R² = 0.059). After adjustment for age, relative knee extension strength remained positively associated with MoCA score (B = 8.30, 95% CI - 0.07 to 16.70,  = 0.052; adjusted R² = 0.18). In the model additionally adjusted for HbA1c, the association was similar (B = 8.40, 95% CI - 0.059 to 16.80,  = 0.052; adjusted R² = 0.14). In the fully adjusted model including age, HbA1c, and visceral fat area, the estimated association between relative knee extension strength and cognitive function remained positive (B = 6.12, 95% CI - 2.72 to 14.97,  = 0.168), although the confidence interval included the null value. CONCLUSIONS: Relative knee extension strength was positively associated with cognitive function in older adults with T2DM after adjustment for age and metabolic factors. These findings suggest that lower-limb muscle strength may represent a relevant physical correlate of cognitive function in this population. Longitudinal studies are needed to clarify causality. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-026-02031-1.

INTRODUCTION: The evaluation of diastolic function in patients with diabesity (i.e., combined obesity and type-2 diabetes mellitus) undergoing incretin-based therapy could facilitate its early detection and help prevent its progression to heart failure. METHODOLOGY: In this small descriptive study, performed for exploratory and proof-of-concept purposes, a group of 15 diabesity cases with chest x-ray examinations (< 1 month) before and after ≥ 12 months of incretin-based therapy (absent ventricular/valvular dysfunction) were identified. Standard diabesity characteristics (Body Weight (kg), Body Mass Index (kg/m), and Hemoglobin A1c) and AI-model diagnostic predictions of pulmonary venous hypertension (aka "pulmonary congestion") [None; Stage 1: vascular distention/redistribution but minimal interstitial edema; or Stage ≥ 2: vascular congestion with ≥ mild interstitial or alveolar edema] by validated AI-enabled chest x-ray staging, representing mean left atrial pressure in diastolic dysfunction, were evaluated pre- and post-therapy. RESULTS: According to weight-loss response to incretin therapy, cases clustered into equal-sized therapeutic categories as follows: (1) Significant Responders (9-30% decreases); (2) Insignificant Responders (0-2% decreases); and (3) Non-Responders (2-12% increases). Regarding hemoglobin A1c changes: (1) Significant Responders collectively decreased; (2) Insignificant Responders varied; and (3) Non-Responders were largely stable. Pre-therapy, all 15 cases demonstrated AI-enabled chest x-ray pulmonary venous hypertension staging evidence of diastolic dysfunction; post-therapy, 4 improved (especially the cases of greatest weight loss or hemoglobin A1c reduction), 5 were stable, and 6 worsened. Per therapeutic category, AI-enabled chest x-ray signs of functional response were: (1) Significant Responders (all demonstrating unequivocally decreased obesity and improved diabetes) collectively showed stable-decreased dysfunction; (2) Insignificant Responders (all demonstrating at most minimally decreased obesity, but stable-worsening diabetes in most) reflected stable-increased dysfunction in 60%; and (3) Non-Responders (all demonstrating increased obesity, but stable-improved diabetes) showed increased dysfunction in 80%. CONCLUSION: AI-enabled chest x-ray pulmonary venous hypertension staging potentially detects background subclinical diastolic dysfunction in diabesity and monitors its functional response to incretin-based therapy. The confirmation (or disproof), and assessments of durability and generalizability, of these preliminary results await a larger more definitive and controlled prospective study on the subject.

INTRODUCTION: Patients with atherosclerotic cardiovascular disease (ASCVD) and systemic inflammation (SI) or chronic kidney disease (CKD) have poorer outcomes than those without SI or CKD. This study evaluated the impact of both SI and CKD on major adverse cardiovascular events (MACE), healthcare costs, and healthcare resource utilization (HCRU) in patients with ASCVD. METHODS: This retrospective cohort study examined the association between SI and revised MACE, healthcare costs, and HCRU among adult patients with ASCVD from the Komodo Healthcare Map®. CKD stage 3-4 was determined from claims or laboratory data. SI was defined as ≥ 1 high-sensitivity C-reactive protein (hsCRP) value of 2-10 mg/l (without SI, all hsCRP values < 2 mg/l). The primary endpoint, revised MACE, was defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality. RESULTS: Of 74,884 patients with ASCVD and ≥ 1 eligible hsCRP value, 8.5% had CKD stage 3-4, and 49.2% had SI. Patients with SI had a higher comorbidity index and a greater prevalence of obesity, hypertension, and type 2 diabetes than those without SI. Compared with patients with ASCVD without CKD or SI, SI alone was associated with a 24% higher risk (hazard ratio [HR] 1.24; 95% CI 1.15-1.34), CKD stage 3-4 with a 33% higher risk (HR 1.33; 95% CI 1.16-1.51), and both SI and CKD stage 3-4 with a 62% higher risk (HR 1.62; 95% CI 1.45-1.82) of revised MACE. In patients with ASCVD without CKD, total healthcare costs were $18,002 PPPY with SI vs. $15,070 PPPY without SI. In patients with ASCVD with CKD stage 3-4, costs were $26,089 PPPY with SI vs. $20,753 PPPY without SI. Across groups, SI was associated with higher HCRU. CONCLUSIONS: SI is associated with increased risk of MACE and higher total healthcare costs and HCRU in patients with ASCVD with or without CKD.

AIMS/HYPOTHESIS: The aim of this study was to evaluate hepatic, pancreatic and abdominal fat depots across glycaemic categories in Asian Indians with matched BMI, and to identify predictors of dysglycaemia. METHODS: In this cross-sectional study, 45 adults (15 each with normoglycaemia or living with prediabetes and newly diagnosed type 2 diabetes) were matched for BMI. Fat fractions in the liver and pancreas were quantified on the basis of the proton density fat fraction (PDFF) measured using multi-echo chemical-shift-encoded MRI (CSE-MRI). We quantified the cross-sectional area of following abdominal fat compartments by MRI: subcutaneous adipose tissue (SCAT) (anterior, posterior, superficial, deep), intra-abdominal adipose tissue (IAAT), intra-peritoneal adipose tissue, retroperitoneal adipose tissue etc. Total body fat (%) and total fat mass (g) were measured using dual-energy x-ray absorptiometry (DEXA). Insulin sensitivity and beta cell function were derived from HOMA indices. RESULTS: The hepatic fat fraction (HFF) was nearly twofold higher in the prediabetes group (10.78 ± 6.50%) and the type 2 diabetes group (10.35 ± 9.95%) compared with the normoglycaemia group (5.34 ± 4.69%), with significant differences for both comparisons (p=0.009 and p=0.026, respectively). The fat fractions in the pancreas were similarly elevated in individuals living with prediabetes (5.83 ± 4.73%) and type 2 diabetes (5.35 ± 4.75%) compared with the normoglycaemic group (2.97 ± 3.56%, p<0.05). IAAT, superficial SCAT, posterior SCAT and retroperitoneal adipose tissue were significantly higher in individuals living with prediabetes and those with type 2 diabetes than in the normoglycaemic group (p<0.05). Superficial SCAT and posterior SCAT were also significantly higher in individuals living with prediabetes compared to those with type 2 diabetes (p<0.05). After adjustment for age and BMI, only fat fractions in the liver remained an independent predictor of dysglycaemia (OR 1.11 per 1% increase; p=0.023). Each 1% increase in the fat fraction in the liver increased odds of prediabetes by 16% and those of overall dysglycaemia by 11%. HOMA-β was preserved or elevated in individuals living with prediabetes but decreased in those with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Asian Indians living with prediabetes or type 2 diabetes at a modestly increased BMI of approximately 25 kg/m exhibit marked ectopic fat. The fat fraction in the liver independently predicted dysglycaemia. These findings highlight the need for early and aggressive interventions at the stage of normoglycaemia and prediabetes to avert beta cell decline and diabetes progression in Asian Indians. TRIAL REGISTRATION: Clinical Trials Registry of India (CTRI/2023/06/054228).

Recent awareness that metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver condition in individuals with type 2 diabetes and carries a significant risk of cirrhosis and extrahepatic disease has called for an examination of its relationship with diabetes-related complications. MASLD, especially at-risk steatohepatitis (metabolic dysfunction-associated steatohepatitis [MASH]) with significant fibrosis ≥F2, shares many metabolic abnormalities with type 2 diabetes, including insulin resistance, gluco- and lipotoxicity, chronic subclinical inflammation and mitochondrial impairment. In addition, many cross-sectional and longitudinal observational studies suggest an association between MASLD and micro- and macrovascular complications of type 1 and type 2 diabetes. However, a causal pathogenic relationship has been difficult to confirm given the overlap of cardiometabolic risk factors (CMRFs) in MASLD and type 2 diabetes. Complicating matters further, most of the available evidence has significant limitations. These include shortcomings in participant selection, heterogeneity in study design, use of diagnostic tools with low sensitivity for liver disease and diabetes-related complications, inadequate control for alcohol consumption or CMRFs, and lack of repeat measurements during longitudinal studies. Nevertheless, current evidence suggests that MASLD is a 'risk enhancer' for both micro- and macrovascular disease in diabetes, rather than an independent risk factor. Here, we review the underlying mechanistic pathways and clinical evidence that appear to link both conditions and identify knowledge gaps in need of future research. Until more robust evidence emerges, we hope that a greater awareness about the link between MASLD and diabetes-related micro- and macrovascular complications will prompt clinicians to educate their patients and peers on the potentially heightened health risks of MASLD and encourage clinicians to take a more proactive approach to risk stratification and intervention.

UNLABELLED: Obesity is a chronic relapsing disease leading to weight-related health risks for disorders such as cardiovascular diseases, type 2 diabetes, osteoarthritis, and depression. Many studies focus on these weight-related health risks. However, research on current self-reported social impacts and health complaints is limited. This study aims to investigate self-reported social impact and health complaints, received care aiming at lifestyle change, and perceived effectiveness of this care, by children with obesity and their parents. Secondarily, differences concerning sex, age, obesity-severity and frequency of received care were studied. Questionnaires were collected from children and adolescents aged 0-18 years visiting Obesity Center CGG. Data were analyzed regarding their social impacts, health complaints, received care, and perceived care effectiveness (0-10 scale). Children were categorized into sex, age, BMI, and care categories. Descriptive statistics were performed using chi-square tests and post hoc analyses to examine differences between categories. 86.8% of the patients self-reported experiencing social impact and 92.3% reported health complaints. Most frequently reported social impacts were difficulty to find fitting clothes (70.1%), problems in mobility and sports (63.7%), and bullying (41.6%); most reported health complaints were abdominal pain (38.8%), headache (34.8%), and musculoskeletal pain (34.1%). The dietician (64.1%) was most frequently reported as received care, and effectiveness scores ranged between 0 and 4 out of 10. CONCLUSIONS:  A substantial percentage of patients experience social impacts and health complaints affecting their well-being and quality of life. Low perceived effectiveness of interventions calls for a more innovative and comprehensive care framework incorporating these children's needs. WHAT IS KNOWN: • Children with overweight and obesity face a wide range of adverse health consequences and social challenges. • However, the number and types of health issues experienced by children themselves and studying per range of age, BMI-stage or care trajectory have not been systematically investigated. WHAT IS NEW: • A high percentage of children experience social impacts (87%) and health complaints (70%) aff ecting their well-being and quality of life, and perceived eff ectiveness of lifestyle interventions is low. The main reported healthcomplaints abdominal pain, headache, musculoskeletal pain and snoring loudly were mostly observed in girls withobesity aged 12-18 years, who received three or more care types. • The study demonstrated that perceived treatment effectiveness by children and parents declined with increasingobesity severity.

Prior randomized trials have shown that en bloc transurethral resection of bladder tumor (ERBT) is noninferior to conventional transurethral resection of bladder tumor (cTURBT) for pathological staging. To address gaps in long-term oncologic outcomes, we conducted a post hoc analysis of a single-center randomized trial including 219 of the 248 patients treated between 2018 and 2021, evaluating overall survival (OS), cancer-specific survival (CSS), and cumulative incidence of urothelial recurrence with a median follow-up of 60 mo (interquartile range = 53-79). ERBT was performed in 124 patients (57%) and cTURBT in 95 (43%). Overall, 77 patients experienced recurrence. With updated follow-up, 60-mo cumulative urothelial recurrence rates ranged from 8% (95% confidence interval [CI] = 2-14) for cTURBT to 10% (95% CI = 5-18) for ERBT. Even after competing-risk multivariable adjustment for overall mortality, as well as age, sex, tumor stage and grade, comorbidities (hypertension and diabetes mellitus), prior bladder tumor, and adjuvant therapy, recurrence rates did not differ between ERBT and cTURBT. Rates of upgrading (low grade to high grade) and upstaging (Tx/Ta/T1-T2) were also similar between groups. During follow-up, 41 patients died, including 5 bladder cancer-related deaths; 60-month OS was 76% (95% CI = 68-86) for cTURBT and 83% (95% CI = 76-90) for ERBT, with no difference in 60-mo CSS (97% vs 97%).

INTRODUCTION: Rothia spp. are commensal organisms involved in serious infections such as infective endocarditis (IE). There is a significant lack of information regarding de clinical course and management of Rothia spp. IE in immunocompetent patients. METHODS: This study describes 11 cases of Rothia spp. bacteremia over a 10-year period in a secondary hospital, analyzing clinical, demographic, and microbiological data. True infection was defined based on clinical signs, microbiological criteria, and radiological evidence. RESULTS: Three cases (27.3%) were confirmed as true infections, all presenting as infective endocarditis. All three infections were caused by Rothia mucilaginosa in non-immunocompromised patients. Identified risk factors included type 2 diabetes, pre-existing valvular disease, prosthetic implants, and odontogenic foci. 100% of cases developed severe central nervous system complications. Total bacterial eradication without recurrence was achieved, and no acute valve surgery was required. CONCLUSIONS: Rothia spp. can cause true bacteremia and IE in non-immunocompromised patients. Time to positivity (TTP) and clinical correlation are fundamental to distinguish between true infection and contamination. Individualized shorter antibiotic regimens might be explored in selected cases, although conventional durations remain the standard due to the severity of complications.

BACKGROUND AND AIMS: Recent randomised controlled trials have demonstrated the efficacy of tirzepatide in inducing weight loss among adults with overweight or obesity, irrespective of diabetes mellitus status. However, evidence from real-world settings remains limited. This study aimed to evaluate the effectiveness and safety of tirzepatide for weight management in routine clinical practice. METHODS: This prospective, longitudinal, observational study assessed the effects of tirzepatide in 107 participants with a body mass index of ≥30 kg/m or ≥27 kg/m and at least one weight-related comorbidity in real-world conditions. The primary outcomes were changes in body weight and body composition after 6 months of treatment. Secondary assessments included anthropometric and cardiometabolic parameters, quality of life, and tolerability. RESULTS: The median tirzepatide dose at 6 months was 7.5 mg. At this visit, the mean body weight reduction was 18.04 kg, representing a 17.21% decrease from baseline. A total of 95.35% of participants achieved at least 5% weight loss, and 60.47% achieved ≥15%. Significant improvements were observed in glycaemic and lipid profiles, with enhancements in health-related quality of life and a favourable tolerability profile. The dropout rate was 3.7%. CONCLUSIONS: This prospective real-world study confirms the effectiveness and safety of tirzepatide for weight management, even at maintenance doses lower than the approved dose, and supports findings from randomised clinical trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic retinopathy (DR), a predominant microvascular complication of diabetes mellitus, is pathologically characterized by endothelial dysfunction and blood-retinal barrier (BRB) disruption. Asiaticoside (AC), a bioactive phytochemical constituent derived from traditional Chinese medicinal herbs, has shown promising therapeutic potential against a spectrum of diabetic complications. Nevertheless, the explicit molecular targets and the detailed pharmacological mechanisms underlying the protective effects of this herbal ingredient against DR have not yet been fully elucidated. AIM OF THE STUDY: This study aimed to investigate the therapeutic effects and underlying mechanisms of AC in attenuating the progression of DR by targeting Cyclin D1 (CCND1) to negatively regulate the PI3K-AKT-mTOR pathway and activating mitophagy, thereby providing a promising therapeutic strategy for DR treatment. MATERIALS AND METHODS: C57BL/6J mice were utilized to establish diabetic mouse model via intraperitoneal injection of streptozotocin (STZ) then treated with AC. Human microvascular endothelial cells (HMECs) were exposed to high glucose (HG; 35 mM) to construct high-glucose model and treated with AC, mitophagy inhibitor 3-MA, mitophagy agonist CCCP and PI3K agonist 740-YP. Genetic knockdown via siRNA was performed to validate CCND1 effect on cellular senescence and mitophagy. The senescence level of retina, mice visual contrast sensitivity and retinal vascular leakage were evaluated by western blotting, immunofluorescence, OptoDrum eyes tracker system and evans blue staining respectively. Cell viability, cellular senescence, cell migratory capacity, apoptosis, mitophagy, mitochondrial morphology, mitochondrial function, and ultrastructural changes were assessed by CCK8 assays, wound-healing assay, western blotting, immunofluorescence, and transmission electron microscopy (TEM) respectively. RESULTS: AC treatment significantly lowered the visual contrast threshold by approximately 18% and reduced retinal vascular leakage in diabetic mice. In vitro, AC ameliorated high glucose-induced endothelial cell senescence, attenuated cellular and mitochondrial dysfunction as well as reactive oxygen species (ROS) production, and induced mitophagy. Bioinformatics analysis identified CCND1 as one of the key senescence-related genes upregulated in DR, AC intervention significantly inhibited its overexpression. Furthermore, knockdown of CCND1 recapitulated the protective effects of AC, enhancing mitophagy and suppressing senescence phenotypes. Mechanistically, AC treatment or CCND1 knockdown inhibited high glucose-induced activation of the PI3K-AKT-mTOR signaling pathway, while the PI3K agonist 740YP completely reversed these beneficial effects of AC. CONCLUSION: We firstly revealed that AC attenuates DR progression by alleviating cellular senescence in HMECs by modulating CCND1. Notably, the present study is the first to explore the pathological role of CCND1 in DR beyond its classical cell-cycle regulatory function, which provides a novel and promising therapeutic target and intervention strategy for DR treatment.

BACKGROUND: Cardio-renal-metabolic multimorbidity is defined as the coexistence of cardiovascular disease, type 2 diabetes, and chronic kidney disease. We examined the relationships between C-reactive protein-triglyceride glucose-index and its five obesity derivatives with CRMM incidence and progression. METHODS: We included 374,513 participants from UK Biobank and 6,401 participants from CHARLS. Cox, RCS, and multistate models were used to assess incident CRMM and disease transitions. Predictive performance was evaluated using time-dependent ROC, C-index, NRI, and IDI. RESULTS: Over 15.98 years of follow-up, 13,315 participants developed CRMM.six indices were positively associated with CRMM risk in UK Biobank.CTI-WC showing the strongest association (HR 1.974, 95% CI 1.943-2.007), followed by CTI-WHtR (HR 1.919, 95% CI 1.890-1.950). Multistate analyses also supported associations with CRMM progression, particularly for transitions from healthy to FCRMD, again strongest for CTI-WC (HR 1.538, 95% CI 1.526-1.550). Adding CTI-derived indices improved prediction, with NRI ranging from 21.161% to 23.929%, IDI from 1.051% to 1.512%, and ΔC-index from 0.029 to 0.038 , suggesting improved risk stratification beyond traditional measures. In CHARLS, associations were directionally consistent but attenuated,likely due to the smaller validation cohort. CONCLUSIONS: CTI-derived obesity-related indices, especially CTI-WC and CTI-WHtR, were associated with CRMM incidence and progression and may improve risk stratification.

Lipotoxicity-induced β-cell failure in type 2 diabetes mellitus (T2DM) involves intrinsic damage and inflammatory crosstalk with islet macrophages, but the initiating signals remain undefined. We identify NOX2 as the hub linking metabolic stress to macrophage-dependent β-cell injury. In high-fat diet-fed and Cybb-knockout mice, and in MIN6-RAW264.7 co-cultures, palmitate upregulates NOX2 in β-cells, activating TLR2/NF-κB/NLRP3 signaling and impairing insulin secretion. Damaged β-cells recruit macrophages via chemokines and drive M1 polarization. Activated macrophages release IL-1β and other cytokines, which suppress PDX1 and amplify β-cell apoptosis-a feedforward amplification loop. Genetic Cybb deletion or apocynin treatment disrupted this cycle, preserved insulin secretion, and improved glucose tolerance. We define the NOX2/TLR/NF-κB/NLRP3/IL-1β axis as the mechanistic link between lipotoxicity and paracrine inflammation in β-cell failure, and identify NOX2 as a therapeutic target for preserving islet function in T2DM.

Blood glucose metabolism is a key process for maintaining normal physiological functions of the human body. The maintenance of its homeostasis relies on complex hormone regulation and the synergistic effect of tissues and organs. However, when insulin resistance occurs in skeletal muscles, insulin signalling is impaired, and glucose uptake decreases, leading to elevated blood sugar levels. This study investigates the SARS-CoV-2 spike protein's effect on insulin resistance in type 2 diabetes (T2DM) skeletal muscle in a specific demographic. In the cell experiment, we used human C2C12 skeletal muscle cells and co-cultured them with the spike protein to observe the effects of the spike protein on the proliferation, apoptosis, and glucose uptake. The research results show that the spike protein may reduce the expression and transport of GLUT4 by inhibiting the PI3K/AKT/mTOR signalling pathway, thereby decreasing glucose uptake, intensifying insulin resistance in skeletal muscle, and affecting blood glucose metabolism.

AIMS: We aimed to compare the discriminatory performance of Body Shape Index and Body Roundness Index with traditional anthropometric measures, including body mass index, waist circumference, and waist-to-height ratio, for identifying prevalent diabetes among Indian adults. METHODS: Data from the fifth round of the National Family Health Survey were analyzed, including 574,099 women and 74,761 men (aged 15-49 years). Diabetes was defined by self-reported diagnosis, current use of glucose-lowering medication, or a random blood glucose ≥200 mg/dL. Anthropometric indices were derived from measured height, weight, and waist circumference. Survey-weighted prevalence estimates, multivariable logistic regression, receiver operating characteristic analysis, DeLong tests, and trend tests were used. RESULTS: The weighted prevalence of diabetes was 13.6% and increased with age, urban residence, higher wealth, education, obesity, and hypertension. Waist circumference showed the highest correlation with diabetes (r = 0.1446) and the highest, though modest, discrimination (area under the curve = 0.61). Body mass index, Body Roundness Index, and waist-to-height ratio performed similarly (area under the curve = 0.60 each), whereas Body Shape Index showed the lowest discrimination (area under the curve = 0.55). DeLong comparisons showed that waist circumference and Body Roundness Index performed significantly better than Body Shape Index, while Body Roundness Index showed no meaningful incremental discrimination beyond waist-to-height ratio. CONCLUSIONS: Waist circumference, waist-to-height ratio, and Body Roundness Index performed similarly to, and modestly better than, the Body Shape Index for identifying prevalent diabetes in Indian adults. Simpler waist-based measures, particularly waist circumference and waist-to-height ratio, may be sufficient for population-level diabetes risk screening.

The annual economic burden of obesity has reached 190 billion dollars in the US and around 62 billion Egyptian pounds in Egypt. It is linked to many harmful diseases, including diabetes mellitus, cardiovascular, liver, reproductive, bone diseases, and many others. Modeling of obesity and obesity-associated comorbidities represents a fruitful area of research. Animal models of obesity have many limitations regarding reliability, translatability, and extrapolation to human obesity. Microfluidic "organ on a chip" has emerged in recent decades as a potent in vitro tool for studying human diseases, offering advantages over traditional in vitro models, thereby facilitating the development of a human on a chip model. This review will briefly discuss obesity-associated metabolic disturbances and the recent publications that tried to use microfluidic devices to answer obesity-related questions. This review covers the role of in vitro modeling using microfluidic devices in obesity research. The different species of invertebrates utilized in obesity research have also been investigated, including nematodes, with a highlight on Caenorhabditis elegans. Research on anti-obesity drugs, which could potentially aid in managing obesity, has been increasing daily. Natural anti-obesity phytoconstituents have shown considerable therapeutic potential in obesity, with many plant extracts and single components with promising effects. In conclusion, integrating microfluidics, invertebrate models, and phytochemical screening is promising for obesity research, yet it requires further standardisation and clinical validation to enable personalised therapies.

Per- and polyfluoroalkyl substances (PFAS), including emerging alternatives, have been implicated in type 2 diabetes (T2D), but epidemiological evidence remains inconsistent and the underlying mechanisms are unclear. We aimed to investigate the associations of individual and mixed PFAS exposure with T2D risk and to explore the roles of triglyceride-glucose (TyG)-related indices and metabolomic alterations. A total of 1647 participants (749 participants with T2D and 898 controls) were included. Multivariable logistic regression and weighted quantile sum (WQS) regression were used to evaluate the associations of single PFAS and mixed PFAS with T2D risk, respectively. Mediation analyses were conducted for TyG-related indices, and untargeted metabolomics and sequential mediation analyses were further performed in a nested case-control subset. Most individual PFAS were positively associated with T2D risk. Mixed-exposure analyses consistently showed that PFAS mixture was associated with increased T2D risk, with 6:2 FTS, PFNS, and PFPeS identified as the main contributors. Mediation analyses indicated that TyG-related indices (TyG, TyG-BMI, TyG-WC, and TyG-WHtR) were significantly associated with both PFAS mixture and T2D. Metabolomic analyses identified 35 shared metabolites associated with both PFAS mixture and T2D, mainly enriched in lipid-related pathways. Sequential mediation analyses further suggested that palmitic acid, stearic acid, and glutamine, together with TyG, might be involved in the pathways in the association between PFAS exposure and T2D risk. PFAS exposure was associated with T2D, with TyG-related indices and metabolites potentially involved in this association.

BACKGROUND: Nivolumab and other immune checkpoint inhibitors (ICIs) have improved survival in advanced gastric cancer. However, optimal management after progression on ICI-containing therapy remains uncertain. We report a case of HER2-negative esophagogastric junction (EGJ) cancer that showed a marked radiological and metabolic response to second-line ramucirumab plus paclitaxel (RAM + PTX) after nivolumab-based chemotherapy, allowing conversion-intent surgery, after which pathological complete response (pCR) was confirmed in the resected specimen. CASE PRESENTATION: A 76-year-old woman was diagnosed with advanced HER2-negative EGJ adenocarcinoma with para-aortic lymph node metastases (cT3N3bM1[Lym], Stage IVB according to the 15th edition of the Japanese Classification of Gastric Carcinoma). The tumor was classified as Siewert type III with minimal esophageal invasion. First-line SOX plus nivolumab was administered, but disease progression with mediastinal lymph node enlargement and suspected pulmonary metastases was observed after five cycles. Second-line RAM + PTX was subsequently initiated and resulted in marked regression of the primary tumor and metastatic lesions on computed tomography and endoscopy, with metabolic complete response on positron emission tomography-computed tomography. Although chemotherapy was temporarily interrupted because of immune-related type 1 diabetes mellitus, metabolic complete response was maintained after glycemic control with insulin therapy. Following multidisciplinary evaluation of treatment response and resectability, robot-assisted proximal gastrectomy with D2 lymphadenectomy and double-flap reconstruction was performed. Histopathological examination demonstrated no residual viable tumor cells (ypT0N0), consistent with pCR. The postoperative course was uneventful, and the patient remains clinically recurrence-free 10 months after surgery. CONCLUSIONS: This case suggests that RAM + PTX after nivolumab-based chemotherapy may achieve substantial tumor regression in selected patients with advanced EGJ cancer and may provide an opportunity for conversion surgery. Robot-assisted proximal gastrectomy with double-flap reconstruction was feasible after successful systemic therapy. Careful multidisciplinary assessment and accumulation of further clinical evidence are needed to clarify the role of sequential systemic therapy and surgical intervention in this setting.

AIMS: Type 1 diabetes mellitus (T1DM) is frequently associated with other autoimmune disorders, particularly autoimmune thyroid disease (AITD) and celiac disease. Guidelines recommend screening for thyroid and celiac disease in T1DM patients. Nevertheless, in case of their positivity, indicating the presence of an autoimmune polyendocrine syndrome (APS), there is a lack of guidance on how to proceed. Should we screen these patients for other autoimmune diseases? This study's aim was to evaluate the prevalence of additional autoimmune conditions in a cohort of T1DM patients with AITD and/or celiac disease. METHODS: This cross-sectional study includes adult T1DM patients identified through electronic medical records. Patients with concomitant AITD or celiac disease were invited to undergo an extended screening workup for autoimmune disorders. RESULTS: 639 T1DM patients were identified, and 198 (31%) met the clinical criteria for APS (T1DM plus AITD and/or celiac disease), but only 17 (8.6%) had a formal APS diagnosis in their records. After the extended screening in 139/198 patients, 39% exhibited previously unknown autoantibody positivity, and 11.5% had new autoimmune diseases. Overall, among the patients who underwent the extended screening, 32% (44/139) were diagnosed with at least three autoimmune diseases. CONCLUSIONS: Our study shows that APS is often under-recognized and rarely formally documented in patients with T1DM. In addition, 32% of T1DM patients with AITD or celiac disease have at least a third autoimmune disease. These findings highlight that the identification of AITD or celiac disease in T1DM marks only one stage of the diagnostic journey. APS recognition should lead to a formal diagnosis and ensure heightened clinical vigilance with tailored evaluation of further autoimmune comorbidities during lifelong patient follow-up.

BACKGROUND: The introduction of combination antiretroviral therapy (cART) has improved survival among people living with HIV (PLHIV) but increased the risk of non-communicable diseases, including diabetes mellitus (DM). In East Africa, estimates of DM prevalence among PLHIV vary widely, and contributing factors are not well defined. This study aimed to estimate the pooled prevalence of DM and identify associated risk factors among PLHIV in the region. METHODS: A systematic review and meta-analysis were conducted following PRISMA 2020 guidelines (PROSPERO: CRD420251129591). Databases including PubMed, Embase, CINAHL, Web of Science, African Journals Online, and Google Scholar were searched for cross-sectional, cohort, and case-control studies reporting DM prevalence or associated factors among PLHIV aged ≥ 16 years in East Africa. Data were extracted independently by two reviewers, and study quality was assessed using the Joanna Briggs Institute checklist. A random-effects model using DerSimonian-Laird method was applied to estimate pooled prevalence. Heterogeneity was assessed with Cochran's Q and I², and publication bias was evaluated via funnel plot, Egger's test, and trim-and-fill analysis. Adjusted odds ratios (AORs) were pooled to identify factors associated with DM. RESULTS: A total of fourteen studies were included. The pooled prevalence of DM was 6.4% (95% CI: 4.3-9.7%; I² = 94.9%). Trim-and-fill analysis did not change the estimate. Significant risk factors included higher education (AOR = 8.56, 95% CI: 3.82-19.17), obesity/overweight (AOR = 6.68, 95% CI: 2.58-17.32), positive family history of diabetes (AOR = 7.60, 95% CI: 3.56-16.22), longer duration of ART (AOR = 4.78, 95% CI: 1.22-18.81), and history of hypertension (AOR = 2.98, 95% CI: 1.69-5.27). Male sex and elevated triglycerides were not significantly associated. CONCLUSION: DM affects one in every 16 PLHIV in East Africa, with modifiable and non-modifiable risk factors identified. Integrating DM screening and preventive strategies into HIV care is critical to reduce cardio-metabolic complications.