BACKGROUND: Irisin is an exercise-induced myokine that has been proposed to exert beneficial effects on metabolic health. However, its response to different exercise training modalities in individuals with overweight or obesity remains inconsistent. This systematic review and meta-analysis primarily aimed to evaluate the effects of various exercise interventions on circulating irisin levels as the primary outcome in overweight and obese adults. Additionally, we assessed changes in other selected myokines and metabolic markers as secondary outcomes to provide a better understanding of exercise induced physiological adaptations. METHODS: A systematic search was conducted in Web of Science, EMBASE, Cochrane Library, PubMed, SCOPUS, and Google Scholar (up to 22 April 2025) to identify randomized controlled trials (RCTs) evaluating the effects of different exercise training protocols (aerobic, resistance, concurrent, and high-intensity interval training) on circulating irisin levels in adults with overweight or obesity. The primary eligibility criterion to include studies was the measurement of circulating irisin. Within the RCTs meeting this criterion, we additionally extracted data on selected myokines (follistatin, myostatin, and FGF21) and metabolic markers (glycemic control and lipid profiles) when reported. These secondary outcomes were analyzed to contextualize irisin responses within broader metabolic adaptations, but no separate systematic search was performed for these variables. Pooled effect sizes were calculated using random-effects models and expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Using the median split technique, subgroup analyses were computed according to exercise training modality. RESULTS: A total of 50 studies comprising 1780 participants (1104 in exercise groups and 676 in passive control groups) were included. For the primary outcome, exercise training was associated with a significant increase in circulating irisin (SMD 0.62, 95% CI 0.39-0.85, p < 0.001, n = 76 arms, 1721 subjects) compared with passive controls. Among the secondary outcomes, training was also associated with increases in high-density lipoprotein cholesterol (SMD 0.25, 95% CI 0.03-0.47, p = 0.030], n = 18 arms, 420 subjects), follistatin (SMD 0.89, 95% CI 0.37-1.41, p = 0.008, n = 7 arms, 141 subjects), and fibroblast growth factor 21 (FGF-21; SMD 1.00, 95% CI 0.10-1.91, p = 0.003, n = 13 arms, 280 subjects). In contrast, exercise training did not significantly affect myostatin levels (SMD - 0.45, 95% CI - 1.07 to 0.18, p = 0.160, n = 11 arms, 283 subjects). Additionally, exercise training significantly reduced fasting blood glucose (SMD - 0.61, 95% CI - 0.89 to - 0.33, p < 0.001, n = 28 arms, 696 subjects), insulin (SMD - 0.80, 95% CI - 1.11 to - 0.50, p < 0.001, n = 24 arms, 566 subjects), homeostatic model assessment for insulin resistance (SMD - 0.75, 95% CI - 1.08 to - 0.43, p < 0.001, n = 28 arms, 609 subjects), hemoglobin A1C (HbA1C) (SMD - 0.96, 95% CI - 1.23 to - 0.70, p < 0.001, n = 12 arms, 275 subjects), and low-density lipoprotein cholesterol (SMD - 0.38, 95% CI - 0.74 to - 0.02, p = 0.040, n = 18 arms, 443 subjects). Exploratory subgroup analysis showed significant increases in irisin following resistance training (SMD 0.88 [95% CI, 0.44 to 1.33], [p = 0.001], n = 21 arms, 537 subjects, I = 79% [p = 0.001]), high-intensity interval training (SMD 0.61 [95% CI, 0.13 to 1.09], [p = 0.001], n = 17 arms, 346 subjects, I = 75% [p = 0.001]), and concurrent training (SMD 0.42 [95% CI, 0.16 to 0.68], [p = 0.002], n = 18 arms, 356 subjects, I = 21% [p = 0.20]). Although resistance training demonstrated numerically larger effects, differences between exercise modalities were not statistically significant (p > 0.05). CONCLUSIONS: Regular exercise is an effective intervention for increasing circulating irisin levels and favorably modulating other myokines such as follistatin and FGF-21 in adults with overweight or obesity. Resistance training showed larger numerical effects, but the differences between exercise types were not statistically significant. These adaptations, alongside improvements in metabolic markers, support the role of structured exercise as part of a comprehensive strategy for improving metabolic health in this population. CLINICAL TRIAL REGISTRATION: PROSPERO CRD42025637476.

BACKGROUND: Multimorbidity, defined here as the co-occurrence of cardiovascular disease (CVD), type 2 diabetes (T2D), and/or cancer is a major public health challenge. However, its underlying biological mechanisms remain unclear, limiting progress toward identifying shared interventional targets. METHODS: We applied large-scale plasma proteomics (SomaScan 7k; 7,289 aptamers) in 13,270 European Prospective Investigation into Cancer and Nutrition (EPIC) participants to identify protein signatures of multimorbidity. We modelled multimorbidity progression as sequential disease transitions, i.e., from the disease-free state at baseline to a first disease and from the first disease to a second disease. Using weighted multivariable Cox regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for risk of cancer, CVD, and T2D. Risk associations were replicated using Olink proteomics in UK Biobank (N = 44,567). RESULTS: We identified 422 aptamers associated with more than one disease (FDR-corrected P < 0.05), e.g., 265 aptamers were shared between CVD and T2D. Thirty-eight aptamers were associated with multimorbidity progression. Among these, 27 aptamers showed consistent positive associations across sequential disease transitions, including SEMA6A (disease-free to cancer HR: 1.14; 95% CI 1.05, 1.23; cancer to T2D HR: 2.61; 95% CI 1.76, 3.80). Four aptamers showed consistent inverse associations, including NLGN1 (disease-free to T2D HR: 0.72; 95% CI 0.61, 0.84; T2D to cancer HR: 0.57; 95% CI 0.43, 0.75). Nineteen of the identified proteins were also measured in UK Biobank, with broadly consistent associations. CONCLUSIONS: This study identifies candidate proteins that may indicate molecular pathways to multimorbidity of cardiometabolic diseases and cancer. Future studies should evaluate the causal roles of these proteins for targeted interventions and risk stratification.

BACKGROUND: The C-reactive protein-triglyceride-glucose index (CTI), a composite biomarker reflecting insulin resistance and systemic inflammation, has been linked to metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic diseases (CMDs). However, the role of CTI and its obesity-related derivatives in cardiometabolic multimorbidity (CMM) development and progression among MASLD patients remains unclear. The study evaluated associations of CTI-related indices with the incidence and progression of CMM, assessed their incremental predictive value, and explored potential biomarkers. METHODS: This cohort study included 109,181 UK Biobank participants with MASLD and without CMDs at baseline. CMM was defined as the coexistence of ≥ 2 CMDs, including type 2 diabetes mellitus (T2DM), ischemic heart disease (IHD), and stroke. Four CTI-related indices were calculated: CTI, CTI-body mass index (CTI-BMI), CTI-waist circumference (CTI-WC), and CTI-waist-to-height ratio (CTI-WHtR). Associations with CMM incidence and progression were analyzed using traditional Cox and multistate models. Predictive performance was assessed using the C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Exploratory mediation analyses were conducted to examine whether metabolic, inflammatory, hepatic, and renal biomarkers statistically accounted for part of the associations. RESULTS: Over a median follow-up of 16 years, 4,219 participants developed CMM. All four indices were positively associated with incident CMM, with CTI-WHtR and CTI-WC showing more pronounced associations. Hazard ratios (HRs) (95% confidence interval) per 1-SD increase were 1.62 (1.58-1.66) for CTI-WHtR, 1.57 (1.53-1.61) for CTI-WC, 1.53 (1.49-1.57) for CTI-BMI, and 1.50 (1.45-1.54) for CTI (all P < 0.001). Multistate analyses indicated consistent positive associations with transitions from baseline to first CMD (FCMD) (HRs: 1.41-1.53), FCMD to CMM (HRs: 1.17-1.24), and CMM to death (HRs: 1.07-1.21), particularly for CTI-WHtR and CTI-WC. Subtype-specific analyses confirmed their pronounced associations, notably for T2DM incidence and IHD-to-CMM progression. Adding CTI-related indices to the conventional model resulted in modest but statistically significant improvements in predictive performance, with CTI-WC and CTI-WHtR showing the greatest improvements in the C-index, NRI, and IDI. Biomarkers of glycemic dysregulation, lipid metabolism, systemic inflammation, and organ dysfunction may partly account for the associations between CTI indices and incident CMM. CONCLUSION: CTI-related indices, particularly CTI-WHtR and CTI-WC, were significantly associated with the incidence and progression of CMM in individuals with MASLD. These indices provided modest incremental predictive value and may serve as complementary markers for risk stratification. Further external validation and clinical utility assessment are needed before their routine use in clinical practice.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death globally. The C-reactive protein-triglyceride-glucose index (CTI) integrates inflammation and insulin resistance. However, research on cumulative effects and longitudinal patterns of CTI combined with body shape indices for CVD risk assessment is limited. We examined association of cumulative CTI-CVAI (CumCTI-CVAI) exposure and longitudinal patterns with new-onset CVD, heart disease, and stroke in middle-aged and older Chinese adults. METHODS: Data were from the CHARLS. A two-stage design (cross-sectional screening + longitudinal validation) was employed. Cross-sectional analysis (n = 9,475) identified CTI-CVAI as the optimal composite indicator. In longitudinal analysis (n = 3,803; median follow-up 56.6 months), cumulative CTI-CVAI was calculated using time-weighted averages (2011-2015). The landmark time was set at 2015 to avoid immortal time bias. Cox regression, RCS, K-means clustering, subgroup analyses, and sensitivity analyses (lag analysis, interval deletion analysis, competing risk model, etc.) were performed. NRI and IDI were calculated. A nomogram was constructed using LASSO regression, with AUC for discrimination and calibration/DCA for clinical utility. RESULTS: Cross-sectional analysis identified CTI-CVAI as the optimal indicator (AUC = 0.617). In longitudinal analysis, each 1-SD increase in CumCTI-CVAI was associated with a 9% higher CVD risk (HR = 1.09, 95%CI:1.04-1.14, P < 0.001). The highest tertile had a 63% higher risk than the lowest (HR = 1.63, 95%CI:1.33-2.00). A nonlinear dose-response relationship was observed (P < 0.001; inflection point:6192.15). For secondary outcomes, each 1-SD increase in CumCTI-CVAI was associated with a 7% higher risk of heart disease (HR = 1.07, 95%CI:1.01-1.14) and a 16% higher risk of stroke (HR = 1.16, 95%CI:1.06-1.27). K-means clustering identified three exposure patterns: low-stable, moderate-stable, and high-stable. Compared to the low-stable group, the high-stable group had 68% higher CVD risk (HR = 1.68), 43% higher heart disease risk (HR = 1.43), and 133% higher stroke risk (HR = 2.33). Hierarchical NRI/IDI analysis showed that adding inflammation to TyG-CVAI significantly improved reclassification (IDI: from 0.018 to 0.090, P < 0.001). The nomogram (age, lung disease, CumCTI-CVAI) achieved AUCs of 0.618-0.638. CONCLUSION: Elevated cumulative CTI-CVAI exposure and unfavorable longitudinal patterns are independently associated with increased CVD risk in middle-aged and older Chinese adults. CTI-CVAI provides incremental predictive value beyond obesity and insulin resistance alone, supporting its potential as an adjunctive screening tool in primary care.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Type 1 Diabetes (T1D), but a subset of individuals remains free from macrovascular or renal complications despite decades of hyperglycaemia and a significant risk factor burden. We used a targeted proteomic approach (Olink Cardiovascular panel III, targeting 92 proteins) to characterize the proteomic profile of cardiovascular resilience in T1D by comparing 92 patients with long-standing T1D (age 59.8 [53.2, 69.1], duration 40.0 [35.0, 45.2] years) free from macrovascular complications or nephropathy against a reference group of 57 T1D patients with accelerated vascular pathology (age 42.0 [32.0, 56.0], duration 22.0 [18.0, 27.0] years), proliferative retinopathy and/or nephropathy in relation to diabetes duration, termed Rapid Progressors (RP). Twenty proteins differed significantly between RP and Escapers (False Discovery Rate [FDR] < 0.05) after adjustment for age, sex, HbA1c, and eGFR: Caspase-3 was significantly higher in RP (Adjusted difference: + 2.12 Normalized Protein eXpression [NPX], p < 0.001). Proteins associated with platelet activation and leukocyte adhesion with increased levels in RP included Junctional Adhesion Molecule A (+ 1.40 NPX), Glycoprotein VI (GP6: + 1.29 NPX), and P-Selectin (+ 0.82 NPX) (all p < 0.001). PECAM-1 (+ 0.55 NPX) and TNFRSF14 (+ 0.43 NPX), were also elevated. RP also showed higher levels of metabolic and tissue-remodelling proteins; Transferrin Receptor (+ 0.53 NPX) and Fatty Acid Binding Protein 4 (+ 0.52 NPX), as well as higher Bleomycin Hydrolase, Trefoil Factor 3, GDF-15, U-PAR, and Cystatin B. Conversely, von Willebrand Factor (vWF) levels (- 1.35 NPX, p < 0.001) and Paraoxonase 3 (PON3) was lower in RP (- 0.34 NPX, p = 0.003). In conclusion, escaping complications in long-term T1D appears to be associated with active molecular mechanisms. Progression is marked by apoptosis (Caspase-3), fibrosis (CHI3L1) and platelet activation (GP6), whereas resilience is associated with a distinct signature involving higher vWF and PON3. These findings highlight a profound biological divergence between extreme T1D phenotypes and provide a foundation for further research into vascular resilience.

BACKGROUND: Paediatric endocrine disorders represent a spectrum of conditions that affect hormone synthesis, regulation and function in childhood and adolescence. They present with intraoral features that may compromise the long-term well-being and oral health of affected individuals, potentially persisting into their adult years when appropriate diagnosis and therapeutic intervention are delayed or inadequate. This study aims to determine the prevalent oral manifestations of endocrine disorders among children attending the Paediatric Endocrinology Clinic of the Lagos University Teaching Hospital (LUTH). METHODS: A cross-sectional study was done among 50 paediatric patients aged (6-18 years) with endocrine disorders, recruited via consecutive sampling. Data collection employed interviewer-administered questionnaires covering medical and dental histories, followed by standardized intraoral examinations of soft and hard tissues. Ethical approval, informed consent, and participant assent were obtained. Data was analysed using SPSS version 25. Descriptive statistics included frequencies and percentages. Inferential analysis was performed using Chi-square test to evaluate associations between categorical variables. Statistical significance was set at p < 0.05. RESULTS: Type 1 diabetes mellitus was the predominant condition among the participants (n = 27, 54.0%), followed by hypothyroidism (n = 7, 14.0%). Other endocrine disorders, including congenital adrenal hyperplasia (n = 6, 12.0%), Turner syndrome, Cushing syndrome, adrenal insufficiency, and metabolic syndrome, were each represented by single cases (2.0% each). Oral dryness emerged as the leading soft tissue manifestation (n = 27, 54.0%), accompanied by oral pigmentation (n = 20, 40.0%), gingivitis (n = 7, 14.0%), and oral ulceration (n = 6, 12.0%). Enamel defects, crossbite, dental crowding, open bite, and dental caries were the primary hard tissue findings, each occurring in eight participants (n = 8, 19.0%). CONCLUSIONS: There is a significant prevalence of oral pathologies among paediatric patients with endocrine disorders. Findings support incorporating dental evaluations into endocrinological care protocols and highlight the need for coordinated inter-professional management involving endocrinologists, paediatric dentists, and orthodontists.

BACKGROUND: Neonatal conjunctivitis (NC) is a common ocular condition during the neonatal period and may lead to serious complications if not properly managed. Although maternal conditions contribute to its development, birth-related and neonatal factors also play an important role. OBJECTIVE: To evaluate birth-related and neonatal factors, along with maternal characteristics, associated with the development of NC. METHODS: This retrospective case-control study was conducted at a tertiary referral center and included neonates born between 34 and 42 weeks of gestation between January 2022 and December 2024. A total of 203 neonates diagnosed with conjunctivitis within the first 28 days of life were compared with 355 randomly selected controls without conjunctivitis from the same source population and study period. Maternal, obstetric, neonatal, and laboratory characteristics were extracted from electronic medical records. Univariable and multivariable logistic regression analyses were performed to identify independent predictors of NC. RESULTS: A total of 558 neonates were included, comprising 203 cases of NC and 355 controls. Neonates with conjunctivitis were more frequently male and had lower gestational age, higher rates of prematurity, and lower Apgar scores than controls. Maternal age, maternal diabetes, and maternal CRP levels were significantly higher among cases. After adjustment for potential confounders, maternal age (OR 1.08, 95% CI 1.03-1.13), maternal diabetes (OR 2.64, 95% CI 1.17-5.94), male sex (OR 1.84, 95% CI 1.24-2.75), and maternal CRP level (OR 1.11, 95% CI 1.07-1.16) were independently associated with neonatal conjunctivitis (all p < 0.05). CONCLUSION: In this case-control study, advanced maternal age, maternal diabetes, elevated maternal CRP levels, and male sex were independently associated with NC. Recognition of these maternal and neonatal factors may facilitate earlier identification of at-risk infants and improve postnatal monitoring strategies.

INTRODUCTION: The incidence of multidrug-resistant Enterobacterales (MDRE) associated urinary tract infection (UTI) in patients with diabetes mellitus is increasing and it is associated with poor prognosis. Due to antibiotic resistance, re-emerging antibiotics like fosfomycin are garnering interest. OBJECTIVES: This study examined the effectiveness and safety of oral fosfomycin in treating MDRE related UTIs in patients with diabetes mellitus at a tertiary care centre in North India. It also studied MDRE infection risk factors present in the local population. METHOD: Seventy-three type 2 diabetes mellitus patients were recruited in this single-centre, single-arm prospective interventional study. Oral fosfomycin was tested for clinical & microbiological efficacy, and its safety profile was also assessed. Antimicrobial susceptibility and prevalence profile of uropathogens in study population was also determined. RESULTS: The average patient age was 54.32 years, with 68.49 % female. E. coli (42.4 %) and Klebsiella (31.5 %) were the most prevalent pathogens. Clinical improvement was achieved in 91 % men and in 98 % women, while microbiological improvement was noted in 82.6 % males and in 90 % for females. Overall, 78.1 % of patients recovered both clinically and microbiologically. Fosfomycin was well tolerated in general, with minimal side effects. CONCLUSION: Fosfomycin appears to be an effective and well-tolerated therapeutic option for type 2 diabetes mellitus patients with MDRE UTIs in our study, although larger comparative studies are needed.

BACKGROUND: Type 2 diabetes (T2D) is a heterogeneous cardio-nephro-hepato-metabolic disease whose clinical expression is shaped by multimorbidity, obesity, sarcopenia, frailty, chronic complications, cardiovascular disease, chronic kidney disease, and functional decline - dimensions that frequently coexist rather than defining mutually exclusive categories. International guidelines appropriately recognise the multidimensional benefits of physical activity, including cardiorespiratory fitness, muscle strength, body composition, physical function, and quality of life; however, translating this increasing clinical complexity into personalised, prioritised exercise prescriptions remains an unresolved operational challenge. OBJECTIVE: To propose a phenotype-informed clinical prioritisation framework for Adapted Physical Activity (APA) in T2D that complements condition-specific exercise recommendations by supporting clinicians in identifying the dominant clinical complexity domain and corresponding therapeutic priority at a given point in the patient's trajectory. METHODS: Evidence from international guidelines, consensus statements, systematic reviews, and meta-analyses was synthesised within a conceptual model integrating functional status, frailty, sarcopenia, and cardiorenal risk as determinants of exercise prescription. RESULTS: Four overlapping domains of clinical complexity are described: adiposopathic insulin-resistant; muscle failure (frailty-sarcopenia); cardiorenal-metabolic; and complication-driven. For each, the dominant therapeutic priority, exercise modality, intensity, and safety considerations are defined with explicit evidence linkage. A six-step clinical algorithm integrates multidimensional assessment, risk stratification, identification of the dominant clinical complexity domain, prioritised prescription, and dynamic reassessment. CONCLUSIONS: Adapted Physical Activity should be prescribed using the same principles of multidimensional assessment, therapeutic prioritisation, monitoring, and dynamic adaptation that increasingly guide modern diabetes pharmacotherapy - supporting the diabetologist's evolving role as a clinician of complexity within a precision exercise medicine approach.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often linked to vitamin D deficiency. Insulin resistance (IR) plays a central role in MASLD and is tied to an abnormal activation of hepatic gluconeogenesis, contributing to the hyperglycemia found in this condition. This study evaluated whether vitamin D supplementation improves MASLD and reduces hepatic glucose production in cafeteria diet-induced obese rats. Inflammation, oxidative stress, and IR were additionally assessed both systemically and in the liver. Gluconeogenic and glycogenolytic fluxes were measured in perfused livers. Wistar rats received a cafeteria or standard diet for 60 days and remained on these diets for another 5 weeks; during this period, a subgroup in each condition received weekly vitamin D (5,600 IU/kg) by oral gavage. The cafeteria diet promoted obesity, MASLD, IR, oxidative stress and inflammation. Obese rats displayed elevated hepatic gluconeogenesis from lactate and intensified glycogenolysis and glycolysis. Vitamin D supplementation reduced food intake and body weight gain and improved IR and glucose tolerance, changes accompanied by lower hepatic steatosis. The treatment decreased hepatic mRNA expression of NF-κB, TNFα, and IL-6, and increased Nrf2 expression. It also elevated vitamin D receptor, sirtuin-1 and FGF21/β-klotho axis expression, findings associated with higher IRS-2 and Nrf2 expression and lower NF-κB expression. Vitamin D reduced the elevated gluconeogenesis and glycogenolysis in obese rats, as determined by direct metabolic flux measurements, likely due to improvements in IR/MASLD. The results support the therapeutic potential of vitamin D in MASLD induced by a cafeteria diet that resembles obesogenic human dietary patterns and suggest benefits for controlling hyperglycemia in obesity.

Emerging evidence links air pollution to metabolic dysfunction, including Type 2 diabetes (T2D). However, findings remain inconsistent, particularly in areas with complex environmental pressures. We investigated the association between long-term exposure to multiple ambient air pollutants (PM, PM, NO, SO, CH) and the incidence of T2D in River Sacco Valley (RSV), an area in Central Italy designated as a Site of National Interest (SIN) due to severe chemical contamination and air pollution. This retrospective cohort study included 392,133 residents aged ≥35 years in RSV and Frosinone province (2008-2018). Incident T2D cases were identified through administrative databases using a validated algorithm. Individual pollutant exposure was assigned at residential addresses using a dispersion model (1×1 km resolution). Exposure to critical industrial environments was also considered. Cox proportional hazards models estimated Hazard Ratios (HR) per 1 μg/m pollutant increase, adjusting for sex, municipality, socioeconomic status and proximity to industrial plants, River Sacco and SIN municipalities. Effect modification by sex was also evaluated. 31,556 T2D incident cases were identified. SO exposure was associated with T2D incidence (HR: 1.01; 95% CI: 1.00-1.02), particularly among women (HR 1.02; 95% CI: 1.01-1.04), suggesting sex-specific vulnerability. Unexpectedly, PM10, PM2.5 and C6H6 showed inverse associations, while NO was not linked to T2D. Notably, residing within 1 km from River Sacco consistently increased T2D risk. These findings may reflect local exposure patterns, residual confounding or the influence of β-hexachlorocyclohexane contamination near the river, highlighting the need for environmental health research in burdened areas to inform equitable prevention strategies.

ETHNOPHARMACOLOGICAL RELEVANCE: Gymnema sylvestre (Retz.) R.Br. ex Sm. is a traditional herb widely used in Indian and Chinese ethnomedicine for diabetes and obesity management. Although its hypoglycemic and hypolipidemic effects have been extensively reported, a system-level understanding of how G. sylvestre modulates glucose-lipid metabolism has not been fully elucidated. AIM OF THE STUDY: The study aimed to explore metabolic alterations associated with G. sylvestre intervention in type 2 diabetes mellitus using an integrated multi-omics strategy. MATERIALS AND METHODS: A type 2 diabetic mouse model was induced using a high-fat diet plus streptozotocin. Mice received graded doses of G. sylvestre extract for six weeks. Metabolic parameters, oxidative stress indices, and liver histopathology were assessed. Proteomic and metabolomic profiling coupled with integrative bioinformatics identified pathway-level metabolic alterations related to G. sylvestre treatment, with selected targets further examined by Western blot analysis. RESULTS: G. sylvestre treatment significantly improved glycemic control and lipid profiles, as shown by decreased fasting blood glucose, total cholesterol, triglycerides, and low-density lipoprotein cholesterol, along with enhanced insulin sensitivity and hepatic glycogen storage. Integrated multi-omics analysis revealed coordinated alterations in 160 proteins and 43 metabolites, predominantly associated with glucose-lipid metabolism, including energy homeostasis and lipid metabolic regulation-associated pathways. Five proteins associated with lipid and energy metabolism were identified, including fatty acid synthase (FAS), carnitine palmitoyltransferase 1A (CPT1A), acetyl-CoA carboxylase alpha (ACACA), fatty acid-binding protein 5 (FABP5), and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), together with metabolites involved in linoleic acid and glycerophospholipid metabolism, were identified as representative molecular features associated with G. sylvestre treatment. CONCLUSION: This study provides integrative multi-omics evidence of coordinated glucose-lipid metabolic remodeling associated with G. sylvestre treatment in type 2 diabetes mellitus. By combining ethnopharmacological context with integrated multi-omics analyses, the results offer scientific support for the traditional application of G. sylvestre in metabolic disorder management.

Exposure to metals has been associated with elevated oxidative stress, which may contribute to diabetic macrovascular complications. However, current methods for evaluating oxidative stress, which mainly rely on quantifying individual byproducts of oxidative damage, may not fully characterize the effects of metal exposure on global redox imbalance, especially in the setting of type 2 diabetes mellitus (T2DM). Here, by assessing global redox status using the novel marker oxidation-reduction potential (ORP) and performing elemental profiling of 35 plasma metals/metalloids in a large cohort of 3142 patients with T2DM, we successfully identified a mixture of 5 redox-related metals (including nickel, zirconium, titanium, strontium, and vanadium), which showed strong associations not only with ORP, but with conventional markers of protein, lipid, and DNA oxidation. Importantly, high exposure to the redox-related metal mixture cross-sectionally correlated with obstructive coronary artery disease (CAD) and prospectively predicted adverse events after percutaneous coronary intervention (PCI) in patients with T2DM. Further cytokine profiling found that changes in cytokines within the nuclear factor-kappa B (NF-κB) pathway might mediate the associations of the redox-related metal mixture with obstructive CAD and post-PCI outcomes. Notably, ex vivo experiments of peripheral blood mononuclear cells (PBMCs) showed that exposure to redox-related metals induced a specific pattern of bioenergetic dysfunction characterized by impaired respiration of mitochondrial complexes I and III, leading to mitochondrial oxidant overproduction and consequent NF-κB activation. Collectively, our findings indicate ORP as a promising marker of metal-induced oxidative stress and support the links of redox-related metals to cardiometabolic risk in patients with T2DM.

In an effort to identify potent α-glucosidase inhibitors for the treatment of type 2 diabetes (T2DM), a series of hybrid pyrazole-containing thiazolidine-2,4-dione derivatives 10 (a-i) were synthesized, and evaluated for their α-glucosidase inhibitory activity. Furthermore, an in silico ADMET study validates passive GI absorption, whereas molecular docking and dynamics highlighted stable interactions with key residues between receptor proteins and the scaffold. Most of the synthesized compounds exhibited potent α-glucosidase inhibitory capability with IC values ranging from 3.32 ± 1.27 to 25.58 ± 2.77 μM, compared to standard acarbose 69.89 ± 1.29 μM. Among synthesized compounds, 10e showed highest α-glucosidase inhibition by 21.05-fold higher than acarbose with moderate antioxidant activity. In vivo antihyperglycemic activity evaluation of compound 10e at doses 10 mg/kg and 50 mg/kg demonstrated a significant reduction in the blood glucose level in streptozotocin induced rats, thereby validating its T2DM action. Moreover, biochemical estimations showed that the levels of alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), urea, blood urea nitrogen and total protein restored to normal in 10e treatment group as compared to the diabetic group.

Dysregulated metabolism of saturated fatty acids (SFAs) in the liver is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), contributing to lipotoxicity and insulin resistance in hepatocytes. While SFAs such as palmitic acid (PA) and myristic acid (MA) are altered in patients with obesity and MASLD, the role of branched-chain fatty acids (BCFAs) remains less well defined. This study aimed to evaluate hepatic BCFAs signatures in MASLD and their effects in in vitro models of PA-induced lipotoxicity. Hepatic BCFAs levels were evaluated in 91 patients with severe obesity using GC-MS. The effects of PA, MA, and specific BCFAs (13-methylmyristic acid (13-MMA) and 12-methylmyristic acid (12-MMA)) were tested in HepG2 cells and in patient-derived human liver organoids (HLOs) by assessing cell viability and CK-18 release. Endoplasmic reticulum (ER) stress markers expression was measured by RT-qPCR. Results showed that hepatic BCFAs were significantly altered in patients with MASLD, particularly 12-MMA and 13-MMA. Furthermore, 12-MMA/MA and 13-MMA/MA ratios were reduced in the presence of MASLD, negatively correlating with histopathological features. In both HepG2 cells and HLOs, PA induced cytotoxicity and CK-18 release, whereas co-incubation with 12-MMA and 13-MMA, but not MA, mitigated cell death and reduced CK-18 levels. Furthermore, BCFAs alleviated ER stress marker expression in PA-treated HepG2 cells. Our findings suggest that both 12-MMA and 13-MMA may exert a hepatoprotective effect against PA-lipotoxicity in human hepatic cell models, highlighting the potential relevance of BCFAs in mitigating liver damage associated with MASLD.

OBJECTIVE: We evaluated the relationships between demographic, metabolic and biochemical risk factors and the presence, localisation and severity of carpal tunnel syndrome (CTS) in a large Turkish cohort. METHODS: In total, 3144 participants were retrospectively included in this 2-year study. Among these, 1458 had an electrophysiologically confirmed diagnosis of CTS, while the remaining 1686 individuals served as the control group. Demographic characteristics, comorbidities and biochemical parameters were recorded for all participants. The CTS patients were further stratified by electrophysiological severity and the anatomical localisation of the involvement. RESULTS: The median age (57 vs 48 years) and body mass index (BMI) (30.6 vs 27.9 kg/m) were significantly higher in the CTS group. Regarding comorbidities, diabetes mellitus (DM), hypertension (HT) and hyperlipidemia were more frequent among CTS patients, with these differences persisting in severe cases. Furthermore, advanced age and the presence of DM and HT were more prevalent in the bilateral CTS subgroup. In a multivariate model, age and BMI remained independently associated with the presence of CTS. CONCLUSIONS: Advanced age and high BMI were confirmed as independent predictors of CTS, whereas female sex was not. Furthermore, components of metabolic syndrome were the most common comorbidities identified in this Turkish cohort.

PURPOSE: To describe glycemic trends following hypoglossal nerve stimulation (HNS) therapy in patients with obstructive sleep apnea (OSA) and type 2 diabetes. METHODS: A retrospective review was conducted of patients with type 2 diabetes who underwent HNS therapy at an academic institution. The study population consisted of 17 diabetic patients who received HNS therapy between Jan 2020 to Oct 2024. Data collected included patient demographics, as well as baseline and post-operative apnea-hypopnea index (AHI) values obtained via polysomnography to assess OSA severity. Diabetes-related parameters included hemoglobin A1c (HbA1c), insulin use, and diabetes medication use. Statistical analyses were performed using IBM SPSS Statistics version 31.0.1.0 with P < 0.05 considered statistically significant. RESULTS: The cohort was 52.9% male with a mean age of 65.3 ± 6.4 years, body mass index of 30.4 ± 3.6 kg/m2, and baseline AHI of 32.4 ± 14.4 events/h. Post-implantation, mean HbA1c decreased from 6.60 to 6.26 (mean change -0.31, p = 0.24). Of the 6 patients who were insulin-dependent prior to HNS implantation, 3 (50%) were able to discontinue insulin use during follow-up. Pearson correlation analysis demonstrated an association between AHI improvement and HbA1c improvement (r = -0.69, p = 0.027). Greater reductions in medication burden were significantly associated with improvements in both AHI and HbA1c. CONCLUSION: In this retrospective cohort, HNS therapy was associated with trends toward lower HbA1c and reduced insulin dependence, although these findings did not reach statistical significance. These results underscore the need for further studies to better understand the role of HNS in improving glycemic control.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe and aggressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent liver-specific consequences of systemic metabolic dysfunction. This review synthesises current evidence on the metabolic and hormonal determinants of MASLD progression, with a particular focus on the mechanisms linking systemic dysfunction across multiple tissues to hepatic inflammation and fibrosis. MASLD pathogenesis is driven by complex interactions between insulin resistance, impaired glucose metabolism, dysfunctional adipose tissue lipolysis and altered hepatic de novo lipogenesis. Central to this process is the dysregulation of key metabolic hormones, including insulin and glucagon, whose imbalance disrupts both glucose and lipid fluxes, leading not only to hepatic steatosis but also to altered hepatic glucose handling, increased substrate delivery and reduced metabolic flexibility. This promotes lipid accumulation as well as glucotoxic and lipotoxic stress. These metabolic disturbances trigger hepatocellular injury and activate inflammatory signalling pathways, including adipokine-mediated crosstalk between adipose tissue and the liver, promoting hepatic stellate cell activation and ultimately leading to a state of chronic low-grade inflammation (metaflammation) that integrates hepatocyte stress, immune cell activation and hepatic stellate cell-driven fibrogenesis. This review also highlights sex-specific hormonal regulation and the gut-liver-adipose axis as determinants of disease heterogeneity and immunometabolic injury. By integrating mechanistic insights across glucose and lipid metabolism, tissues and hormonal pathways, this review underscores how systemic metabolic dysfunction is translated into progressive liver injury and fibrosis. Understanding these interconnected mechanisms of disease progression is essential for identifying therapeutic targets and advancing mechanism-based and precision medicine approaches for MASLD and MASH.

AIMS/HYPOTHESIS: The aim of this study was to explore associations between gender and hypoglycaemia experience among people with type 1 diabetes or insulin-treated type 2 diabetes in a free-living environment in the Hypo-METRICS study. METHODS: The Hypo-METRICS study was a 10-week prospective, cross-sectional observational study of the hypoglycaemia experience. Participants (274 with type 1 diabetes and 321 with type 2 diabetes) wore blinded continuous glucose monitor (CGM) devices and recorded their hypoglycaemia symptoms in real time using a bespoke Hypo-METRICS app. Symptomatic hypoglycaemia was defined as a glucose level <4 mmol/l or any episode of hypoglycaemic symptoms that was resolved by carbohydrate ingestion. Hypoglycaemia symptoms were defined as autonomic (hunger, sweating, shaking, palpitations) or neuroglycopenic (confusion, difficulty speaking, coordination difficulties, headache). Differences between genders were assessed using χ, Fisher's exact and Wilcoxon rank-sum tests and combination analyses. RESULTS: In the type 1 diabetes cohort, 54% were women and 76% of the entire cohort used CGM routinely. In the type 2 diabetes cohort, 63% were men and 41% of the entire cohort used CGM routinely. There were no significant differences in time in hypoglycaemia between genders in either cohort (all p>0.05), but women reported more episodes of symptomatic hypoglycaemia per week (4.3 vs 3.3 episodes/week in the type 1 diabetes cohort [p=0.003]; 1.4 vs 1.0 episodes/week in the type 2 diabetes cohort [p=0.006]). In the type 1 diabetes cohort, women reported a broader range of symptom combinations, spanning autonomic and neuroglycopenic symptoms. Confusion was the only reported symptom of hypoglycaemia in 0.9% of episodes in women and 2.3% of episodes in men. In the type 2 diabetes cohort, there were more symptom combinations, and both genders reported a combination of autonomic and neuroglycopenic symptoms. Confusion alone accounted for 0.3% of symptomatic episodes in men in the type 2 diabetes cohort; confusion alone was not observed in women. CONCLUSIONS/INTERPRETATION: Despite similar exposures to hypoglycaemia, there were differences in hypoglycaemia symptoms between genders in this free-living environment. Further work is needed to elucidate the potential underlying causes of these findings.

Wild guava ( L.) leaf extract shows promise for type 2 diabetes mellitus (T2DM) management through its effects on the gut microbiota, gene expression, and metabolism. This study examined the extract's effects on probiotic growth, gut microbiota, and diabetes-related gene expression in a zebrafish T2DM model. The extract enhanced probiotic growth of , , and YC-381 by up to 33.11% in hyperglycaemic conditions. In diabetic zebrafish, it restored gut microbiota diversity, reduced pathogenic genera, and increased beneficial taxa like c and . Functional analysis showed improved microbial polyphenol and lipid metabolism. The extract downregulated , normalised insulin receptor expression, reduced , and moderately increased . Transcriptomic analysis revealed the homeostatic effects of the extract on metabolic pathways, in contrast to the pharmacological modulation of metformin. These results demonstrate the potential of wild guava leaf extract as a T2DM intervention through its effects on the microbiome-transcriptome-phenotype axis.

Iodine status and thyroid disorders remain understudied subjects in low-income countries such as ours. The objectives of the present study were to assess the serum iodine (SI) level and thyroid function in Malagasy adults seen at the Soavinandriana Hospital Center in Antananarivo and to determine the association between high levels of serum iodine (HLSI) and dysthyroidism. This cross-sectional study was conducted over the course of two years (September 1, 2021 to August 31, 2023). The SI was used as a proxy for iodine status in the absence of urinary assays. Thyroid function was assessed by thyroid stimulating hormone (TSH) and free tetra-iodothyronine (fT4). The HLSI was defined by the total serum iodine >100 µg/L. Dysthyroidism was defined by abnormal TSH and/or fT4 levels indicative of hypo- or hyperthyroidism. Among 195 patients, the prevalences of serum iodine excess and dysthyroidism were 12.8% and 15.4%, respectively. HLSI was significantly more common in subjects <60 years old (-value < 0.0001), and less common in those with hypertension (-value < 0.0001), dyslipidemia (-value < 0.0001), diabetes mellitus (-value = 0.0082) and ex-smoking (-value < 0.0001). Adjusted for age and gender, the association between HLSI and dysthyroidism was significant (OR = 108 [17-680]). HLSI and dysthyroidism were prevalent among Malagasy adults. The presence of one condition would encourage the search for the other. Their management is primarily preventive through their periodic monitoring.

OBJECTIVE: Social determinants of health influence maternal and perinatal outcomes, yet tools to operationalize these risks in clinical care remain scarce. We aimed to study social determinants in Brazilian pregnant women and develop a social vulnerability index (SVI) that could correlate with pregnancy and perinatal outcomes. METHODS: The present study was a secondary analysis of 1565 low-risk nulliparous women enrolled in two Brazilian cohort studies. We selected vulnerability indicators from sociodemographic data and tested the performance and risk association of multiple SVI models with any adverse outcome (preterm birth, gestational diabetes mellitus, pre-eclampsia, small or large for gestational age, low 5-min Apgar score, neonatal intubation, neonatal intensive care unit admission, fetal or neonatal death) using chi-square tests, logistic regression, and receiver operating characteristic analysis. RESULTS: Advanced maternal age, non-white ethnicity, and exclusive publicly funded antenatal care were the most consistent vulnerability predictors of adverse outcomes. The final three-variable SVI demonstrated a significant dose-response gradient, with maternal adverse outcomes increasing from 16.4% (no vulnerabilities) to 43.8% (3 vulnerabilities) and perinatal adverse outcomes rising from 22.1% to 35.6%. The model presented a sensitivity of 64.71%, a specificity of 42.56%, a positive predictive value of 47.46% and a negative predictive value of 60.07% for any adverse outcome. CONCLUSION: The three-variable SVI offers a simple, reproducible, and context-adapted screening tool for primary care. Either for individual or population screening, it can be easily combined with clinical risk assessment, targeting those who may benefit from equity-oriented maternal health strategies.

Obesity is a global health issue linked to increased risks of type 2 diabetes and cardiovascular diseases. A reduced resting metabolic rate contributes to obesity. Plant-based diets are often recommended for weight control, but their effect on resting metabolic rate is underexplored. This study assesses the association between plant-based dietary patterns and resting metabolic rate in women with overweight and obesity. In this cross-sectional study, 285 women with overweight and obesity were selected from health centers in Tehran. Body composition was measured using bioelectrical impedance analysis, dietary intake was assessed using a semi-quantitative food frequency questionnaire. Adherence to plant-based diets was evaluated through three indices: the overall plant-based diet index, the healthful plant-based diet index and the unhealthful plant-based diet index. Resting metabolic rate was measured via indirect calorimetry. Higher plant-based diet index and healthful plant-based diet index scores were significantly associated with increased resting metabolic rate per kilogram of body weight, even after adjusting for confounders. Conversely, higher unhealthful plant-based diet index scores were linked to lower resting metabolic rate per kilogram. Participants with higher adherence to plant-based diet index reported greater intakes of energy, most macronutrients and several micronutrients, while those with higher adherence to the unhealthful plant-based diet index reported lower intakes of energy and selected nutrients. Greater adherence to healthful plant-based diets is associated with a higher resting metabolic rate in women with overweight and obesity, suggesting potential benefits for weight management and metabolic health.