Melioidosis, caused by , produces a wide range of clinical manifestations and may be difficult to diagnose in the pediatric population. We describe the case of a 12-year-old girl with poorly controlled type 1 diabetes mellitus that posed diagnostic challenges. Over 4 months, she experienced relapsing fever, multiple splenic abscesses with a 'target sign' on ultrasonography, right-sided preseptal cellulitis, and a left thigh ulcer. Repeated cultures of superficial swabs and blood yielded no growth of bacteria. Radiological mimicry and culture-negative results raised concerns regarding a fungal etiology, leading to empiric amphotericin B therapy. The definitive diagnosis was made after incision and drainage of a 4 × 6 cm frontal abscess. Pus culture isolated , identified by matrix‑assisted laser desorption/ionization time‑of‑flight mass spectrometry (MALDI‑ToF MS). Patient was treated with intravenous meropenem for 4 weeks followed by oral cotrimoxazole for a planned 3‑month eradication course. The patient recovered with no relapse on follow‑up. This case highlights the need to consider melioidosis in diabetic patients presenting with recurrent, culture-negative abscesses that display a target sign in endemic regions. Deep tissue culture remains essential for diagnosis, as superficial swabs may be misleading. Source control, coupled with dual-phase antimicrobial therapy, remain the cornerstones of effective management.

OBJECTIVES: Diabfrail-Latam is a project funded by the Horizon 2020 program of the European Commission (EC) and the Global Alliance for Chronic Diseases (GACD). The main objective of this protocol is to describe the clinical validation of a multimodal intervention aimed at older people with type 2 diabetes mellitus (T2DM) and frailty in Latin America, involving multicomponent physical exercise (based on VIVIFRAIL), nutritional education, and adjustment of therapeutic targets to be scaled up to other countries in Latin American region. METHODS: The Diabfrail-Latam CE is international, multicenter, single-blind and with two parallel groups with 1:1 randomization (multimodal intervention or usual clinical practice). More than 700 people over 65 years of age, frail or pre-frail, with T2DM, are expected to be recruited in four countries (Colombia, Peru, Mexico and Chile). The primary objective of this clinical validation is to evaluate the effectiveness of the multimodal intervention in improving functionality (measured by the Short Physical Performance Battery, SPPB) after one year of follow-up. Secondary objectives include changes in frailty status, adherence, feasibility, economic impact, biomarkers and caregiver burden. The intervention is expected to significantly improve functionality, reduce frailty progression, and demonstrate feasibility for large-scale implementation in Latin American health systems. CONCLUSION: Diabfrail-Latam will allow to validate and adapt interventions that have demonstrated efficacy in previous studies in European population, providing solid evidence for scaling and replication in the Latin American region and its context.

Diabetic foot ulcer (DFU) is a severe complication of diabetes mellitus (DM), contributing significantly to morbidity and healthcare burden. Kerala, a South Indian state, has a high prevalence of diabetes, yet limited data exist on the genetic risk factors for DFU in this population. In this study, we assessed the association of four common vitamin D receptor (VDR) gene polymorphisms-rs7975232 (ApaI), rs731236 (TaqI), rs1544410 (BsmI), and rs2228570 (FokI)-with DFU in Kerala population. Mean serum 25-hydroxyvitamin D 25(OH)D) levels were 17.7 ± 14.2 ng/mL in the DFU group, 19.5 ± 12.4 ng/mL in the DM group, and 20.6 ± 13.9 ng/mL in the control group. Although the mean 25(OH)D levels did not differ significantly among the groups, the prevalence of vitamin D deficiency was significantly higher in the DFU group than in the DM and control groups (χ² = 6.03, P = 0.04), indicating a greater burden of vitamin D deficiency among patients with diabetic foot ulcers. Among the SNPs studied, rs731236 and rs1544410 showed significant associations with DFU. The AG genotype of rs731236 was associated with a reduced risk of DFU compared to both DM patients and non-diabetic Controls (p < 0.05, OR = 0.51). Similarly, the TC genotype of rs1544410 showed a protective association (p = 0.0219, OR = 0.51). No significant associations were found for rs2228570 and rs7975232. Functional docking analysis of rs2228570 indicated favourable calcitriol binding to both VDR isoforms, with slightly higher affinity for the shorter 424 aa variant (- 7.8 vs. - 7.7 kcal/mol). these findings suggest that vitamin D deficiency and genetic variation in the VDR gene, particularly rs731236 and rs1544410, may contribute to susceptibility to diabetic foot ulcer in the Kerala population, warranting further validation in larger, multicentre studies and functional investigations.

PURPOSE: Hypothalamic obesity (HO) is a treatment-related complication in craniopharyngioma (CP) survivors that markedly impairs long-term health and quality of life. Although overall survival exceeds 90% for both pediatric and adult CP, HO prevalence and clinical course differ substantially by age at onset. We aimed to compare HO manifestations, mechanisms, and treatment response between pediatric and adult CP cohorts. METHODS: We conducted a scoping review of studies published between 2000 and 2025, comparing pediatric (childhood-onset) versus adult-onset CP cohorts, classified by age at diagnosis. Data on obesity prevalence, mechanistic pathways, therapeutic interventions, and cardiometabolic outcomes were extracted and synthesized. RESULTS: In pediatric CP survivors, obesity rates rise from 5.7% pre-treatment to 57% post-treatment; in adults, from 19.2% to 29.2%. HO severity correlates with the extent of hypothalamic damage by Puget and QST grading. Key mechanisms include disrupted melanocortin signaling, central leptin and insulin resistance, and neuroinflammation via resistin-TLR4 and NLRP3 pathways. GLP-1 receptor agonists (exenatide, semaglutide) have produced marked weight loss in small case series (up to 17% over 6 months with semaglutide), but randomized trials did not meet their primary weight outcomes and direct pediatric-versus-adult comparisons are lacking. Bariatric procedures yield moderate success; sleeve gastrectomy achieves 5-year weight loss comparable to that in non-CP controls (21.7% vs. 21.8%), whereas Roux-en-Y gastric bypass is less effective than in controls (22.7% vs. 32.0%). Both cohorts face significant long-term risks: 2.2-fold higher all-cause mortality and 9.3-fold higher diabetes risk in adults, non-alcoholic fatty liver disease in 47% of pediatric survivors, metabolic dysfunction-associated fatty liver disease in 67.4% of adults, and insulin resistance in approximately 30% of pediatric patients. CONCLUSION: HO following CP shows distinct age-dependent trajectories in prevalence, underlying mechanisms, and clinical course; suggested age-related differences in treatment response remain to be confirmed in direct comparative studies. Tailored management integrating mechanistic insights and age-specific therapies is critical to mitigating the cardiometabolic burden in these patients.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide, yet effective therapeutic targets remain limited. Podocyte injury and podocyte to mesenchymal transition represent critical pathological events driving renal fibrosis and progressive dysfunction in DN. METHODS AND RESULTS: Through integrated transcriptomic data from public databases, we discovered that the RNA-binding protein PTBP3 is aberrantly elevated in DN. PTBP3 upregulation was validated in renal tissues from streptozotocin (STZ)-induced diabetic mice and in high glucose (HG) challenged podocytes, suggesting its potential involvement in DN pathogenesis. In PTBP3 knockdown mice, STZ-induced 24 h urinary protein, serum creatinine and blood urea nitrogen were significantly attenuated. Histological analyses revealed ameliorated glomerular hypertrophy and mesangial expansion, and reduced renal fibrosis upon PTBP3 knockdown. In addition, the results showed that the PTBP3 expression in glomeruli of diabetic mice was increased and PTBP3 silencing inhibited the EMT of podocytes in diabetic mice, which was accompanied with the decreased expression of SMAD3. This was evidenced by the restored expression of E-cadherin and the reduced expression of N-cadherin, vimentin, and fibronectin. The results from culture podocytes showed similar results. Mechanistically, the dual-luciferase and RNA immunoprecipitation assays demonstrated that PTBP3 interacted with the 3'-UTR of SMAD3 mRNA to facilitate its stabilization and increase its total protein and subsequent phosphorylation levels. CONCLUSIONS: Notably, PTBP3 knockdown ameliorated renal fibrosis and preserved renal function, underscoring the therapeutic potential of targeting podocyte epithelial-mesenchymal transition in DN.

OBJECTIVES: Diabetic neuropathy (DN), a common complication of type 2 diabetes, is associated with oxidative stress, inflammation, and persistent hyperglycemia. Naringin, a flavonoid with antioxidant and anti-inflammatory properties, is limited by poor bioavailability. This study aimed to develop and optimize a naringin-loaded phytosomal formulation to enhance bioavailability and evaluate its efficacy in DN. METHODS: Naringin-loaded phytosomes were prepared and optimized using a Box-Behnken design to achieve high entrapment efficiency, favorable particle size, polydispersity index (PDI), and zeta potential. In silico docking assessed binding with PPAR-γ, α-glycosidase, AMPK, NF-κB, and Nrf2. Ex vivo intestinal permeability studies evaluated absorption. In vivo efficacy was tested in streptozotocin-induced diabetic rats by assessing pain thresholds, biochemical parameters, antioxidant enzyme activities, TNF-α levels, and gastric emptying time. RESULTS: The optimized formulation showed 93% entrapment efficiency, desirable particle size, low PDI, stable zeta potential, and enhanced permeability. Docking confirmed strong binding to molecular targets regulating glucose metabolism and oxidative stress. In vivo, naringin phytosomes significantly improved pain thresholds, reduced glucose and lipid levels, increased antioxidant enzyme activities, decreased TNF-α, and improved delayed gastric emptying compared to plain naringin. DISCUSSION: Phytosomal delivery markedly enhanced naringin's bioavailability and therapeutic potential in DN, likely due to improved uptake and multi-targeted action. These findings support naringin phytosomes as a promising candidate for DN management, meriting further clinical evaluation.

BACKGROUND: Serum uric acid (SUA) has been linked to vascular injury, but its impact on stroke risk in diabetic patients-a population inherently prone to cerebrovascular events-remains uncertain, and whether a threshold effect exists is unclear. METHODS: We included 3718 diabetic patients from two clinical centers. Multivariable-adjusted Cox proportional hazards models with stepwise covariate adjustment were used to assess associations between SUA and overall stroke and its subtypes. Kaplan-Meier curves estimated cumulative incidence across SUA quartiles. Restricted cubic spline regression examined dose-response relationships and potential threshold effects, and sex-stratified analyses were also performed. RESULTS: Elevated SUA was significantly associated with increased risks of stroke and subtypes. The highest SUA quartile showed a significantly higher cumulative risk. RCS revealed threshold effects: risks of stroke, ischemic stroke, and hemorrhagic stroke increased when SUA exceeded 335, 330, and 340 μmol/L, respectively. Sex-stratified analyses yielded consistent findings, with thresholds at 335 μmol/L for males and 350 μmol/L for females. CONCLUSION: In conclusion, this observational study confirms a significant association between SUA and stroke risk in diabetic patients with a threshold effect, suggesting potential clinical value for monitoring and urate-lowering therapy. However, sex-specific threshold findings should be interpreted cautiously as hypothesis-generating, and prospective randomized controlled trials are needed for validation.

Early fetal echocardiography and serial surveillance are crucial in pregnancies complicated by pregestational diabetes. Tetralogy of Fallot with absent pulmonary valve syndrome may cause progressive cardiomegaly, ventricular hypertrophy, hydrops, and fetal demise. Timely diagnosis enables informed parental counseling and multidisciplinary perinatal planning.

PURPOSE: We investigated the association between tongue characteristics and musculoskeletal (MSK) pain in patients with type 2 diabetes mellitus (T2DM) and explored potential noninvasive tongue-based biomarkers. PATIENTS AND METHODS: This cross-sectional study enrolled 586 patients with T2DM (420 without and 166 with MSK pain) between January 2023 and December 2024 at the Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine. Tongue images were obtained using a standardized tongue-imaging device. Color parameters in the Lab and RGB color spaces were extracted from the tongue proper and coating. Multivariate logistic regression was used to examine associations between individual tongue parameters and MSK pain. Principal component analysis was applied separately to tongue proper and coating parameters to derive composite scores, and latent profile analysis (LPA) was used to identify tongue-based subgroups. RESULTS: After adjustment for confounders, higher TC-b (Odds ratio [OR], 1.26; 95% confidence interval [CI], 1.151-1.379; P<0.001) and CC-b (OR, 1.199; 95% CI, 1.111-1.294; P<0.001) values were significantly associated with an increased risk of MSK pain. The tongue-proper composite score was positively associated with MSK pain risk (OR, 1.649; 95% CI, 1.240-2.193; P<0.001), whereas the tongue-coating composite score showed a negative association (OR, 0.586; 95% CI, 0.425-0.807; P=0.001). LPA identified five distinct tongue-imaging subgroups, including one subgroup with high TC-b and CC-b that exhibited a significantly higher risk of MSK pain. CONCLUSION: Tongue color characteristics are associated with MSK pain in patients with T2DM and may serve as potential noninvasive biomarkers for the auxiliary assessment of MSK pain. Prospective studies are needed to clarify their clinical relevance and potential utility.

PURPOSE: The purpose of this study was to evaluate the individual influences of knowledge and attitudes about continuous glucose monitors (CGMs) among adults with type 1 or type 2 diabetes. METHODS: Adults diagnosed with type 1 or type 2 diabetes completed an online survey regarding knowledge and attitudes about CGM use. Knowledge was measured using the benefits subscale of the CGM Satisfaction Scale, and attitudes were measured using the hassles subscale. Binomial regression was used to evaluate the individual influence of knowledge and attitudes and their predictive ability for current CGM use. RESULTS: A total of 58 adults participated. Of these, 38 (66%) reported current CGM use, and among current users, 90% reported a diagnosis of type 1 diabetes, and 10% reported a diagnosis of type 2 diabetes. Attitudes regarding CGM were statistically better than knowledge. Current use of a CGM correlated with knowledge and attitudes, and therefore, knowledge and attitudes were entered into binomial logistic regression. The model was statistically significant, explaining 36% of the variance in current CGM use. Participants with better attitudes were more likely to use a CGM, while those with greater knowledge were less likely to do so. CONCLUSIONS: Consistent with the hypothesis, knowledge and attitudes influenced use of CGM differently. Based on these findings, patient education to promote use of CGM should focus on improving attitudes regarding the hassles of CGM as these exert the greatest influence on current use.

BACKGROUND: Traditional Moroccan herbal teas are widely consumed and have been traditionally used for managing chronic metabolic disorders, particularly type 2 diabetes mellitus (T2DM). Although these preparations have a long history of ethnomedicinal use, their phenolic composition and biological activities remain insufficiently characterized. Scientific validation is needed to support their traditional application and provide evidence for their potential relevance to T2DM management. This study aimed to characterize the phenolic profile, antioxidant potential, and carbohydrate-digestive enzyme inhibitory activity of 21 traditional Moroccan herbal teas used for glycaemic control. METHODS: Phenolic constituents were identified and quantified using HPLC-MS. Antioxidant capacity was evaluated through DPPH, ABTS, and FRAP assays. Inhibitory effects on α-amylase and α-glucosidase were assessed in vitro. Correlation analyses were conducted to explore associations between phenolic constituents and biological activities. FINDINGS: Marked variability in total phenolic content (TPC) was observed, with Mentha × piperita and Thymus broussonetii exhibiting the highest levels at 883.2 ± 13.0 and 746.8 ± 22.4 mg GAE/g dry weight, respectively. Antioxidant activity varied substantially among the investigated teas, with T. broussonetii (FRAP reducing power: 423.6 ± 9.8 µg/mL) and Mentha rotundifolia (162.6 ± 0.6 µg/mL) showing significant reducing capacities. TPC exhibited strong positive correlations with antioxidant indices (r = 0.93-0.96). Pelargonium graveolens presented potent α-amylase inhibition (IC = 2.98 ± 1.7 µg/mL), whereas Mentha viridis and Calamintha officinalis were among the most active α-glucosidase inhibitors (IC = 1.9 ± 0.4 and 1.2 ± 0.1 µg/mL, respectively). Negative correlations were found between rutin (r = - 0.49) and gallic acid (r = - 0.44) contents and α-amylase IC values. CONCLUSION: The investigated Moroccan herbal teas exhibited variable antioxidant and digestive-enzyme inhibitory activities that were associated with their phenolic composition. Variability among samples may reflect differences in plant species and environmental or agronomic factors. These findings provide comparative in vitro evidence supporting the traditional use of Moroccan herbal teas and highlight several species as promising sources of bioactive phenolics. However, the present findings do not establish therapeutic efficacy, and further in vivo, mechanistic, pharmacokinetic, and clinical studies are required to confirm their efficacy, safety, and clinical relevance.

Type 2 Diabetes (T2D) is a complex disease that has increased in prevalence in the last years affecting over 530 million people around the world. T2D increases mortality and morbidity by different mechanisms. As a complex disease, it is caused by many genetic changes and, consequently, T2D genetics has been analyzed from different points of view and using different strategies. Most studies have focused on inherited Single Nucleotide Variants (SNVs) present in genomic DNA, while other types of genetic variants have received less attention. The aim of the present review is to examine the limitations of the studies conducted to date, and the importance of non-SNVs and non-germinal variants in the genetics of this disease. In this way, structural variants, mobile elements and tandem repeats have a crucial role in T2D. In addition, variations in mitochondrial DNA and somatic variations have been shown to play an important role in metabolic alterations that may lead to the development of T2D.

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal Dendrobium species have long been used in Chinese materia medica and ethnomedicinal practices to promote fluid production, nourish yin, clear heat, and relieve thirst. Traditional records of their use for "Xiaoke" provide an ethnopharmacological rationale for investigating the hypoglycemic effects of Dendrobium polysaccharides. AIM OF THE REVIEW: This review summarizes the structural characteristics, hypoglycemic mechanisms, and structure-activity relationships of Dendrobium polysaccharides and critically evaluates the limitations of the available evidence and the barriers to clinical translation. MATERIALS AND METHODS: Relevant literature published between January 1998 and July 2026 was identified by searching the Web of Science Core Collection, Scopus, PubMed, SciFinder-n, and China National Knowledge Infrastructure (CNKI). These searches were supplemented by Google Scholar, reference list screening, and consultation of pharmacopoeias, materia medica, and ethnomedicinal sources. RESULTS: Dendrobium polysaccharides are structurally heterogeneous polymers. Many fractions are enriched in mannose and glucose, and acetylated β-(1→4)-mannans and glucomannans are frequently identified among the active fractions. The reported molecular weights of these compounds vary widely. Although 5-200 kDa is the most commonly reported range for active fractions, higher molecular weight fractions also exhibit activity. Branching patterns and higher-order conformations vary according to the botanical origin and preparation method. Evidence from cell and animal models indicates that these polysaccharides may protect pancreatic β cells, attenuate insulin resistance, regulate glucose and lipid metabolism, reduce oxidative stress and inflammation, and modulate the gut microbiota and intestinal barrier. The activity of these polysaccharides is associated with their monosaccharide composition, glycosidic linkages, molecular weight, O-acetylation, and higher-order conformation. However, most of these associations are based on comparisons across species, fractions, and experimental conditions, preventing the clear distinction of the effects of individual structural features. CONCLUSIONS: Preclinical evidence supports the hypoglycemic potential of Dendrobium polysaccharides via multiple pathways. However, structural heterogeneity, methodological inconsistency, and limited human evidence impede cross-study comparisons and clinical translation. Future research should prioritize standardized preparation and characterization, controlled structure-activity comparisons, additional in vivo efficacy and safety studies, and rigorous clinical validation.

BACKGROUND: The skeletal muscle plays a central role in glucose metabolism, but absolute muscle mass is strongly influenced by both body size and adiposity. Herein, we investigated whether residual appendicular lean mass (ALM), a body-size-adjusted measure of the skeletal muscle reserve, was associated with insulin resistance and whether this association differed according to the obesity status of Korean adults. METHODS: This cross-sectional study included 14,647 adults extracted from the Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2010. Residual ALM was derived as the standardized (z-score) residual from a linear regression model including the age, sex, and body mass index (BMI). Associations between residual ALM and log-transformed homeostasis model assessment of insulin resistance (HOMA-IR) were examined using complex survey-weighted linear regression models. Metabolic syndrome was evaluated as a secondary clinical outcome. RESULTS: In the unadjusted analyses, residual ALM was positively associated with HOMA-IR (β = 0.041, 95% confidence interval [CI] 0.030-0.052; P < 0.001). After adjusting for age, sex, and BMI, higher residual ALM was associated with lower HOMA-IR (β = -0.060, 95% CI -0.070 to -0.049; P < 0.001); this association remained significant after further adjustment for hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease, smoking status, and hepatic steatosis index (β = -0.043, 95% CI -0.053 to -0.033; P < 0.001). The magnitude of the inverse association differed according to obesity status (P for interaction = 0.007), and was more pronounced among individuals without obesity. Higher residual ALM was further associated with lower odds of metabolic syndrome after adjusting for BMI and hepatic steatosis index (odds ratio 0.86, 95% CI 0.81-0.92; P < 0.001). CONCLUSIONS: Higher residual ALM was independently associated with lower insulin resistance and lower odds of metabolic syndrome in Korean adults. Higher body-size-adjusted skeletal muscle reserve was associated with a more favorable metabolic profile, particularly among non-obese adults.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are an established treatment for management of type 2 diabetes mellitus (T2DM) and obesity. While these agents provide clinical benefits, chronic rodent bioassays have shown a consistent increase in thyroid C-cell tumors, raising regulatory concerns for human carcinogenicity risk and resulting in a boxed warning for medullary thyroid carcinoma (MTC). However, the human relevance of the rodent tumors is unclear due to species differences in GLP-1 receptor (GLP-1R) biology. Carcinogenicity testing of pharmaceuticals is described in ICH S1 guidelines. ICH S1B(R1) outlines experimental approaches to carcinogenicity evaluation including a weight-of-evidence (WoE) framework to determine whether long-term rat carcinogenicity studies add value to human cancer risk assessments. This manuscript applies that framework across seven approved GLP-1RAs: lixisenatide, exenatide, liraglutide, dulaglutide, semaglutide, tirzepatide, and albiglutide, to evaluate the relevance of rodent thyroid tumors and the utility of 2-year bioassays for this drug class. Across all six WoE domains, the evidence supports concluding that GLP1-RAs are tumorigenic in rats via a known human-irrelevant mechanism. Thus, within the S1B(R1) WoE framework, future carcinogenicity testing in rats is unlikely to provide additional value for regulatory decision-making for this class of pharmaceuticals.

BACKGROUND: Tools to non-invasively capture dynamic metabolic responses to diet in humans remain limited. Saliva has emerged as an accessible complementary biofluid, but its responsiveness to diet-induced metabolic adaptations remains insufficiently characterized. METHODS: In this controlled crossover study, twelve healthy adults completed three 7-day dietary interventions enriched in protein, lipids, or carbohydrates, each preceded by a Mediterranean-style washout. Fasting blood and stimulated saliva samples were collected at baseline and after each intervention, with an additional salivary assessment at day 4. Blood biochemical markers and salivary biochemical and physicochemical parameters were analyzed. Temporal responses were assessed using repeated-measures ANOVA, and selected associations between within-participant changes from baseline to day 7 were evaluated using Spearman rank correlations, with Holm adjustment across the three focal associations. RESULTS: Macronutrient-specific diets induced distinct and coordinated metabolic responses detectable in both blood and saliva. The high-protein diet increased blood urea nitrogen and salivary ammonium and reduced blood uric acid. Within-participant changes in blood urea nitrogen and salivary ammonium were positively associated (Spearman ρ = 0.620, P = 0.032). The high-carbohydrate diet reduced salivary pH and buffering capacity, but their associations with changes in HOMA-IR did not reach statistical significance. The high-lipid diet reduced circulating GOT and LDH without significant changes in the evaluated salivary parameters. CONCLUSIONS: Short-term dietary modulation induces distinct and non-identical biochemical responses in blood and saliva. The parallel nitrogen-related responses observed following the high-protein diet support further investigation of saliva as a complementary biofluid for studying dietary adaptations. However, the exploratory associations do not establish equivalence or robust concordance between salivary and blood biomarkers.

This study investigated the effects of eight weeks of combined exercise training, resveratrol supplementation, and acute acoustic stress on mitochondrial biogenesis markers and metabolic parameters in the soleus muscle of male diabetic rats. Sixty male Wistar rats were randomly assigned to twelve groups (n = 5 per group): control, diabetes, stress, diabetes + stress, diabetes + exercise, diabetes + resveratrol, diabetes + exercise + resveratrol, stress + resveratrol, stress + exercise, stress + exercise + resveratrol, exercise + resveratrol, and diabetes + stress + exercise + resveratrol. Type 2 diabetes was induced by intraperitoneal injection of streptozotocin (60 mg/kg). Following VOmax assessment, the animals underwent an 8-week concurrent training program (5 days/week) consisting of endurance running and resistance ladder-climbing exercise with loads corresponding to 30-100% of body mass. During the intervention period, the supplementation groups received resveratrol (100 μg/kg/day) dissolved in 100 μL carboxymethylcellulose (CMC) gel, whereas the remaining groups received an equivalent volume of CMC via oral gavage. The results demonstrated significant effects of the interventions on peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α; P = 0.008, F = 71.008), mitochondrial transcription factor A (Tfam; P = 0.002, F = 38.588), fibronectin type III domain-containing protein 5 (FNDC5; P = 0.001, F = 8.535), irisin (P = 0.001, F = 45.801), blood glucose (P < 0.001, F = 555.853), insulin (P < 0.001, F = 76.616), insulin resistance (P = 0.001, F = 133.576), β-cell function (P = 0.001, F = 33.600), and VOmax (P = 0.038). Combined exercise training and resveratrol supplementation, particularly under conditions of acute acoustic stress, improved mitochondrial biogenesis-related markers and metabolic regulation in diabetic rats. The greatest improvements were observed in the diabetes + stress + exercise + resveratrol (DSER) group, suggesting that combined intervention may provide additional benefits compared with individual interventions on mitochondrial function, glucose homeostasis, insulin sensitivity, and aerobic capacity.

Pancreatic β-cell dedifferentiation is a pathological mechanism that contributes to β-cell dysfunction and loss during type 2 diabetes (T2D), but the underlying mechanisms remain incompletely understood. MicroRNAs (miRNAs) are key post-transcriptional regulators of cellular identity and function. We previously identified miR-483 as a β-cell-enriched miRNA that promotes β-cell function by targeting Aldh1a3. Here, we investigated its role under high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced metabolic stress. β-cell-specific miR-483 deficiency exacerbated hyperglycemia and impaired glucose tolerance, accompanied by increased ALDH1A3 expression and reduced insulin expression in GFP-labeled cells. Under HFD/STZ-induced metabolic stress, miR-483 deficiency also increased glucagon production and the abundance of GFP+GCG+ and ALDH1A3+GCG+ cells, consistent with loss of β-cell identity and emergence of α-cell-like characteristics. Single-cell RNA sequencing revealed increased β-cells heterogeneity, including a subpopulation with glucagon expression and an altered endocrine phenotype. In addition, miR-483 deficiency was associated with mitochondrial fragmentation, impaired respiratory function, and increased oxidative stress. Together, these findings suggest that miR-483-ALDH1A3 axis contributes to the coordination of β-cell identity with mitochondrial and metabolic homeostasis during metabolic stress.

Perilla frutescens (PF) is rich in flavonoids and other secondary metabolites with antioxidant properties. This study explored the lifespan-modulating effects and underlying mechanisms of an ethyl acetate extract of PF leaves (EAEPF) using Caenorhabditis elegans (C. elegans) as a model organism. EAEPF treatment significantly prolonged lifespan, enhanced pharyngeal pumping and head thrashing frequencies, and reduced the accumulation of lipofuscin and reactive oxygen species (ROS). The extract improved antioxidant enzyme activity, decreased malondialdehyde (MDA) levels, and increased resistance to thermal and juglone-induced oxidative stress. EAEPF markedly reduced lipid storage in nematodes, indicating a lipid-lowering effect. Mechanistically, EAEPF activated the insulin/IGF-1 signaling (IIS) pathway, and upregulated the transcription factors DAF-16/FOXO and SKN-1/Nrf2, which in turn promoted the expression of downstream stress-response genes (sod-3, gst-4, hsp-16.2). EAEPF reprogrammed lipid metabolism and enhanced glutathione metabolism, may represent a potential source of nutritional hormetins. These findings demonstrated the potential of EAEPF as a nutraceutical for lifespan extension and healthspan improvement.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) are interrelated metabolic disorders worldwide. We aimed to characterize global co-occurrence patterns of T2DM and MASLD from a spatial perspective and to identify shared risk factors. METHODS: We extracted incidence rates of T2DM and MASLD and exposure rates of 68 risk factors among individuals aged ≥ 20 years, derived from Global Burden of Disease Study 2021. Three co-occurrence areas were classified based on four quartiles of both diseases incidence. Interpretable machine learning and negative binomial linear mixed-effects model were applied to identify and quantify effects of risk factors. We calculated population-attributable fraction (PAF) to evaluate incidence burden of T2DM and MASLD attributable to identified risk factors. RESULTS: Fifty-nine countries were classified as consistent, 71 as T2DM-dominant, and 74 as MASLD-dominant. Three areas overlap spatially with exposure rates to metabolic, environmental, and behavioral risk factors. After feature selection, we identified nine risk factors with substantial effects on the comorbidity. Functionally, T2DM incidence was mainly attributable to metabolic risks (PAF = 35.28%) and behavioral risks (11.78%), whereas MASLD incidence was attributable to behavioral risks (28.84%), environmental risks (21.65%), and metabolic risks (14.63%). Overall, 42.9% of T2DM incidence and 52.41% of MASLD incidence were attributed to cumulative exposure to risk factors, with specific combinations and variations of these factors significantly impacting the disparate co-occurrence patterns worldwide. CONCLUSION: Comorbidity of T2DM and MASLD is a prevalent global health issue. Co-management of T2DM and MASLD can proceed from interventions targeting corresponding modifiable risk factors.

The gut microbiota influences host metabolism through diverse metabolites, many of which have been linked to glucose homeostasis and type 2 diabetes (T2D). Understanding microbial contributions to metabolite biosynthesis is essential for developing dietary and microbiota-targeted T2D prevention and treatment strategies. We performed targeted plasma metabolomics in individuals with T2D and healthy controls, all receiving histidine supplementation, before and after gut microbiota suppression using 7-day broad-spectrum antibiotic treatment. Associations between pre-antibiotic metabolite levels and fecal metagenomics-derived gut microbiota composition were examined using co-abundance network analysis and Random Forest modeling. Indole-3-propionic acid (IPA) was the only gut-derived metabolite differing between groups before antibiotics, with lower levels in T2D and higher levels associated with reduced T2D odds. Antibiotic treatment reduced IPA to near-undetectable levels in both groups, confirming its predominantly microbial origin. Beyond established inverse associations with BMI and glycemic markers, we found a novel inverse correlation between IPA and glycemic variability, consistent with a protective association with T2D. Plasma IPA was associated with gut microbiota beta diversity. IPA-associated species clustered within a single co-abundance module, but did not include known IPA producers, suggesting plasma IPA is influenced by broader microbial community composition rather than IPA-producing capacity of individual taxa alone. This study provides direct human evidence that plasma IPA is virtually exclusively gut microbiota-derived in individuals with T2D, extending prior findings in healthy populations. It highlights IPA's relevance to metabolic health and T2D, and guides future research on dietary and microbiota-targeted strategies to modulate IPA, advancing T2D prevention and treatment.

The timing of physical activity and exercise has been suggested to play a role in metabolic health. This narrative review synthesises current evidence on the impact of habitual physical activity and exercise timing on glucose homeostasis and insulin sensitivity, blood lipids and body composition among individuals with overweight, obesity and impaired glucose homeostasis. To this end, we reviewed evidence from both observational and experimental studies. Overall, current evidence on physical activity/exercise timing and metabolic health is inconsistent, with several studies reporting no significant time-dependent differences, and other studies suggesting more favourable glucose-related outcomes and improved insulin sensitivity and lipid profiles when physical activity/exercise is performed later in the day. Body composition outcomes appear to be largely independent of exercise timing. The interpretation of the current evidence is limited by the small number of studies, heterogenous study designs and variability in exercise modalities and durations. We identify important gaps in knowledge, particularly regarding sex-specific responses, the role of chronotype and the real-world feasibility of timing-based exercise recommendations. While engaging in physical activity or exercise at any time of day is more beneficial than remaining inactive, further studies are warranted to clarify the optimal timing for metabolic health in individuals at risk of type 2 diabetes.

Obesity is an important risk factor for chronic kidney disease (CKD), yet only a subset of individuals with obesity develops albuminuria, declining estimated glomerular filtration rate (eGFR), and progressive kidney disease. This variability indicates that excess body weight alone is insufficient to explain obesity-induced kidney injury. In this review, we propose that cardio-kidney-metabolic (CKM) syndrome provides a useful framework to understand this heterogeneity. We discuss major pathophysiological contributors to kidney vulnerability in obesity, including haemodynamic stress, metabolic toxicity/insulin resistance, visceral and ectopic fat, inflammation, oxidative stress, adipokine imbalance, and reduced nephron reserve. Several of these contributors converge on a common intrarenal pathway characterized by increased single-nephron workload, maladaptive glomerular hyperfiltration and intraglomerular hypertension, followed by podocyte stress, albuminuria, and progressive kidney injury. On this basis, we propose a conceptual framework comprising four overlapping CKM-related kidney vulnerability domains, which may help identify individuals at increased CKD risk, support earlier screening and longitudinal monitoring, and inform preventive strategies.

This study investigated associations between exercise, intestinal barrier-related gene expression, and cardiac Nlrp3 inflammasome-related gene expression in a diabetic mouse model. Metabolic dysregulation was induced in male C57BL/6J mice using a high-fat diet combined with low-dose streptozotocin, followed by 8 weeks of treadmill exercise (5° slope, 12 m/min, 20-50 min/day, 5 days/week). Compared with sedentary diabetic mice, exercised mice showed lower fasting glucose, insulin resistance, and serum lipid levels, along with higher colonic Occludin mRNA expression (relative expression: 0.38 ± 0.04 in diabetic mice vs. 0.79 ± 0.05 in exercised mice, P < 0.001), lower cardiac Nlrp3, IL-1β, TNF-α, Col1a1, and Tgfb1 mRNA expression, and a lower Bax/Bcl-2 mRNA ratio (3.06 ± 0.19 vs. 1.48 ± 0.10, P < 0.001). Fecal qPCR analysis of six selected taxa showed that exercise was associated with increased relative abundances of Akkermansia muciniphila (0.31 ± 0.04 to 0.84 ± 0.07) and Lactobacillus (0.48 ± 0.05 to 1.01 ± 0.07) and decreased Escherichia coli (3.84 ± 0.33 to 1.68 ± 0.13, P < 0.01). In exercised mice, A. muciniphila abundance was negatively correlated with cardiac Nlrp3 mRNA expression (R = -0.81, P = 0.0046). These correlational findings indicate associations among exercise, cardiac and intestinal transcriptional changes, and selected gut microbial taxa in diabetic mice but do not establish causal relationships. All molecular findings are limited to mRNA-level changes and do not demonstrate intestinal barrier function, inflammasome activation, myocardial fibrosis, apoptosis, or other functional or protein-level effects.