Abstract: Background: Chronic hyperglycemia promotes non-enzymatic glycation of hemoglobin, increasing oxygen affinity, shifting the oxyhemoglobin dissociation curve leftward, and inducing tissue-level pseudohypoxia a state termed glycohypoxia. This meta-synthesis quantitatively validates this concept by estimating the HbA1c-dependent change in P₅₀ and the resulting deficit in oxygen unloading, linking biochemical glycation to microvascular dysfunction. Methods: From six pivotal studies (1984–2012; N = 450 diabetic and control subjects), paired HbA1c and oxygen-release metrics (P₅₀, k, SpO₂–SaO₂ bias) were extracted. Study-specific slopes (ΔP₅₀ mmHg per 1% HbA1c) were pooled via random-effects meta-regression (REML), with sensitivity adjustment excluding 2, 3-DPG compensation. Translational modeling integrated the pooled ΔP₅₀ into the Hill equation for hemoglobin saturation across microvascular PO₂ (20–40 mmHg). Results: The pooled slope was −0.19 mmHg/% HbA1c (95% CI: −0.26 to −0.11; P < 0.001; I² = 45%), indicating a 0.5–1.3% decline in tissue oxygen unloading per 1% HbA1c rise, and a 1.5–3.9% cumulative loss from 6–9%. Independent clinical validation in 261 ventilated type 2 diabetes patients showed higher pulse oximetry versus arterial saturation for HbA1c >7% (SpO₂: 98.0 ± 2.6%, SaO₂: 96.2 ± 2.9%), despite similar PaO₂. The mean SpO₂–SaO₂ bias (1.83 ± 0.55%) correlated with HbA1c (r = 0.307, P < 0.01), confirming pseudonormoxia and leftward ODC shift. Conclusions: Glycohypoxia represents a quantifiable, reversible oxygen-delivery defect driven by HbA1c. Each 1% HbA1c rise translates to measurable hypoxic stress. Efaproxiral (RSR13; ~2.3 mg/kg per 1% HbA1c) could normalize P₅₀ and attenuate related complications by 30–55%, supporting metabolic reoxygenation as a therapeutic frontier in diabetes.

Abstract: Type 2 diabetes mellitus (T2DM) evolves through a continuum of biochemical injuries culminating in both receptor-level and molecular-level insulin dysfunction. Building on the glycohypoxia paradigm, this paper identifies insulin inactivation itself as a biochemical complication of T2DM, arising when chronic hyperglycemia and oxygen-release impairment converge. Elevated HbA1c not only reflects glucose excess but also amplifies tissue hypoxia by left-shifting the oxyhemoglobin dissociation curve, creating a redox environment that accelerates non-enzymatic insulin glycation. Mass spectrometric and kinetic evidence indicate that monoglycated insulin species (+164 Da) progressively accumulate once HbA1c exceeds ~7.5–8%, marking a “glycation threshold” where native insulin begins losing post-receptor activity. Across integrated datasets, every 1% HbA1c rise corresponds to an estimated 15–20% decline in functional insulin bioactivity, paralleling the oxygen unloading deficit observed in glycohypoxia. At this inflection point, insulin molecules though structurally preserved and immunoreactive become signaling-deficient, displaying up to 70% loss in PI3K/Akt activation and GLUT4 translocation. Thus, hyperglycemia transforms viable hormone into oxidized inert mass, coupling metabolic hypoxia with hormonal decay. This analysis reframes insulin failure not as a downstream event, but as a quantifiable biochemical complication of the glycohypoxic state in type 2 diabetes.

Abstract: The energy balance model (EBM) and its operational form, calories-in-calories-out (CICO), have dominated obesity research and clinical practice for decades. While these frameworks have yielded valuable public health insights, they rely on indirect conversions between mass and energy and rest on misconceptions about thermodynamic principles. This Perspective argues that a mass balance model (MBM) provides a conceptually simpler, mathematically consistent, and biologically more faithful paradigm. By tracking macronutrient mass directly – without intermediate energy-unit conversions or misapplications of thermodynamic laws – the MBM aligns analysis with physiological reality and better predicts body composition dynamics. Clarifying that the first law of thermodynamics concerns only energy (not mass), that calories cannot be eaten or oxidized, and that E=mc² has no relevance to human metabolism paves the way for more precise translational interventions in metabolic medicine.

Abstract: Background: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with the risk of several chronic and acute diseases. However, updated data on vitamin D status in Mediterranean countries, including Italy, remain limited, hindering effective public health strategies. Objective: To assess serum 25(OH)D levels and their seasonal variation in healthy blood donors aged 18–65 years living in Northern Italy and not taking vitamin D supplements. Given the latitude and high levels of environmental pollution, cutaneous vitamin D synthesis may be impaired in this population. Recent Italian guidelines on supplementation highlight the need for updated data on hypovitaminosis D prevalence and seasonal synthesis capacity. Methods: In this exploratory cross-sectional study, 534 blood donors (268 men and 266 women) attending the Transfusion Medicine Unit of Verona University Hospital were enrolled between April 2016 and May 2018. Serum 25(OH)D concentrations were analysed according to season. Clinical, lifestyle, pharmacological and dietary characteristics were also collected. Results: Among healthy, normal-weight individuals, the prevalence of vitamin D insufficiency (25(OH)D<50 nmol/L) was low and limited to one-two months per year. Overweight and obesity significantly reduced the likelihood of achieving adequate 25(OH)D levels through cutaneous synthesis for several months. Mean 25(OH)D concentrations were higher than those previously reported in the same area, while seasonal variation remained preserved. Conclusions: Despite persistent environmental pollution, seasonal vitamin D synthesis is not impaired in this Northern Italy population. Updated data show higher 25(OH)D levels compared to past studies, supporting current recommendations against routine supplementation in healthy normal-weight individuals under 70 years

Abstract: Background/ Objectives Patients with poor sleep are at high risk for developing diabetes (T2DM). Since T2DM is linked to increased risk of obstructive sleep apnea (OSA), and Metformin is commonly used to treat T2DM, we examined how Metformin affects sleep stages in patients with concurrent T2DM and OSA-related symptoms of snoring and fatigue. T2DM patients on Metformin, progressively develop increased insulin resistance associated with sleep disturbances, and poor glycemic control. We explored changes in sleep patterns in T2DM patients on Metformin. We explored if Metformin affects sleep Architecture in T2DM patients. Methods Evaluate PSG (polysomnogram data from T2DM patients on Metformin along with data on age, BMI and sex. Data to be analyzed as mean +SE and linear regression, t test p< 0.5 taken as significant. Results Non-obese patients taking Metformin experienced a significant decrease in REM duration compared to patients on alternative therapies (p = 0.036). There was no such change in REM for obese patients taking Metformin. While there was no change in N3 duration with Metformin use, linear regression identified a moderate negative correlation between N3 and age in patients taking non-Metformin therapies (R2 = 0.4555). No significant correlations between sleep stage duration and patient sex, smoking status, or body-mass index (BMI) were identified. Conclusion T2DM patients on Metformin had OSA with reduced deep sleep (N3) and REM (Rapid Eye Movement) sleep. These diabetic patients with OSA being treated with Metformin had decreased REM sleep, regardless of sex, smoking history, and BMI. N3 and REM sleep are needed for timely secretion of growth hormone and memory consolidation. Metformin affects sleep architecture and impacts N3 and REM sleep. This may contribute to the development of insulin resistance. Future studies are needed to explore potential causes for this decrease and how it may affect treatment of T2DM.

Abstract:

Background: Extremely low-frequency electromagnetic fields (ELF-EMFs), generated mainly by power infrastructure and household devices, have raised scientific interest due to their potential impact on the endocrine system. Animal research consistently shows effects on melatonin secretion, stress hormone levels, thyroid activity, and reproductive function—largely mediated by oxidative stress and calcium ion imbalance. In contrast, human studies remain inconsistent, often hindered by methodological limitations and insufficient exposure characterization. Objective: This review synthesizes experimental and epidemiological studies examining ELF-EMF exposure (≤100 kHz) and its influence on hormonal regulation. Methods: A bibliometric analysis highlights focused interest on specific endocrine targets, particularly the pineal gland. Importantly, many experimental studies use field strengths above those found near high-voltage power lines, limiting direct applicability. Conclusions: While a definitive causal link has not been established, the widespread exposure justifies precautionary considerations. There are several key research gaps (of whom many are identified by this review); the topic of ELF EMF effect on endocrine system calls for more rigorous, long-term human studies with accurate exposure assessment.

Abstract: Background: Obesity is a heterogeneous chronic disease in which eating behavior phenotypes may influence treatment response. Yet, anti-obesity medication (AOM) selection is still largely guided by anthropometric and metabolic parameters, with limited use of behavioral phenotyping in routine practice. We evaluated whether multidimensional eating behavior changes, measured by the Brazilian Eating Behavior Phenotype Scale (Escala de Fenótipos do Comportamento Alimentar, EFCA), differ across commonly used AOMs in a real-world cohort. Methods: We conducted a retrospective, observational real-world study in obesity outpatient care settings in São Paulo, Brazil. Adults with obesity (18–65 years) treated with a single principal AOM for 6 months and paired baseline/6-month follow-up EFCA and anthropometric data were included. Analyses focused on early responders (≥5% total body weight loss at 3 months). Five AOM groups available in Brazil were analyzed: semaglutide (oral or subcutaneous), naltrexone/bupropion, sibutramine, topiramate, and tirzepatide. Outcomes included percent weight loss, EFCA total score, and five EFCA subscales (hedonic, emotional, compulsive, hyperphagic, disorganized). Within-medication behavioral changes were assessed using paired tests and standardized effect sizes (Cohen’s dz, 95% CI), summarized in heatmap form. Results: The analytical cohort comprised 66 early responders with paired EFCA assessments at baseline and 6 months. EFCA profiling revealed distinct behavioral response fingerprints across AOMs. Effect-size mapping showed predominantly large behavioral effects (many dz ≥0.8) in hedonic, emotional, hyperphagic, and compulsive domains. Strongest signals included emotional eating reductions with naltrexone/bupropion (dz 2.04), tirzepatide (dz 1.77), semaglutide (dz 1.52), and topiramate (dz 1.54); hedonic reductions with tirzepatide (dz 2.06), semaglutide (dz 1.55), and naltrexone/bupropion (dz 1.52); hyperphagic reductions with tirzepatide (dz 1.50) and semaglutide (dz 1.34); and compulsive reductions with topiramate (dz 1.41) and consistent effects across tirzepatide, semaglutide, and sibutramine (≈dz 0.95–0.96). Disorganized eating showed heterogeneous/attenuated responsiveness, from near-null with tirzepatide (dz 0.03) to large but imprecise effects in smaller groups (e.g., topiramate dz 1.24, wide CI). Conclusion: In this responder-enriched real-world cohort, AOMs showed distinct and reproducible EFCA behavioral signatures, supporting a clinically actionable phenotype-informed framework to prioritize, sequence, and monitor obesity pharmacotherapy beyond nonspecific weight reduction, while highlighting disorganization as a potential target for adjunctive behavioral strategies.

Abstract: Activation of hedgehog (Hh) signaling in the liver is implicated in the progression of chronic liver diseases. Here, we show that increases in the expression of hepatic Indian hedgehog (Ihh), a hepatokine, its transcriptional regulator TAZ, periostin, and lipogenesis-related genes, as well as in plasma Ihh levels, precede weight gain in C57BL6 mice fed a high-fat diet compared with a chow diet. Intake of whey protein isolate, a milk protein, significantly suppressed these high-fat diet-induced changes independently of body weight. In addition, despite increased tryptophan levels, whey protein intake markedly reduced colonic 5-HT levels in high-fat diet-fed mice. Moreover, genetic ablation of tryptophan hydroxylase 1 (Tph1), the enzyme responsible for gut-derived 5-HT synthesis from tryptophan, attenuated increases in hepatic TAZ and Ihh expression, and in plasma Ihh levels independently of body weight. These findings suggest that Tph1-mediated increases in hepatic Ihh expression and plasma Ihh levels occur at an early stage of high-fat diet-induced metabolic dysfunction. Whey protein intake suppresses these changes, potentially by inhibiting gut-derived serotonin.

Abstract: Background/Objectives: Secondary hypertension requires complex diagnostic reasoning and guideline-based management, posing challenges for artificial intelligence–based clinical decision-support systems. This study aimed to comparatively evaluate the performance of three large language models (LLMs) in diagnostic reasoning, clinical management, follow-up planning, and patient-oriented communication related to secondary hypertension. Methods: In this cross-sectional blinded study, three LLMs (ChatGPT-5.2, Claude Sonnet 4.6, and Gemini 3.0 Pro) were evaluated using 10 expert-developed clinical case vignettes representing major etiologies of secondary hypertension. Model outputs were anonymized and independently assessed by three senior clinicians (two endocrinologists and one cardiologist) using a 7-point Likert scale across five domains: (1) accuracy and hallucination control, (2) quality and comprehensiveness, (3) reliability and clinical guidance, (4) cost-efficiency, and (5) clinical usability. Group differences were analyzed using Kruskal–Wallis tests with Bonferroni-corrected pairwise comparisons. Inter-rater agreement was evaluated using two-way mixed-effects intraclass correlation coefficients with absolute agreement. Results: A total of 90 blinded expert ratings were analyzed. Claude Sonnet 4.6 achieved the highest composite performance score (6.63 ± 0.45), followed by ChatGPT-5.2 (5.82 ± 0.55) and Gemini 3.0 Pro (5.27 ± 0.89) (H = 40.055, p < 0.001). Claude Sonnet 4.6 significantly outperformed both models across all evaluation domains. ChatGPT-5.2 demonstrated intermediate performance and significantly exceeded Gemini 3.0 Pro in reliability and clinical usability. Performance differences were most pronounced in domains requiring complex clinical reasoning, whereas cost-efficiency scores were relatively comparable among models. Claude Sonnet 4.6 ranked first in nine of ten clinical vignettes. Inter-rater agreement demonstrated consistent ranking patterns among evaluators. Conclusions: Large language models exhibit heterogeneous performance in secondary hypertension–related clinical tasks. Although advanced models show promising capabilities as clinical decision-support tools, performance remains model-dependent, particularly in complex endocrine–metabolic scenarios. Domain-specific validation and prospective clinical studies are required before routine clinical implementation.

Abstract: Of the many clinical phenotypes of obesity the most prevalent are metabolically “healthy” (MHO) and metabolically “unhealthy” obesity (MUO), the latter being associated with a range of comorbidities, in-cluding type 2 diabetes mellitus (T2DM). The underlying causes of different obesity phenotypes and the mechanisms of conversion of one phenotype into another, have yet to be fully elucidated. However, in-creasing evidence suggests the key role of low-grade metabolic inflammation (metaflammation) in patho-genesis of obesity and metabolic dysfunction. This review compares numerous pro-inflammatory media-tors observed in MHO and MUO to identify the role of metaflammation in obesity phenotype. A mechanis-tic model is proposed for the progression from MHO to MUO with the exacerbation of metaflammation and dysfunction of insulin-sensitive organs. MUO is characterized by the excess of visceral adiposity, both local and systemic insulin resistance (IR). Obesity is accompanied by a shift in the immune profile from anti-inflammatory to pro-inflammatory, with its worsening in MUO. However no clinically significant pa-rameter has been identified among soluble factors or leukocyte subtypes in the blood as a predictor of MHO to MUO conversion. Structural and functional changes in adipose tissue are not resolved immediately following bariatric interventions. The persistence of «metabolic memory» in the form of epigenetic modi-fications in macrophages of adipose tissue and the emergence of large numbers of CD4+ and CD8+ effec-tor memory T cells with senescent phenotype, may predispose to weight regain and T2DM relapse post-surgery. The review discusses mechanisms underlying metabolic memory and potential reversibility of metabolic disturbances after bariatric surgery.

Abstract: This Data Descriptor presents an anonymized, shuffled dataset of creatinine-normalized urinary metabolite measurements from 73 Bulgarian children with autism spectrum disorder (ASD), released to support reuse in secondary analyses and cross-cohort comparisons. Spot urine results are provided as individual-level values after creatinine normalization; for trimethylamine, values below the limit of quantification (LOQ) were replaced with LOQ/2. The deposit contains measurements for 24 urinary markers grouped into three functional classes (neurotransmitters and aromatic amino acid precursors; one-carbon/methylation and vitamin-related metabolites; and energy metabolism/organic acids with microbiome-related amines). The release includes the results table in both XLSX and CSV formats, a reference limits and units file for contextual interpretation, a data dictionary, a README, a changelog, and SHA-256 checksums for integrity verification. Cohort-level demographics and additional sampling details are described in the companion publication cited in the main text. Dataset: https://doi.org/10.5281/zenodo.18614881 Dataset License: Creative Commons Attribution 4.0 International.

Abstract: Background: The clinical management of refractory Small Intestinal Bacterial Overgrowth (SIBO) and persistent gastrointestinal dysmotility represents a significant challenge, as these symptoms are often resistant to standard antibiotic treatments. While frequently categorized as functional disorders, the chronicity and systemic nature of these presentations suggest a possible underlying involvement of the autonomic nervous system. We explore the hypothesis that systemic iron dysregulation, rather than isolated dysbiosis, may contribute to these neuro and gastrointestinal manifestations. Hypothesis: We propose that iron overload mediated by HFE mutations, potentially exacerbated by low ferroxidase activity (ceruloplasmin), may lead to the accumulation of non-transferrin-bound iron (NTBI) in its reactive ferrous state (Fe2+). In this framework, we examine whether a lack of efficient iron chaperoning creates a pro-oxidative environment that could interfere with normal autonomic function. Mechanism: The suggested mechanism involves the Fenton reaction, where excess Fe2+ facilitates the generation of hydroxyl radicals. It is hypothesized that this localized oxidative stress may affect the unmyelinated neurons of the myenteric plexus, potentially leading to autonomic dysregulation. Such an environment could impair intestinal motility, thereby creating a substrate for recurrent and refractory SIBO. Furthermore, this iron dysregulation may act as a nutrient for pathogenic microbiota. This availability supports bacterial proliferation and biofilm formation, further contributing to the refractory nature of SIBO. Clinical Relevance: This model suggests that in patients with overlapping HFE variants and low ceruloplasmin, refractory SIBO may be a symptom of a broader metabolic dysregulation. Consequently, therapeutic strategies could consider the management of the systemic iron burden. Therapeutic phlebotomy is discussed as a potential intervention to reduce reactive iron levels, which might mitigate oxidative stress and support the stabilization of autonomic gastrointestinal function.

Abstract: Newborn screening for Congenital adrenal hyperplasia (CAH) is effective in identifying patients with severe forms before a potentially lethal crisis but has a relatively high false positive rate. The aim of this study was to improve the national neonatal screening program in Sweden, and the positive predictive value by implementing a LC-MS/MS second-tier testing. A combination of two independent parameters, the steroid hormone ratio (androstenedione+17-hydroxyprogesterone)/cortisol and the concentration of 21-deoxycortisol and adjustment of cut-off levels resulted in an increase of the positive predictive value (PPV) from 14 % to 84 % for full-term infants. In total the false positive screening cases decreased by 88 %. CYP21A2 genotyping was used to determine the severity of CAH in identified cases. We report on the stepwise approach that was used to optimize the cut-off levels for full-term and preterm infants in order not to miss any true cases in the process.

Abstract: Background: Childhood obesity is associated with important alterations in body composition that may impair muscular strength and functional capacity. While higher body mass is often accompanied by greater absolute strength, the independent impact of adiposity on muscular strength after accounting for lean tissue remains insufficiently understood. The aim of this study was to examine the associations between adiposity, body composition, and muscular strength in children and adolescents, with particular focus on the independent effects of fat mass after adjustment for growth- and maturation-related factors. Methods: This cross-sectional study included 84 children and adolescents aged 5–18 years. Anthropometric measurements were used to calculate body mass index, waist-to-hip ratio, and waist-to-height ratio, with weight status classified according to World Health Organization BMI-for-age criteria. Body composition was assessed using bioelectrical impedance analysis (Tanita), providing estimates of body fat percentage and Tanita-derived muscle mass. Pubertal stage was assessed using Tanner classification. Muscular strength was evaluated using dominant handgrip strength, and habitual physical activity was recorded as hours per week. Associations between adiposity-related indices and muscular strength were explored using correlation and multiple linear regression analyses, with adjustment for age and Tanita-derived muscle mass. Results: Body mass index showed a positive association with handgrip strength, reflecting the contribution of overall body mass. Central adiposity indices demonstrated weak to modest associations with muscular strength. Body fat percentage showed only a limited association with handgrip strength in unadjusted analyses. However, in multivariable regression models adjusting for age and Tanita-derived muscle mass, higher body fat percentage emerged as an independent negative predictor of handgrip strength. Age did not show an independent association with muscular strength in adjusted models. Conclusions: Excess adiposity is independently and negatively associated with muscular strength in children and adolescents, even after accounting for age and Tanita-derived estimates of muscle mass. These findings suggest that increased fat mass may impair neuromuscular performance beyond its effects on body size or lean tissue. Pediatric obesity interventions should therefore focus not only on weight reduction but also on improving body composition and preserving functional strength.

Abstract: Background: The purpose of this research is to explore the relationship between vitamin B6 status (measured by pyridoxal-5′-phosphate, PLP levels) and central obesity in children and adolescents. Additionally, the study seeks to examine how this relationship might influence the link between exposure to tobacco and central obesity in this age group. Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey spanning 2005 to 2010. Central obesity was identified by waist circumference measurements that were equal to or exceeded the 90th percentile, with adjustments made for age and gender. To assess the relationship between tobacco exposure and central obesity, both weighted univariate and multivariate logistic regression analyses were applied. An analysis was performed using PLP concentration categories (PLP ≥ 53.74 nmol/L and PLP < 53.74 nmol/L) to determine the impact of tobacco exposure on central obesity in each respective PLP group. Results: The final sample included 5,865 participants. Higher tobacco exposure [odds ratio (OR): 1.25, 95% confidence interval (CI): 1.03-1.53, P =0.027] and lower PLP levels (OR: 1.28, 95% CI: 1.05-1.57, P =0.016) were each independently linked to an increased risk of central obesity in children and adolescents. Among children and adolescents with lower PLP levels, cotinine exposure was related to an increased risk of central obesity (OR: 1.36, 95% CI: 1.05-1.76, P =0.022), particularly in specific subgroups: individuals under the age of 12 years, males, and those with six hours or less of daily screen time. Conclusion: Our results underscore the critical role of nutritional status, specifically vitamin B6 levels, in modulating the relationship between environmental exposures and obesity risk. Future initiatives aimed at primary prevention could be enhanced by recognizing the link between central obesity and adjustable lifestyle elements.

Abstract: Background/Objectives: Metabolic alterations, including dyslipidemia, are increasingly recognized in patients with neuroendocrine tumors and may influence tumor biology and treatment outcomes. However, the clinical relevance of dyslipidemia and the potential impact of lipid-lowering therapies in bronchopulmonary neuroendocrine tumors (BP-NETs) treated with somatostatin analogues (SSAs) remain poorly defined. This study aimed to evaluate the progression-free survival (PFS) in patients with advanced BP-NETs receiving SSAs according to dyslipidemia as well as statin therapy. In addition, an exploratory in vitro analysis was performed to assess the combined biological effect of statins and SSAs. Methods: This study investigated the combined effects of atorvastatin and lanreotide therapy both in vitro and in a clinical setting. In NCI-H727 cells, we assessed cell viability, proliferation, apoptosis, DNA damage, and metabolic activity following single and combined treatments. Concurrently, we retrospectively evaluated the impact of dyslipidemia and statin therapy on progression-free survival (PFS) in patients with advanced BP-NETs receiving SSAs. Results: Combined treatment resulted in reduced cell viability, proliferation, and ATP production, alongside increased apoptosis and DNA damage, and was associated with impaired cellular energy metabolism compared with lanreotide alone and control conditions. In the clinical analysis, dyslipidemia was associated with shorter progression-free survival (PFS), whereas atorvastatin therapy in dyslipidemic patients showed a positive trend toward improved PFS. Conclusions: These findings support the potential relevance of lipid metabolism modulation as an adjunct strategy in advanced BP-NETs, warranting further validation in larger prospective studies and encouraging additional biochemical investigation of the underlying pathways.

Abstract: Aging is a multifactorial process that leads to progressive physiological changes char-acterized by senescence, cellular loss, and organ decline, which accelerate the devel-opment of metabolic syndrome (MetS) in elderly individuals. MetS, in turn, not only significantly increases the risk of developing cardiovascular disease (CVD) but also contributes to decreased functional and cognitive capacity due to the inability of el-derly patients to adopt with metabolic stress. While genetic predisposition has a sub-stantial influence on the risk of developing MetS, other intrinsic factors, including chronic inflammation, insulin resistance (InsR), and altered neurohormonal activation, also play crucial roles. Targeted therapies, lifestyle interventions, and pharmacother-apy can decelerate the progression of CVD, increasing the likelihood of survival with good neurologic and functional outcomes among elderly individuals with MetS. However, drug adverse reactions and the lack of adequate interventions for cognitive decline have led to the emergence of self-medications with nonprescription medicines. The anti-inflammatory, antioxidant, anti-channelopathy, antiaging, and neuroprotec-tive properties of flavonoids, alkaloids, polysaccharides, and polyphenols found in key traditional medicines showed promising data in the treatment of MetS-induced cogni-tive decline. Thus, the objective is to provide a comprehensive review of bioactive compounds and herbal medicine that show promising cognitive benefits for elderly patients with MetS.

Abstract: Background: The aim of the study was to verify the effectiveness of a 5-week intensive protocol of multilayer bandaging alone or in combination with diet, applied to the clinical practice of lipedema. Methods: 114 women with lipedema were studied, divided into three groups: 35 women were treated with multilayer bandaging in biweekly sessions for 5 weeks, 48 were treated with the same bandaging protocol combined with an anti-inflammatory diet, and 31 women received no treatment. The effect on anthropometry, lower limb volume, pain caused by the tissue fold, and subjective symptoms were evaluated. Results: Women who completed the 5-week intensive protocol of multilayer bandaging showed a statistically significant reduction in all observed parameters: body weight, waist and hip circumference, lower limb volume, pain, and subjective symptoms. The group of women treated with multilayer bandaging and diet showed a significantly greater reduction in lower limb volume and body weight. The treatments were effec-tive regardless of age, BMI, clinical stage, and the presence of fovea in both groups. The wearing time with the multilayer bandage had a positive correlation in the group treated with bandage in combination with diet. Conclusion: A 5-week intensive protocol of multilayer bandaging of the lower limbs is an effective treatment for reducing the symptoms and clinical signs of lipedema at all stages of the disease, even in the absence of edema. Adding nutritional therapy during the bandaging cycle increases the effectiveness of the treatment on the volume of the affected extremities and body weight.

Abstract: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of type 2 diabetes and obesity, yet their actions extend beyond glycemic control and weight loss. Accumulating evidence indicates that GLP-1 physiology is closely coupled to circadian timing systems and sleep–wake regulation. In this narrative review, we synthesize emerging data that reframe GLP-1RAs as chronometabolic modulators, acting at the intersection of metabolism, circadian biology, and sleep. We review circadian control of GLP-1 secretion by intestinal L-cells, emphasizing the role of core clock genes and the vulnerability of incretin rhythms to circadian misalignment from shift work, nocturnal light exposure, and sleep loss. We then examine GLP-1 receptor signaling within central and peripheral clock networks, including feedback effects on hypothalamic and hepatic circadian regulation. Comparative discussion of semaglutide, liraglutide, and tirzepatide highlights agent-specific pharmacokinetics and emerging clinical data linking GLP-1RA therapy to sleep outcomes, particularly obstructive sleep apnea. Finally, we outline translational opportunities for chronotherapy and precision medicine, positioning GLP-1RAs as integrative tools for metabolic and sleep-related disease rather than purely weight-centric therapies.

Abstract: Background: Chronic stress is associated with dysregulation of the body’s allostatic systems, contributing to increased allostatic load (AL) and adverse metabolic outcomes. Regular physical activity (PA) is considered a key protective factor that may attenuate AL by enhancing adaptive stress responses and supporting metabolic health. This study examined the differences between PA, primary mediators of AL, and metabolic risk markers in apparently healthy adults in Germany. Methods: Forty-six adults (18 - 45 years) were categorized into moderate intensity (regular PA: ≥ 150 min a week vs non-regular PA: ≤ 150 min a week) group according to current PA recommendations. Primary AL mediators were quantified by cortisol (ug/12h), epinephrine (ug/12h), norepinephrine (ug/12h), and dehydroepiandrosterone sulfate (DHEA-S: ug/ml). Group differences in primary AL mediators and metabolic risk markers were examined using the Mann–Whitney U test. Results: A significant group difference was observed for cortisol levels, with higher values in the regular PA group (p = 0.01) with a moderate negative effect size of r = -0.38. No statistically significant differences (p > 0.05) were found between groups for epinephrine, norepinephrine, DHEA-S, or metabolic risk markers, including triglycerides, blood pressure, body mass index (BMI), and high-density lipoprotein cholesterol (HDL-C). Conclusion: The findings suggest that regular PA may be associated with altered stress-regulatory activity, as reflected by differences in cortisol. While no statistically significant group differences were observed for metabolic risk markers, descriptive patterns indicate more favorable lipid profiles and potential variation in primary AL mediators at higher PA levels. Given the exploratory nature of the analyses and the small and unequal group sizes, these findings should be interpreted with caution and warrant confirmation in future studies with larger and more balanced samples.