Search Results (1,094)

Background: Lipedema is a chronic disorder characterized by disproportionate fat accumulation in the extremities, predominantly affecting women. Unlike obesity, lipedema might be associated with a lower prevalence of metabolic alterations despite often coexisting with overweight or obesity. Fat distribution plays a crucial role in metabolic differences, with gynoid fat in lipedema being associated with a lower risk of insulin resistance and cardiovascular disease. The present study aims to compare biochemical parameters between women with lipedema and those with lifestyle-induced overweight/obesity. Methods: This study involved 108 women, including 53 with lipedema and 55 with lifestyle-induced overweight/obesity. Anthropometric measurements and body composition analyses were conducted, and biochemical parameters related to liver function, lipid profile, kidney and thyroid function, uric acid levels, and carbohydrate metabolism were assessed. Statistical comparisons were made between groups, and multivariate models were used to explore the relationships between disease type, metabolic parameters, and body composition. Results: Women with lipedema exhibited a more favorable metabolic profile than those with overweight/obesity. Dyslipidemia was observed in ~50% of the lipedema group, compared to nearly 70% in the overweight/obesity group. Impaired glucose metabolism and insulin resistance were significantly less prevalent in the lipedema group (18.9% vs. 43.6%, p < 0.05). Conclusions: Despite having a high BMI, women with lipedema demonstrate fewer metabolic alterations than those with overweight/obesity. Fat distribution, rather than overall adiposity, appears to influence metabolic risk. These findings highlight the need for targeted therapeutic approaches to lipedema, distinct from conventional obesity management strategies. Full article

Alzheimer’s disease (AD) is a leading cause of dementia, characterized by multifactorial interactions involving genetic, inflammatory, and metabolic dysregulation. Insulin-like growth factor 1 (IGF-I) plays a critical role in maintaining brain homeostasis through neurogenesis, synaptogenesis, and neuroprotection. However, disruptions in IGF-I signaling have been implicated in hallmark AD processes such as beta-amyloid accumulation, glucose metabolism disturbances, oxidative stress, chronic inflammation, and neuronal death. This review aims to comprehensively analyze the mechanisms by which IGF-I influences AD pathology, emphasizing its potential as both an early detection biomarker and a therapeutic target. By synthesizing clinical and preclinical study findings, we explore how chronic stress, systemic inflammation, and lifestyle factors disrupt IGF-I pathways, accelerating cognitive and social impairments. Special attention is given to high-level cognitive processes, including executive functions and social cognition, which are particularly vulnerable to these disruptions. Highlighting the interplay between IGF-I, neuroinflammation, and stress, this work underscores the need for affordable and accessible diagnostic tools and therapeutic strategies. This review contributes to a deeper understanding of IGF-I’s multifaceted role in AD, offering new insights for addressing the growing global burden of dementia. Full article

Thiamine, crucial for energy metabolism, is associated with various human diseases when deficient. We studied how variations in the SLC19A3 gene, encoding THTR2, a thiamine transporter, may influence type 2 diabetes (T2DM) and gout (arthritis urica, AU). We characterized the SLC19A3 gene variants using bioinformatics and analyzed DNA samples from controls, T2DM, and gout patients to explore associations with physical/laboratory parameters. In human cells, we used a luciferase reporter assay to assess how these variants affect gene expression. We examined four large haplotypes (H1–4) in this gene, identified lead SNPs for the minor variants (MV), and explored potential transcription factor binding sites. We found that in T2DM patients, H3-MV correlated significantly with impaired glucose metabolism (pHOMA = 0.0189, pHbA1c% = 0.0102), while H4-MV correlated with altered uric acid (p = 0.0008) and white blood cell levels (p = 0.0272). In AU patients, H3-MV correlated with increased basophil granulocyte levels (p = 0.0273). In model cell lines, H3-MV presence increased gene expression (p = 0.0351), influencing responses to thiamine depletion and metformin (p = 0.0016). Although H4-MV did not directly affect luciferase expression, thiamine and fedratinib co-treatment significantly enhanced gene expression in thiamine-depleted cells (p = 0.04854). Our results suggest a connection between selected SLC19A3 variants and the severity of metabolic diseases or their response to treatment. Full article

Background/Objectives: Dietary manipulation with carbohydrate restriction has been extensively investigated in diabetes prevention programmes. Carbohydrate (CHO) quality, rather than quantity, is associated with various metabolic outcomes. Few studies examined the fibre/CHO ratio on lipid profiles, liver fat and insulin resistance in individuals with impaired glucose tolerance (IGT). Methods: In this comprehensive cross-sectional study, we evaluated the association of carbohydrate-related nutritional factors with metabolic parameters in a cohort of 177 Hong Kong Chinese with impaired glucose tolerance (IGT). The subjects underwent a 75 g oral glucose tolerance test (OGTT) with measurement of plasma C-peptide and lipid profiles, body composition, transient elastography, and three-day food records. The fibre/CHO ratio is calculated by dividing fibre intake by total carbohydrate intake (in grams). Results: The median (IQR) age of the study cohort was 60 (54–62) with a mean ± SD BMI of 26.7 ± 3.9 kg/m², and 40.7% were female. A higher carbohydrate quality, measured as fibre/CHO ratio, was inversely correlated with triglycerides (r = −0.305, p < 0.001) and positively correlated with High-density lipoproteins cholesterol (HDL-C) (r = 0.354, p < 0.001). These associations remained significant after adjusting for age, gender, lipid-lowering drugs, total calorie, macronutrient and sugar intake, physical activity and sodium/potassium ratio. Blood pressure, liver fat and insulin resistance were also associated with the fibre/CHO ratio after the adjustment of these confounding factors. Consuming more than 5.5 g of fibre per 100 g carbohydrate was associated with lower serum triglycerides. Conclusions: Our results highlight the potential for using the fibre/CHO ratio as a metric for daily carbohydrate quality and the importance of addressing both carbohydrate quality and quantity in designing dietary interventions to reduce cardiometabolic risk. Full article

Background/Objectives: Melanoma is an aggressive skin cancer with intratumor metabolic heterogeneity, which drives its progression and therapy resistance. Natural anthraquinones, such as emodin and aloe-emodin, exhibit anti-cancer properties, but their effects on metabolic plasticity remain unclear. This study evaluated their impact on proliferation and metabolic pathways in heterogenous melanoma human cell lines. Methods: COLO 800, COLO 794, and A375 melanoma cell lines representing distinct metabolic phenotypes were analyzed. Targeted and untargeted metabolomics analyses integrated with Seahorse assays were performed to assess the effects of emodin and aloe-emodin on cell proliferation, mitochondrial function, and redox homeostasis. Glucose tracing using [U-¹³C₆] glucose and metabolic flux analysis (MFA) were carried out to evaluate the glycolysis and TCA cycle dynamics. Results: Emodin and aloe-emodin inhibited proliferation by disrupting glycolysis, oxidative phosphorylation, and energy production across all cell lines. Both compounds impaired glucose metabolism, reduced TCA cycle intermediates, and induced mitochondrial ROS accumulation, causing oxidative stress and redox imbalance. Despite intrinsic metabolic differences, COLO 800 and COLO 794 upregulated antioxidant defenses; A375 enhanced one-carbon metabolism and amino acid pathways to maintain redox balance and nucleotide biosynthesis. Conclusions: Emodin and aloe-emodin can disrupt the metabolic plasticity of melanoma cells by impairing glycolysis, mitochondrial function, and redox homeostasis. Their ability to target metabolic vulnerabilities across diverse phenotypes highlights their therapeutic potential for overcoming resistance mechanisms and advancing melanoma treatment strategies. Full article

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease often associated with metabolic disorders such as diabetes mellitus. Recent research suggests a link between systemic inflammation and insulin–glucose dysregulation in HS. This study investigates the relationship between insulin–glucose homeostasis, diabetes mellitus and the haptoglobin concentration in HS patients. Methods: We assessed 95 HS patients and 49 controls using validated fasting-based function tests, including the Structural Parameter Inference Approach (SPINA), Homeostasis Model Assessment (HOMA) and Quantitative Insulin Sensitivity Check Index (QUICKI). Results: The HS patients had a significantly higher fasting insulin concentration (97.2 vs. 69.0 pmol/L, p = 0.035), increased insulin resistance (HOMA-IR: 3.47 vs. 2.57, p = 0.016) and impaired insulin sensitivity (SPINA-GR: 1.34 vs. 1.76 mol/s, p = 0.017). In diabetes, the insulin sensitivity was more strongly reduced (SPINA-GR: 0.61 vs. 1.41 mol/s, p = 0.0057) and the insulin resistance increased (HOMA-IR: 7.3 vs. 3.2, p = 0.017). Higher haptoglobin concentrations were accompanied by worse glycaemic control, demonstrating a significantly elevated fasting glucose (5.77 vs. 5.11 mmol/L, p = 0.043) concentration and HbA1c (5.7% vs. 5.4%, p = 0.0081) fraction. Conclusions: Our findings suggest that chronic inflammation in HS contributes to metabolic dysregulation, worsening insulin resistance and glycaemic control, particularly in those with elevated haptoglobin or diabetes. Full article

The increasing prevalence of overweight and obesity not only in adults but also among children and adolescents has become one of the most alarming health problems worldwide. Metabolic disorders accompanying fat accumulation during pathological weight gain induce chronic low-grade inflammation, which, in a vicious cycle, increases the immune response through pro-inflammatory changes in the cytokine (adipokine) profile. Obesity decreases life expectancy, largely because obese individuals are at an increased risk of many medical complications, often referred to as metabolic syndrome, which refers to the co-occurrence of insulin resistance (IR), impaired glucose tolerance, type 2 diabetes (T2D), atherogenic dyslipidemia, hypertension, and premature ischemic heart disease. Metabotropic G protein-coupled receptors (GPCRs) constitute the most numerous and diverse group of cell surface transmembrane receptors in eukaryotes. Among the GPCRs, researchers are focusing on the connection of G protein-coupled receptor 120 (GPR120), also known as free fatty acid receptor 4 (FFAR4), with signaling pathways regulating the inflammatory response and insulin sensitivity. This review presents the current state of knowledge concerning the involvement of GPR120 in anti-inflammatory and metabolic signaling. Since both inflammation in adipose tissue and insulin resistance are key problems in obesity, there is a rationale for the development of novel, GPR120-based therapies for overweight and obese individuals. The main problems associated with introducing this type of treatment into clinical practice are also discussed. Full article

Background: Metabolic syndrome (MetS) and related disorders, such as insulin resistance, pose significant health risks in middle-aged women, including cognitive decline. Chronic inflammation, characterized by elevated levels of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α), has been identified as a key mechanism linking metabolic disturbances to neurodegenerative processes. Methods: This study aimed to examine the associations between metabolic disorders, inflammatory markers, and cognitive function among middle-aged women. A cross-sectional study was conducted on 179 non-smoking perimenopausal and postmenopausal women aged 43–73 years. Anthropometric, metabolic, and cognitive parameters were assessed, including body mass index (BMI), waist-to-height ratio (WHtR), fasting glucose (GLU), triglycerides (TG), IL-6, TNF-α, and Mini-Mental State Examination (MMSE) scores. Logistic regression models were applied to evaluate the relationships between inflammation, MetS components, and cognitive impairments. Results: Women with insulin resistance showed significantly worse metabolic profiles and lower MMSE scores (23.98 vs. 24.91, p = 0.032). IL-6 levels were strongly associated with hypertriglyceridemia (OR = 1.096, 95% CI: 1.044–1.151, p < 0.001) and insulin resistance (OR = 1.068, 95% CI: 1.030–1.107, p < 0.001), while TNF-α correlated with abdominal obesity (WHtR OR = 1.429, 95% CI: 1.005–2.031, p = 0.047). Moreover, TNF-α was a significant predictor of cognitive impairments (OR = 1.362, 95% CI: 1.153–1.610, p < 0.001), whereas IL-6 showed no significant association. Conclusions: These findings highlight that TNF-α may be a key inflammatory marker associated with metabolic disturbances and cognitive decline in middle-aged women. IL-6 appears to be more specifically linked to lipid abnormalities and insulin resistance. Targeted interventions to reduce inflammation may moderate metabolic and cognitive risks in this population. Full article

Advanced glycation end products (AGEs) are a series of structurally complex and harmful compounds formed through the reaction between the carbonyl group of reducing sugars (such as glucose and fructose) and the free amino groups of proteins, lipids, or nucleic acids. Excessive accumulation of AGEs in the body can trigger oxidative stress, induce inflammatory responses, and contribute to the development of diabetes, atherosclerosis, and neurological disorders. Within the category of dicarbonyl compounds, methylglyoxal (MGO)—a byproduct resulting from glucose degradation—serves as a pivotal precursor in the formation of AGEs and the induction of neurotoxicity. Specifically, AGEs generated from MGO display significant cytotoxicity toward cells in the central nervous system. Therefore, we aimed to investigate the role of MGO-AGEs in neuroinflammation mediated by CUMS. Interestingly, we found that the overexpression of glyoxalase 1 (GLO1) reduced the levels of MGO in corticosterone-treated microglia, thereby alleviating the inflammatory response. Furthermore, overexpression of GLO1 in the hippocampus of chronically stressed mice reduced MGO levels, mitigating CUMS-induced neuroinflammation and cognitive impairment. Additionally, when using the receptor for advanced glycation end products (RAGE) inhibitor FPS-ZM1 in primary microglia cells, we observed that despite corticosterone-induced elevation of MGO, no significant inflammatory response occurred. This suggests that RAGE clearance can reduce MGO-AGE-mediated neurotoxicity. Subsequently, we used FPS-ZM1 to treat chronically stressed mice and found that it significantly ameliorated neuroinflammation and cognitive dysfunction. These results suggest that targeting MGO metabolism could serve as a therapeutic approach to manage neuroinflammation in stress-related mental disorders. Full article

Loss of muscle mass and strength is a common condition associated with adverse outcomes in critically ill patients. Here, we determined the correlation between non-thyroidal illness (NTIS) and molecular alterations in the muscle of critically ill individuals. We evaluated deiodinase expression, intramuscular triiodothyronine (T3) levels, and mitochondria and sarcoplasmic reticulum components. The cellular colocalization of the enzymes and its influence on myocytes and genes regulated by T3 were shown, including those of mitochondria. A prospective cohort of 96 patients. Blood and muscular samples were collected on admission to the intensive care unit (ICU), as well as clinical data and ultrasonographic measurements. Patients with NTIS showed increased oxidative stress markers associated with critical illness in muscle biopsy, such as carbonyl content and low sulfhydryl and GSH. The distribution pattern of deiodinases in muscle and its biochemical properties showed significant pathophysiological linkage between NTIS and muscle loss, as type 3-deiodinase (D3) was highly expressed in stem cells, preventing their differentiation in mature myocytes. Despite the high type 2-deiodinase (D2) expression in muscle tissue in the acute phase of critical illness, T3 was unmeasurable in the samples. In this scenario, we also demonstrated impaired expression of glucose transporters GLUT4, IRS1, and 2, which are involved in muscle illness. Here, we provide evidence that altered thyroid hormone metabolism contributes to stem cell dysfunction and further explain the mechanisms underlying critical illness-induced myopathy. Full article

Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) are highly prevalent chronic conditions, frequently coexisting due to their shared pathophysiological mechanisms and risk factors. Epidemiological studies estimate that up to 30% of COPD patients have comorbid T2DM, contributing to worsened disease progression, more hospitalizations, and higher mortality rates. Systemic inflammation in COPD contributes to insulin resistance by increasing pro-inflammatory cytokines (TNF-α, IL-6, and CRP), which impair glucose metabolism and beta-cell function. Conversely, hyperglycemia in T2DM exacerbates oxidative stress, leading to endothelial dysfunction, reduced lung function, and impaired pulmonary repair mechanisms. A comprehensive narrative review was conducted to evaluate the interplay between COPD and T2DM, examining shared pathophysiological mechanisms, clinical consequences, and management strategies. The co-occurrence of COPD and T2DM accelerates disease development, elevates hospitalization rates, and deteriorates overall prognosis. Pharmacological interactions complicate illness treatment, requiring a multidisciplinary therapy strategy. Recent data underscore the need to integrate palliative care, facilitate shared decision-making, and provide psychological support to enhance patient outcomes. Efficient therapy of COPD-T2DM comorbidity necessitates a customized, interdisciplinary strategy that targets both respiratory and metabolic health. Preliminary prognostic dialogues, palliative care, and holistic lifestyle modifications can improve patient quality of life and clinical results. Full article

Inositol phosphates are critical signaling messengers involved in a wide range of biological pathways, and inositol polyphosphate multikinase (IPMK) functions as a rate-limiting enzyme for inositol polyphosphate metabolism. IPMK has been implicated in cellular metabolism, but its function at the systemic level is still poorly understood. Since skeletal muscle is a major contributor to energy homeostasis, we have developed a mouse model in which skeletal muscle IPMK is specifically deleted and examined how a loss of IPMK affects whole-body metabolism. Here, we report that skeletal-muscle-specific IPMK knockout mice exhibited a ~12% increase in body weight compared to WT controls (p < 0.05). These mice also showed a significantly impaired glucose tolerance, as indicated by their ~50% higher blood glucose levels during GTT. Additionally, exercise capacity was reduced by ~45% in IPMK-MKO mice, demonstrating a decline in endurance. Moreover, these metabolic alterations were accompanied by a 2.5-fold increase in skeletal muscle triglyceride accumulation, suggesting impaired lipid metabolism. Further analysis revealed that IPMK-deficient myocytes exhibited 30% lower β-oxidation rates. Thus, our results suggest that IPMK mediates whole-body metabolism by regulating muscle metabolism and may be potentially targeted for the treatment of metabolic syndromes. Full article

Aging is associated with a decline in physiological performance leading to increased inflammation and impaired immune function. Polysaccharides (PLs) found in plants, fruits, and fungi are emerging as potential targets for therapeutic intervention, but little is known about their effects on chronic inflammation and aging. This review aims to highlight the current advances related to the use of PLs, with the presence of arabinose, to attenuate oxidative stress and chronic and acute inflammation, and their immunomodulatory effects associated with antioxidant status in monocytes, macrophages, and neutrophil infiltration, and leukocyte rolling adhesion in neutrophils. In addition, recent studies have shown the importance of investigating the ‘major’ monosaccharide, such as arabinose, present in several of these polysaccharides, and with described effects on gut microbiome, glucose, inflammation, allergy, cancer cell proliferation, neuromodulation, and metabolic stress. Perspectives and opportunities for further investigation are provided. By promoting a balanced immune response and reducing inflammation, PLs with arabinose or even arabinose per se may alleviate the immune dysregulation and inflammation seen in the elderly, therefore providing a promising strategy to mitigate a variety of diseases. Full article

The transcription factor carbohydrate response element binding protein (ChREBP) has emerged as a crucial regulator of hepatic glucose and lipid metabolism. The increased ChREBP activity involves the pro-oncogenic PI3K/AKT/mTOR signaling pathway that induces aberrant lipogenesis, thereby promoting hepatocellular carcinomas (HCC). However, the molecular pathogenesis of ChREBP-related hepatocarcinogenesis remains unexplored in the high-fat diet (HFD)-induced mouse model. Male C57BL/6J (WT) and liver-specific (L)-ChREBP-KO mice were maintained on either a HFD or a control diet for 12, 24, and 48 weeks, starting at the age of 4 weeks. At the end of the feeding period, mice were perfused, and liver tissues were formalin-fixed, paraffin-embedded, sectioned, and stained for histological and immunohistochemical analysis. Biochemical and gene expression analysis were conducted using serum and frozen liver tissue. Mice fed with HFD showed a significant increase (p < 0.05) in body weight from 8 weeks onwards compared to the control. WT and L-ChREBP-KO mice also demonstrated a significant increase (p < 0.05) in liver-to-body weight ratio in the 48-week HFD group. HFD mice exhibited a gradual rise in hepatic lipid accumulation over time, with 24-week mice showing a 20–30% increase in fat content, which further advanced to 80–100% fat accumulation at 48 weeks. Both dietary source and the increased expression of lipogenic pathways at transcriptional and protein levels induced steatosis and steatohepatitis in the HFD group. Moreover, WT mice on a HFD exhibited markedly higher inflammation compared to the L-ChREBP-KO mice. The enhanced lipogenesis, glycolysis, persistent inflammation, and activation of the AKT/mTOR pathway collectively resulted in significant metabolic disturbances, thereby promoting HCC development and progression in WT mice. In contrast, hepatic loss of ChREBP resulted in reduced hepatocyte proliferation in the HFD group, which significantly contributed to the impaired hepatocarcinogenesis and a reduced HCC occurrence in the L-ChREBP-KO mice. Our present study implicates that prolonged HFD feeding contributes to NAFLD/NASH, which in turn progresses to HCC development in WT mice. Collectively, hepatic ChREBP deletion ameliorates hepatic inflammation and metabolic alterations, thereby impairing NASH-driven hepatocarcinogenesis. Full article