Search Results (6,711)

Metformin is a first-line oral antidiabetic agent that has attracted increasing interest as a potential geroprotective therapy due to its ability to improve metabolic homeostasis, reduce oxidative stress, and attenuate chronic inflammation. However, its role in skeletal muscle aging and sarcopenia remains controversial. Observational and epidemiological studies suggest that metformin use is associated with a lower prevalence of sarcopenia, particularly in metabolically compromised or insulin-resistant older populations, where improvements in systemic metabolism and inflammatory burden may indirectly support muscle quality and function. In contrast, randomized interventional trials in metabolically healthy older adults indicate that metformin can blunt resistance exercise–induced muscle hypertrophy and protein synthesis, likely through sustained activation of AMP-activated protein kinase (AMPK) and consequent suppression of mammalian target of rapamycin complex 1 (mTORC1) signaling. This perspective argues that these apparently opposing outcomes reflect a con-text-dependent therapeutic paradox rather than inconsistent evidence. Metformin may provide metabolic protection in frail, insulin-resistant individuals, yet limit anabolic adaptations in physically active older adults. These findings emphasize the necessity for precision geropharmacological strategies to balance metabolic longevity with preservation of musculoskeletal health in aging populations. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as one of the greatest challenges for the modern public health system and serves as the foundation for the development of advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH), which may progress to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). MASLD and type 2 diabetes mellitus (T2DM) mutually exacerbate one another. MASLD increases the incidence of T2DM and the risk of complications in patients already affected. T2DM accelerates progression to MASH, which has become the second leading cause of liver transplantation and end-stage liver disease, and is associated with hepatic decompensation, cirrhosis, HCC, chronic kidney disease, and cardiovascular disease. MASLD and MASH are strongly linked to T2DM and obesity, pathogenesis including genetic polymorphisms, environmental factors, and multiple metabolic disturbances: insulin resistance (IR), gut dysbiosis, altered adipokine signaling, such as reduced adiponectin alongside increased pro-inflammatory cytokines. Inflammation plays a central role in the development of HCC in MASH, even in the absence of significant fibrosis. The Fibrosis-4 index (FIB-4) should be used as a first-line noninvasive tool to assess fibrosis risk. Additionally, ultrasound-based transient elastography (FibroScan) supports clinicians in assessing steatosis and fibrosis severity. Histologically, MASH is characterized by steatosis, lobular inflammatory changes, and ballooning degeneration of hepatocytes, with or without associated fibrosis. Accurately diagnosing and stratifying MASLD based on fibrosis risk is crucial to identify patients who may benefit from pharmacological treatment or can be managed only with lifestyle interventions. Patients should attain above 10% weight loss through lifestyle modifications. Resmetirom is recommended in F2/F3 fibrosis stages. For treating T2DM, glucagon-like peptide-1 receptor agonists and coagonists, sodium–glucose cotransporter-2 inhibitors, metformin (if glomerular filtration rate exceeds 30 ml/min), and insulin (in decompensated cirrhosis) are preferred. Clinical insights derived from trials are expected to optimize quality of life and long-term outcomes in patients with MASH. Full article

Metabolic inflammation, a state of chronic low-grade inflammation linked to insulin resistance, plays a central role in the development of obesity-related conditions such as type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disorders. In recent years, two molecules have gained significant prominence in this field, owing to their mechanistic involvement in metabolic inflammation and insulin resistance: fetuin-A (FetA), aliver-derived hepatokine, and chymase, a serine protease released from mast cells. Although they arise from distinct biological sources, they converge on overlapping inflammatory and metabolic pathways. FetA acts as an endogenous ligand for Toll-like receptor 4 (TLR4), activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, driving proinflammatory cytokine release, and impairing insulin signaling. Chymase, on the other hand, generates angiotensin II and activates transforming growth factor-β (TGF-β), thereby promoting oxidative stress, fibrosis, and secondary metabolic dysfunction. This review proposes a conceptual dual-target framework in which FetA and chymase are considered complementary, rather than independent, mediators of metabolic inflammation. Importantly, this framework is not intended to supersede other established pathways implicated in metabolic inflammation, but rather to provide an integrative perspective that complements existing hepatokine and immune-centered models. Their convergence on NF-κB and TGF-β signaling pathways highlights shared mechanistic nodes within metabolic inflammation. Accordingly, the emphasis of this review is on mechanistic integration within metabolic inflammation, rather than on immediate therapeutic innovation or clinical translation. Full article

Morbid obesity is a complex, multifactorial disorder characterized by metabolic and inflammatory dysregulation. The aim of this study was to observe changes in obese patients adhering to a personalized nutrition plan based on multi-omic data. This study included 14 adult patients with a body mass index (BMI) > 40 kg/m² who were consecutively recruited from those presenting to our outpatient clinic and who met the inclusion criteria. Clinical, biochemical, hormonal, and glycomic parameters were assessed, along with whole-genome sequencing (WGS) that included a focused analysis of obesity-associated genes and an extended analysis encompassing genes related to cardiometabolic disorders, hereditary cancer risk, and nutrigenetic profiles. Patients were stratified into nutrigenetic clusters using a patented unsupervised machine learning platform (German Patent Office, No. DE 20 2025 101 197 U1), which was employed to generate personalized nutrigenetic dietary recommendations for patients with morbid obesity to follow over a six-month period. At baseline, participants exhibited elevated glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triglycerides, and C-reactive protein (CRP) levels, consistent with insulin resistance and chronic low-grade inflammation. The majority of participants harbored risk alleles within the fat mass and obesity-associated gene (FTO) and the interleukin-6 gene (IL-6), together with multiple additional significant variants identified across more than 40 genes implicated in metabolic regulation and nutritional status. Using an AI-driven clustering model, these genetic polymorphisms delineated a uniform cluster of patients with morbid obesity. The mean GlycanAge index (56 ± 12.45 years) substantially exceeded chronological age (32 ± 9.62 years), indicating accelerated biological aging. Following a six-month personalized nutrigenetic dietary intervention, significant reductions were observed in both BMI (from 52.09 ± 7.41 to 34.6 ± 9.06 kg/m², p < 0.01) and GlycanAge index (from 56 ± 12.45 to 48 ± 14.83 years, p < 0.01). Morbid obesity is characterized by a pro-inflammatory and metabolically adverse molecular signature reflected in accelerated glycomic aging. Personalized nutrigenetic dietary interventions, derived from AI-driven analysis of whole-genome sequencing (WGS) data, effectively reduced both BMI and biological age markers, supporting integrative multi-omics and machine learning approaches as promising tools in precision-based obesity management. Full article

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia, progressive β-cell dysfunction, and insulin resistance. While numerous chemically induced and transgenic rodent models exist, spontaneous models recapitulating natural type 2 diabetes mellitus (T2DM) progression remain scarce. Here, we characterize Myodes rufocanus as a novel spontaneous T2DM model through comprehensive assessments of 18-week-old male F6 voles, demonstrating hallmark diabetic features including weight gain, hyperphagia, polydipsia, hyperglycemia, insulin resistance, and dyslipidemia. Pancreatic transcriptomic profiling revealed pronounced COX14 (cytochrome c oxidase assembly factor 14) downregulation, as validated by qPCR and Western blotting in pancreatic tissue and MIN6 β-cells. MIN6 cells under chronic high-glucose conditions (30 mM) exhibited diminished mitochondrial membrane potential, impaired ATP biosynthesis, elevated reactive oxygen species, and attenuated glucose-stimulated insulin secretion, with consistent COX14 downregulation suggesting potential association with mitochondrial dysfunction. Additionally, suppressed Nrf2–HO-1 antioxidant signaling appeared to compound cellular injury, with intrinsic apoptotic pathway activation indicated by elevated Bax/Bcl-2 ratios and caspase-3 activity. These findings establish M. rufocanus as a valuable spontaneous T2DM model and implicate COX14 downregulation as a potential correlate of mitochondrial impairment and β-cell failure in diabetes pathogenesis. Full article

Steatosis extends beyond the liver to the pancreas, heart, and skeletal muscle, yet prevailing definitions remain narrowly organ-focused. This narrative review introduces the Metabolic Steatotic Axis (MSA) as a framework that captures the dynamic, bidirectional interactions among these organs, driving systemic metabolic dysfunction. We synthesize evidence linking lipotoxicity, inflammatory signaling, and endocrine cross-talk into a self-amplifying network accelerating insulin resistance, β-cell failure, and cardiometabolic risk. The MSA concept provides a rationale for axis-based staging systems and composite biomarker panels to quantify cumulative disease burden better and refine risk stratification. We highlight phenotypic heterogeneity within MSA stages, the possible hierarchy of organ vulnerability, and the implications for prognosis and therapy. Viewing pharmacological and lifestyle interventions through the MSA lens reframes them as systemic modulators rather than organ-specific treatments, underscoring the need for multi-organ endpoints in clinical trials. Finally, we outline priorities for longitudinal imaging, multi-omics integration, and global harmonization to translate the MSA from a conceptual construct to a clinically actionable paradigm. By unifying fragmented observations into a systemic model, the MSA has the potential to reshape disease classification, therapeutic strategies, and precision medicine in metabolic disorders. Full article

Background: Ischemic stroke remains the most feared complication of atrial fibrillation (AF), and thromboembolic risk is commonly estimated using clinical scores that may not fully capture the cardiometabolic dimension of cerebrovascular vulnerability. The aim of this research was to assess whether additional parameters can be used, to predict ischemic stroke risk in patients with AF, in order to explore whether TG/HDL-C may complement conventional clinical risk scores for ischemic stroke risk stratification in PAF, and to better characterize a metabolically high-risk phenotype beyond the recommendations provided by the CHA₂DS₂-VA score, which is useful but still far from perfect in predicting AF-associated ischemic stroke risk. Methods: In this retrospective, single-center observational study, we evaluated whether the triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDLc), a simple surrogate of atherogenic dyslipidemia and insulin resistance, is associated with ischemic stroke risk in patients with paroxysmal atrial fibrillation (PAF). We screened 1111 consecutive AF admissions between 1 January 2015 and 31 December 2016 and, from these 1111 AF cases, we extracted only the patients with PAF for analysis. Patients were stratified based on TG/HDLc values into two groups, Group 1 (TG/HDLc > 2.5; n = 155) and Group 2 (TG/HDLc < 2.5; n = 194). Statistical analysis was performed with MedCalc v23.4.0 using Chi-square and unpaired/Welch’s t-tests as appropriate, Pearson correlations, Kaplan–Meier analysis with log-rank testing, Cox regression for first ischemic stroke, and multivariable logistic regression to identify independent correlates of TG/HDLc > 2.5. Results: Patients with TG/HDLc > 2.5 had a significantly higher prevalence of ischemic stroke after AF onset compared with those with TG/HDLc < 2.5 (37.4% vs. 21.1%, p = 0.0008), despite similar CHA₂DS₂-VA and HAS-BLED scores, and also exhibited a higher burden of cerebrovascular and neurodegenerative findings, including cortical atrophy and cerebral lacunarism. Ischemic stroke-free survival curves diverged significantly over time (log-rank p = 0.0186), and an elevated TG/HDLc ratio was associated with a 68% higher hazard of first ischemic stroke (HR 1.68; 95% CI 1.09–2.60). In multivariable analysis, type 2 diabetes mellitus (OR 4.53), hyperuricemia (OR 3.83), dyslipidemia (OR 1.94), stroke (OR 1.77), and cortical atrophy (OR 4.48) were independently associated with TG/HDLc > 2.5. Conclusions: These findings suggest that TG/HDLc identifies a metabolically high-risk PAF phenotype associated with greater cerebrovascular burden and reduced ischemic stroke-free survival, providing an inexpensive and broadly available marker that may complement conventional clinical risk scores. Full article

Objectives: Systemic low-grade inflammation is associated with steatohepatitis in adults. We aim to explore if systemic low-grade inflammation, measured by plasma high-sensitivity C-reactive protein (hs-CRP), is also linked to steatotic liver disease in adolescents. Methods: In the cross-sectional Early Vascular Ageing in the YOUth study, systemic low-grade inflammation was measured by hs-CRP and liver fat content was quantified by the controlled attenuation parameters (CAP) derived from FibroScan^® (Echosense, Paris, France) measurements in 14- to 19-year-old Austrian adolescents. Cardiovascular risk factors and anthropometric data were collected through face-to-face interviews, physical examinations, and comprehensive fasting blood analyses. Linear regression models were performed to analyze the association between hs-CRP and CAP values. Results: A total of 1300 adolescents (64.6% female) with a mean age of 17.2 ± 1.3 years were included in this analysis. hs-CRP was significantly associated with CAP values in the simple linear regression model (b = 1.35, p = 0.044) and after adjustment for sex and age (b = 1.84, p = 0.006), suggesting an increase in systemic low-grade inflammation with increasing liver fat content. However, further adjustment for major factors of the metabolic syndrome (Homeostatic Model Assessment for Insulin Resistance, non-high-density lipoprotein cholesterol, body mass index z-score, systolic blood pressure z-score) led to a loss of significance of the mentioned association (b = −0.55, p = 0.419). Conclusions: Systemic low-grade inflammation measured by hs-CRP is linked to higher liver fat content in our adolescent cohort. However, this association is largely driven by components of the metabolic syndrome and the overall metabolic milieu, rather than reflecting liver-specific inflammation. Full article

Background/Objectives: Type 2 diabetes (T2D) and obesity are chronic metabolic disorders associated with cognitive impairment and neuronal damage. The hippocampus, a region sensitive to nutrient excess, is critical for integrating sensory and metabolic signals. This study aimed to determine the early onset of cognitive and motor deficits induced by obesity and/or hyperglycemia and to characterize associated hippocampal alterations in Zucker Diabetic Fatty (ZDF) rats. Methods: Male ZDF rats (13 weeks old) were categorized into three groups: lean control, obese normoglycemic (ZDF-NG), and obese hyperglycemic (ZDF-HG). Assessments included zoometric parameters (weight and adiposity), biochemical assays (glucose tolerance, insulin response, and lipid profile), and behavioral tests (Open Field and Novel Object Recognition). Hippocampal health was evaluated through stereological neuronal density analysis and redox balance markers. Results: Both obese groups exhibited significant visceral adiposity and hyperlipidemia. The ZDF-HG group was further characterized by glucose intolerance, hepatic insulin resistance, and reduced β-cell function. Behavioral results showed that while obesity decreased motor activity, hyperglycemia significantly exacerbated the loss of both short- and long-term recognition memory. Histologically, obesity was associated with decreased neuronal density in the hippocampal DG and CA1 regions. Furthermore, hippocampal ROS was significantly elevated in the ZDF-HG group, and glutathione reductase activity was reduced in both obese phenotypes. Conclusions: The findings demonstrate that obesity initiates hippocampal neurodegeneration and motor decline, and that hyperglycemia severely impairs recognition memory. These results emphasize the critical interplay between metabolic dysfunction and cognitive decline, highlighting the necessity of managing both obesity and T2D to prevent early neurodegenerative changes. Full article

Diabetes is a chronic inflammatory disease due to decreased insulin release or insulin resistance. Diabetes complications stem from high blood sugar damaging blood vessels and nerves, leading to issues like heart disease, stroke, kidney failure, nerve damage, vision loss, foot ulcers, gum disease, skin infections, and digestive/bladder issues. Galectins, especially galectin-3, are emerging as key players in diabetes complications, promoting fibrosis, inflammation, and vascular damage. This suggests that galectins may be potential therapeutic targets in diabetes and its complications, and a need to understand their role and therapeutic potential. The objective of this review is to synthesize current evidence on galectin biology in diabetes mellitus (mainly on type II diabetes) and DFUs, delineate their mechanistic roles in metabolic dysfunction and wound healing, summarize findings from human and preclinical studies, and evaluate emerging diagnostic and therapeutic strategies. Finally, this review highlights key gaps that must be addressed to advance clinical translation. The literature search suggests that galectins play a critical role in the pathogenesis of diabetes and related complications and may be potential therapeutic targets. Full article

Background: Type 2 diabetes (T2D) increases cardiovascular disease (CVD) risk and predisposes individuals to heart failure with preserved ejection fraction. Metabolic dysfunction-associated steatotic liver disease (MASLD), prevalent in T2D, may worsen cardiac remodelling and haemodynamics. This secondary analysis of the DIASTOLIC trial examined the relationship of liver fat to cardiac remodelling in T2D at baseline and after a 12-week intervention or standard care. Methods: Adults with obesity and T2D and matched controls underwent hepatic MRI, cardiac MRI, echocardiography, and adipokine profiling as part of the DIASTOLIC study (NCT02590822). Participants with T2D were randomised to supervised exercise, a low-calorie meal-replacement plan (MRP), or routine care for 12 weeks. A baseline case–control and then pre- and post-analyses in those with T2D were performed. Associations between changes in liver fat and cardiovascular measures were assessed using correlation and adjusted generalised linear models. Results: At baseline, 81 T2D and 35 healthy controls were compared, and 76 subjects with T2D completed the trial. Participants with T2D had ~4× higher hepatic fat and adverse haemodynamics. The MRP arm achieved the greatest reductions in BMI, blood pressure, dysglycaemia, insulin resistance, and hepatic fat (−8.9%), with favourable adipokine changes. Overall, hepatic fat loss was associated with reductions in cardiac index and stroke volume and with additional reductions in end-diastolic volume in the MRP arm, independent of BMI. Conclusions: In T2D, hepatic fat is strongly linked to pathological haemodynamic profiles. Intensive caloric restriction achieves substantial hepatic fat loss and normalisation of hyperdynamic cardiovascular physiology independent of weight loss, identifying hepatic steatosis as a potential therapeutic target for early cardiovascular risk reduction. Full article

Background: A protein called ‘apoptosis inhibitor of macrophage (AIM)’ is involved in the pathogenesis of obesity-associated disease. Although it is widely recognized that concurrent obesity affects the disease progression of chronic liver disease, as does concurrent type 2 diabetes mellitus (T2DM), the involvement of AIM in the pathogenesis of obesity or insulin resistance is not yet understood in patients with primary biliary cholangitis (PBC). Methods: Obesity was defined as a body mass index (BMI) exceeding 25, and insulin resistance was defined as a homeostasis model assessment for insulin resistance (HOMA-IR) value exceeding 2.0, respectively. Hepatic steatosis was estimated based on the classification proposed by Brunt and colleagues. The histological stage was determined by Scheuer’s classification. Results: Twelve (25.0%) of the forty-eight PBC patients had concurrent obesity, and seven (14.6%) had concurrent T2DM. The PBC patients with obesity had significantly higher frequency of hepatic steatosis. Compared to the patients without T2DM, those with concurrent T2DM had significantly higher serum ALT levels and more advanced histological stages. The patients’ serum AIM levels were not associated with concurrent obesity or concurrent T2DM. Our analyses identified the following as the factors that significantly affected the patients’ AIM levels: serum immunoglobulin G, albumin, tumor necrosis factor-α levels, and the histological stages. Conclusions: These results indicate that AIM may not be involved in obesity or insulin resistance, but it may be associated with the disease severity of PBC. Full article

Background: Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory, and cytoprotective properties that also plays a key role in metabolic adaptation to exercise. Although its regulation after resistance exercise has been extensively documented, less is known about its short-term modulation and its correlation with muscle damage markers following resistance training. Methods: Nine resistance-trained young men completed two sessions of total-body resistance exercise: (1) high time under tension (TUT) (5-1-2-1 cadence, to failure; ETS1) and (2) moderate TUT (2-1-2-1 cadence, two repetitions in reserve; ETS2). Plasma and saliva samples were collected before exercise and at 15 min, 24 h, and 48 h after exercise to assess total adiponectin by ELISA. Plasma creatine kinase (CK) and a Visual Analog Scale (VAS) were also measured for muscle soreness. Results: Plasma adiponectin significantly decreased from baseline to 48 h post-exercise in both sessions (p < 0.001), with no differences between the TUT conditions. Salivary adiponectin remained unchanged. Although a significant increase in CK and a decrease in adiponectin were observed at the group level, correlation analysis revealed no significant linear relationship between the magnitude of CK elevation and adiponectin reduction. Conclusions: Overall, these findings support the role of adiponectin as a marker of acute metabolic adaptation to resistance exercise. Acute resistance exercise elicited a time-dependent decrease in circulating adiponectin, irrespective of TUT. The temporal pattern of adiponectin decrease coincided with the rise in muscle damage markers, yet the lack of direct correlation suggests distinct regulatory mechanisms, while the lack of salivary changes underscores the complexity of adipokine regulation in vivo and suggests that saliva is not a reliable indicator of changes in circulating adiponectin. Full article

Background: Mammary ductal hyperplasia represents a spectrum of benign proliferative breast lesions, some of which pose elevated risks for malignant transformation into ductal carcinoma in situ and invasive breast cancer. This narrative review explores why only specific types, particularly those with atypia, exhibit higher progression potential, synthesizing epidemiologic, histopathologic, molecular, and environmental insights. Methods: We reviewed key literature from databases, including PubMed, focusing on classification, risk stratification, genetic/epigenetic mechanisms, tumor microenvironment dynamics, and modifiable factors influencing progression. Results: Benign breast lesions are categorized into non-proliferative, proliferative without atypia, and proliferative with atypia, such as atypical ductal hyperplasia and atypical lobular hyperplasia. Atypia represents a morphologic continuum toward low-grade ductal carcinoma in situ, driven by genetic alterations, epigenetic reprogramming, and changes in the tumor microenvironment, including stromal remodeling, immune infiltration, hypoxia-induced angiogenesis, and extracellular matrix degradation. Dietary factors, such as high-fat intake and obesity, exacerbate progression through inflammation, insulin resistance, and adipokine imbalance, while environmental toxins, including endocrine disruptors, pesticides, and ionizing radiation, amplify genomic instability. Conclusions: Understanding differential risks and mechanisms underscores the need for stratified surveillance, biomarker-driven interventions, and lifestyle modifications to mitigate progression. Future research should prioritize molecular profiling for personalized prevention in high-risk hyperplasia. Full article

Objective: This study evaluated the effects of a 12-week High-Intensity Functional Training (HIFT) program combined with thylakoid supplementation on plasma adipo-myokine levels (Decorin, Myostatin, Follistatin, Activin A, and TGF-β1) in men with obesity. Secondary outcomes included anthropometric indices, lipid profiles, and insulin resistance markers. Methods: Sixty men with obesity (age: 27.6 ± 8.4 years; BMI: 32.6 ± 2.6 kg/m²) were randomly assigned to four groups (n = 15 per group): Placebo (PG), Supplement (SG), HIFT + placebo (TPG), and HIFT + supplement (TSG). To ensure robustness against the 27% attrition rate, statistical analyses included both per-protocol and intention-to-treat (ITT) models. HIFT was performed for 3 sessions/week (Borg scale: 15–17). Results: Following Bonferroni correction for multiple endpoints, repeated-measures ANOVA showed significant Time × Group interactions for most adipo-myokines and metabolic markers. Both training groups (TPG and TSG) demonstrated improvements in body composition and insulin sensitivity compared to PG (p < 0.05). While no significant differences were observed between TPG and TSG for systemic metabolic markers, preliminary data suggested that thylakoid supplementation might provide modest complementary modulations in specific myokines (e.g., decorin and follistatin). However, these observed trends did not reach clinical superiority over exercise alone in the broader metabolic profile. Conclusions: Twelve weeks of HIFT is an effective primary driver for modulating the adipo-myokine network in obese men. Although thylakoid supplementation showed potential for selective complementary effects on certain myokines, these findings are exploratory given the small sample size. The clinical significance and long-term complementary value of thylakoid-exercise interactions require further validation in larger, more diverse cohorts. Full article