Search Results (88)

A fraction of the insulin-stimulated uptake of long-chain fatty acids (FAs) is mediated by the FA translocase cluster of differentiation 36 (CD36) in white adipocytes. Intracellular vesicle-localized CD36 is redistributed to the plasma membrane following insulin stimulation, enhancing the uptake of long-chain FAs across the plasma membrane. We previously developed an epitope-tagged CD36 reporter, which enabled the visualization and quantification of the plasma membrane translocation of CD36. Herein, we demonstrate that the insulin-stimulated CD36 translocation is regulated by the phosphoinositide 3-kinase (PI3K)/Akt2/Rac1/RalA axis in adipocytes of subcutaneous white adipose tissue (WAT) in living mice. The uptake of long-chain FAs by insulin was completely abrogated in white adipocytes isolated from adipocyte-specific rac1-knockout (adipo-rac1-KO) mice. Correspondingly, the translocation of CD36 to the plasma membrane by insulin was also totally inhibited in Rac1-deficient white adipocytes. PI3K and Akt2 acted upstream of Rac1, and the guanin nucleotide exchange factor FLJ00068 served as a regulator for Rac1. Furthermore, the involvement of another small GTPase RalA was suggested by inhibitory effects of a dominant-negative mutant. Taken together, these results support the notion that insulin regulates the plasma membrane translocation of CD36 by mechanisms similar to those for the translocation of the glucose transporter GLUT4 in white adipocytes. Full article

Obesity is a growing public health concern linked to poor dietary habits, physical inactivity, and metabolic disturbances, which can be evaluated using complementary laboratory tests. Among pharmacological interventions, semaglutide, a GLP-1 receptor agonist, has shown promise by acting on the central nervous system to reduce appetite and stimulate insulin secretion, thereby improving the lipid profile and reducing inflammation biomarkers. This review focused on changes in lipid parameters and C-reactive protein (CRP) levels in overweight or obese individuals treated with semaglutide, based on phase 3 studies from the STEP program (“Semaglutide Treatment Effect in People with Obesity”). The STEP clinical trial program was conducted across 36 countries, reflecting a broad and diverse geographic representation. Key findings include significant reductions between placebo vs. semaglutide in body weight (−1.3 vs. −13.0 Kg), body mass index (−0.69 vs. −4.72 kg/m²), and waist circumference (−2.79 × −11.81 cm). Additionally, there were notable decreases in triglycerides (−0.67 vs. −20.89%), VLDL-C (−0.99 vs. 20.82%), and CRP levels (−15.45 vs. −55.55%). These changes reflect improvements in both inflammatory and metabolic markers. The observed benefits suggest that semaglutide may contribute to reducing comorbidities associated with metabolic syndrome and to the prevention of cardiovascular disease. Current evidence also supports its potential role in individualized treatment strategies based on patients’ clinical and biochemical profiles. However, despite these promising findings, further long-term studies are required to confirm the efficacy and safety of semaglutide across diverse populations. Full article

Background/Objectives: Psoriasis is a chronic immune-mediated inflammatory disease increasingly recognized as a systemic disorder associated with significant metabolic and cardiovascular comorbidities. Among these, obesity (defined as BMI > 30 kg/m²) plays a pivotal role, acting both as a risk factor for psoriasis development and as a modifier of disease severity, clinical phenotype, and therapeutic response. The relationship between psoriasis and obesity is bidirectional and sustained by shared inflammatory and metabolic pathways. This review aims to provide a comprehensive and updated synthesis of the epidemiological association between psoriasis and obesity, to elucidate the underlying pathophysiological mechanisms, and to discuss the clinical and therapeutic implications of excess body weight in psoriasis management. Methods: A narrative review of the literature was conducted, including epidemiological studies, mechanistic research, clinical trials, and real-world evidence addressing the interplay between psoriasis and obesity. Relevant data were identified from peer-reviewed publications focusing on inflammatory pathways, metabolic dysfunction, cardiovascular risk, and treatment outcomes in obese patients with psoriasis. The graphical figures included in this manuscript were created with the assistance of a large language model–based image-generation tool, ChatGPT-5 by OpenAI, using author-defined prompts. The prompts requested schematic medical illustrations summarizing the pathophysiological links between obesity and psoriasis, including adipose tissue dysfunction, adipokine imbalance, systemic inflammation, and activation of the IL-23/Th17 axis. For the therapeutic algorithm, the prompt requested a stepwise clinical flowchart for obese patients with psoriasis, including BMI assessment, comorbidity screening, universal weight-management measures, psoriasis severity stratification, obesity-adapted biologic selection, and management of suboptimal response. The generated images were subsequently reviewed, edited, and approved by the authors to ensure scientific accuracy, clarity, and consistency with the manuscript content. Results: Epidemiological evidence consistently demonstrates a higher prevalence of obesity among patients with psoriasis, with obesity independently associated with increased disease severity. Shared mechanisms include adipose tissue–driven cytokine production, dysregulated adipokine secretion, insulin resistance, endothelial dysfunction, and activation of the IL-23/Th17 axis, collectively contributing to systemic inflammation and accelerated atherogenesis. Obesity negatively impacts the efficacy, pharmacokinetics, and long-term drug survival of conventional systemic agents and biologic therapies, leading to suboptimal clinical outcomes. Conclusions: Obesity is a key determinant of psoriasis burden, influencing disease expression, comorbidities, and therapeutic response. Integrating weight reduction strategies into personalized psoriasis management may improve both dermatological outcomes and overall cardiometabolic health, supporting a holistic approach to patient care. Full article

Background: Algorithm-based insulin dosing systems are increasingly used in hospitals and have shown the potential to efficiently and safely enable glycemic control. The goal of this study was to evaluate glycemic control using the ultralong-acting basal insulin degludec (IDeg) in combination with insulin aspart (IAsp) within an algorithm-driven electronic clinical decision support system (cDSS) in inpatients with type 2 diabetes (T2D). Methods: In this non-controlled single-arm pilot study, an electronic, algorithm-based cDSS was applied for the management of insulin treatment in an internal general ward. Thirty hospitalized patients with T2D (18 female, age 74.1 ± 10.9 years, HbA1c 72.4 ± 22.3 mmol/mol, BMI 28.6 ± 5.6 kg/m², diabetes duration 13.2 ± 11.6 years, creatinine 1.5 ± 1.2 mg/dL, length of hospital stay 9.1 ± 4.0 days) were included in the study. Capillary blood glucose (BG) was evaluated four times daily using a point-of-care device integrated into the hospital information system. In addition, all participants received a blinded continuous glucose monitoring (CGM; Abbott Freestyle Libre Pro) system. The primary endpoint was defined as the percentage of BG measurements within the target range of 3.9–7.8 mmol/L. Results: Overall, 722 BG values and 17,242 CGM data points were available. Of those, 52.2% and 55.0% were in the specified target area (3.9–7.8 mmol/L), respectively. Mean BG prior to study start was 11.9 ± 4.4 mmol/L and improved to 7.5 ± 1.9 mmol/L and 7.4 ± 1.4 mmol/L after 6 and 10 days of treatment. BG < 3.9, <3.0 and <2.2 mmol/L was 1.25%, 0.28% and 0%, respectively. Adherence to the total daily insulin dose suggested by the cDSS was 94.2%, and 99.5% of all basal and 85.3% of all bolus insulin suggestions were accepted by the nurses in charge. Basal-bolus therapy using the cDSS covered 85% of the participants’ total hospital stay. Conclusions: Glycemic control using IDeg within an algorithm-driven cDSS could effectively and safely be achieved in the hospital and was highly accepted. Full article

Background: Obesity is a major driver of obstructive sleep apnea (OSA), traditionally managed as a mechanical disorder of upper airway collapse. However, growing evidence supports a broader pathophysiological model involving metabolic dysfunction, systemic inflammation, and ventilatory instability. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated substantial weight loss and cardiometabolic benefits, raising the possibility of a paradigm shift in OSA management. Objective: To critically evaluate whether tirzepatide may act as a disease-modifying therapy in obesity-related OSA beyond its effects on weight reduction. Methods: A narrative review was conducted using PubMed, Scopus, and Web of Science up to January 2026. Evidence from randomized controlled trials, meta-analyses, and mechanistic studies on incretin-based therapies in obesity and OSA was synthesized, with emphasis on clinical outcomes and underlying biological pathways. Results: Tirzepatide is associated with significant reductions in apnea–hypopnea index (AHI), accompanied by substantial weight loss. However, emerging data suggest that improvements in OSA severity may not be entirely explained by weight reduction alone. Potential weight-independent mechanisms include modulation of systemic inflammation, improvements in insulin sensitivity, alterations in adipokine profiles, and effects on autonomic regulation and ventilatory control. These pleiotropic effects may influence key components of OSA pathophysiology, including upper airway stability and chemosensitivity. Despite these findings, current evidence remains insufficient to definitively distinguish weight-dependent from weight-independent effects. Conclusions: Tirzepatide represents a promising therapeutic advance in obesity-related OSA, with potential implications extending beyond weight loss toward disease modification. While current data support a substantial role in reducing OSA severity, definitive confirmation of disease-modifying effects requires further mechanistic and long-term clinical studies. This emerging paradigm points to a shift from purely device-based management toward integrated, pathophysiology-driven treatment strategies. Full article

Background/Objectives: Insulin glargine U300 (IGlarU300) is a second-generation, long-acting insulin analog designed to provide a more stable pharmacokinetic profile compared to insulin glargine U100. However, long-term real-world data reflecting its long-term impact on glycemic control and hypoglycemia across diverse populations remain limited. This study evaluated the 24-month clinical outcomes of transitioning to IGlarU300 in a real-world setting. Methods: This retrospective, single-center, observational study enrolled patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM) who transitioned to IGlarU300 between 2017 and 2021. HbA1c levels, body weight, insulin doses, and hypoglycemia rates were evaluated at baseline and up to 24 months. Results: A total of 242 patients (T1DM: n = 68, T2DM: n = 174) were analyzed. HbA1c levels significantly declined at all follow-up points compared to baseline (mean change at 12 months: −0.85% [95% CI: −1.24 to −0.47%]; p < 0.001]). No significant change in total insulin dose was observed over the one-year follow-up; however, improved glycemic control led to a significant reduction in oral antidiabetic medication use, reflecting successful treatment simplification and a decrease in polypharmacy burden (mean change: -0.50 [95% CI: −0.70 to −0.30]; p < 0.001). Notably, both severe and mild hypoglycemia episodes showed significant reductions (p = 0.010 and p = 0.019, respectively). Switching to IGlarU300 was associated with sustained improvements in glycemic control and a reduction in hypoglycemia rates. Conclusions: These findings suggest that IGlarU300 may be an effective clinical option for optimizing metabolic outcomes, though further controlled studies are warranted to confirm these observational results. Full article

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine–metabolic disorder characterized by endocrine disruption, insulin resistance, hyperandrogenism, and chronic low-grade inflammation, in which oxidative stress has been proposed as a mechanistic link between metabolic and reproductive dysfunction. This narrative review summarizes current evidence on redox-related mechanisms and evaluates dietary and supplemental antioxidants in PCOS. Clinical trials, systematic reviews, and mechanistic studies were examined to assess antioxidant classification, signaling pathways, and outcomes related to metabolic, endocrine, reproductive, and oxidative stress parameters. Antioxidant interventions frequently modify circulating redox biomarkers and may improve selected metabolic indices; however, consistent effects on hormonal regulation, ovulation, and long-term clinical outcomes remain limited and heterogeneous. Differences in study design, antioxidant formulation and dosage, baseline metabolic status, and outcome selection complicate interpretation, while emerging evidence suggests modulation by lifestyle factors and gut microbiota-related mechanisms. Overall, antioxidants appear to act primarily through modulation of endogenous redox regulation rather than direct reactive oxygen species scavenging and are best considered adjuncts to lifestyle-based management. Further phenotype-informed and longitudinal studies using clinically relevant endpoints are required to clarify therapeutic relevance in PCOS. Full article

Physical exercise is a potent non-pharmacological strategy for the prevention and management of Metabolic dysfunction—associated steatotic liver disease (MASLD), a multifactorial disorder characterized by hepatic lipid accumulation, insulin resistance, oxidative stress, and chronic inflammation. Emerging evidence demonstrates that the benefits of exercise extend beyond caloric expenditure and are largely mediated by coordinated molecular and cellular adaptations within the liver and peripheral tissues. This review synthesizes current knowledge on the mechanisms through which exercise modulates MASLD pathophysiology, emphasizing intracellular signaling pathways, mitochondrial remodeling, antioxidant defenses, and myokine-driven muscle–liver crosstalk. Exercise induces acute and chronic activation of pathways such as AMPK, PGC-1α, Nrf2, and Akt, resulting in enhanced mitochondrial biogenesis, improved fatty acid oxidation, restored insulin signaling, and reduced inflammatory and oxidative stress. Repeated skeletal muscle contraction stimulates the release of myokines—including irisin, IL-6, and FGF21—that act through endocrine and paracrine routes to regulate hepatic lipid metabolism, promote systemic metabolic flexibility, and attenuate disease progression. Epigenetic modifications and exercise-responsive microRNAs further contribute to long-term hepatic metabolic reprogramming. Collectively, these molecular adaptations position exercise as a systemic, disease-modifying stimulus capable of restoring hepatic homeostasis, slowing the transition from steatosis to NASH and fibrosis, and improving long-term metabolic health. Understanding these mechanisms provides a foundation for developing targeted, personalized exercise-based interventions in the clinical management of MASLD. Full article

Background: Gestational diabetes mellitus (GDM) complicates a significant number of pregnancies and is associated with both short- and long-term risks for the mother and child. Twin pregnancies are inherently high risk, and the coexistence of GDM may amplify these risks. While the effects of GDM in singleton pregnancies have been widely studied, data on its impact in twin gestations remain limited. The aim of this study was to determine differences regarding metabolic characteristics, treatment requirements, and maternal as well as fetal outcomes between twin and singleton pregnancies with GDM to contribute to improved perinatal care. Methods: This retrospective study included obstetric data from 73 twin pregnancies (146 neonates) and 1664 singleton pregnancies with a GDM diagnosis at a tertiary perinatal center in Berlin, Germany, between 2015 and 2022. Baseline characteristics and perinatal outcomes were assessed. Adjusted multiple linear and logistic regression analyses were used for group comparisons. Results: Women with GDM in twin and singleton pregnancies exhibited comparable glucose values in the 75 g oral glucose tolerance test (OGTT) (median fasting: 95 vs. 96 mg/dL; 1 h: 183 vs. 183 mg/dL; 2 h: 144 vs. 139 mg/dL). Despite this, insulin therapy was required significantly less often in twin (5.5%) compared to singleton pregnancies (22.3%) (OR = 0.86; 95% CI: 0.78–0.96). Among insulin-treated women, combined insulin therapy was most common in twins (75%), while singleton mothers most frequently received long-acting insulin alone (61.7%), followed by combined therapy (31.3%) and short-acting insulin alone (7%). Birthweight was significantly lower in twins (β = –0.83 kg; 95% CI: –0.98 to –0.69), and when evaluated using twin-based growth standards, twins were more likely to be classified as having intrauterine growth restriction (IUGR, <3rd percentile) (OR = 3.37; 95% CI: 0.96–9.11), being small for gestational age (SGA, <10th percentile) (OR = 2.50; 95% CI: 1.23–4.76), or having a birthweight below the 30th percentile (OR = 6.11; 95% CI: 3.49–11.12). No large-for-gestational-age (LGA, >90th percentile) neonates were observed in the twin group. Conclusions: GDM manifests differently in twin and singleton pregnancies. Despite similar OGTT values, twin mothers require insulin less frequently. Growth-related complications such as IUGR and SGA are significantly more frequent in twins, likely reflecting the physiological constraints of multiple gestations rather than GDM itself. Conversely, LGA is predominantly a concern in singleton pregnancies. These findings underscore the need for individualized diagnostic criteria and management strategies for GDM in twin pregnancies. Full article

Multiple sclerosis (MS) is a chronic, immune-mediated neurological disorder characterized by inflammation, demyelination, and progressive neurodegeneration. While genetic susceptibility contributes to disease risk, a growing body of evidence highlights the crucial role of modifiable lifestyle factors in influencing MS onset, disease activity, progression, and overall quality of life. In this narrative review, we explored the relevant literature from commonly used datasets (PubMed, Scopus, Google Scholar), using search terms such as “Lifestyle and Multiple Sclerosis”, “Diet and Multiple Sclerosis”, “Sleep and Multiple Sclerosis”, “Alcohol consumption and Multiple Sclerosis”, and “Physical Activity and Multiple Sclerosis”. Obesity, particularly during adolescence, has emerged as a significant risk factor for MS, acting through immunometabolic mechanisms such as chronic low-grade inflammation, insulin resistance, and dysregulated adipokine signaling. Sleep disturbances are increasingly recognized as contributors to neuroinflammation and cognitive dysfunction, potentially mediated by impaired glymphatic clearance. Smoking is consistently associated with accelerated disability progression, while alcohol consumption shows dose-dependent effects, with excessive intake negatively impacting sleep and glymphatic function. Overall, lifestyle factors converge on shared biological pathways involving immune regulation, metabolic health, vascular integrity, and glymphatic function. Integrating evidence-based lifestyle counseling with disease-modifying therapies may represent a complementary strategy to optimize long-term outcomes in people with MS, while highlighting key areas for future translational and clinical research. Full article

The efficacy of platelet-rich plasma (PRP) has long been associated with platelet concentration, yet clinical outcomes remain highly variable and frequently inconsistent. This review challenges the assumption that platelet count alone defines PRP efficacy, proposing instead that functional platelet quality and growth-factor bioactivity are equally critical determinants of therapeutic outcomes. Platelets act as carriers of bioactive molecules stored within alpha granules, including growth factors such as platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), and insulin-like growth factor (IGF), which orchestrate the cellular and molecular events of tissue repair. Variations in donor biology, age, metabolic status, and oxidative stress profoundly influence platelet functionality and growth-factor release. Likewise, centrifugation parameters, temperature control, and activation methods dictate whether these mediators are preserved or prematurely exhausted. Collectively, these findings reveal that platelet number alone cannot predict regenerative potency. The future of PRP standardization requires the integration of platelet quality indices, growth-factor quantification, and patient optimization protocols into clinical practice. By shifting focus from platelet enumeration to bioactivity assessment, regenerative medicine can achieve more consistent, personalized, and scientifically accurate outcomes. Full article

Polycystic Ovary Syndrome (PCOS) is characterized by a self-perpetuating vicious cycle between insulin resistance (IR) and hyperandrogenism (HA). While lifestyle management remains the internationally recommended first-line treatment, current clinical management, primarily relying on combined oral contraceptives and metformin, offers symptomatic relief or “masking” of the phenotype but fails to adequately disrupt this core pathophysiological loop, while also carrying potential intergenerational safety concerns. This review systematically evaluates the paradigm shift toward mechanism-based precision medicine. First, we analyze emerging precision-targeted therapies that intervene in specific pathological nodes: (1) metabolic regulators (e.g., GLP-1RAs, SGLT2i, and brown adipose tissue (BAT) activators) that target systemic glucotoxicity and the novel “BAT-Ovarian axis”; (2) neuroendocrine modulators (e.g., NK3R antagonists) that act as negative modulators of the hyperactive GnRH pulse generator; and (3) innovative androgen synthesis inhibitors (e.g., Artemisinins) that utilize a degradation-at-source mechanism. Complementing these, we explore the strategic value of Natural Products through the lens of “Network Pharmacology”, highlighting their ability to restore systemic homeostasis via multi-target modulation. Finally, we address critical translational challenges, specifically the need to establish long-term reproductive and offspring safety, providing a roadmap for developing true disease-modifying treatments for PCOS. Distinct from reviews limited to isolated therapeutic modalities, this article uniquely bridges current clinical management with emerging organ-specific precision targets and natural product networks. Full article

Physical exercise is a potent non-pharmacological strategy for the prevention and management of chronic non-communicable diseases (NCDs), including type 2 diabetes, cardiovascular diseases, obesity, and certain cancers. Growing evidence demonstrates that the benefits of exercise extend beyond its physiological effects and are largely mediated by coordinated molecular and cellular adaptations. This review synthesizes current knowledge on the key mechanisms through which exercise modulates metabolic health, emphasizing intracellular signaling pathways, epigenetic regulation, and myokine-driven inter-organ communication. Exercise induces acute and chronic activation of pathways such as AMPK, PGC-1α, mTOR, MAPKs, and NF-κB, leading to enhanced mitochondrial biogenesis, improved oxidative capacity, refined energy sensing, and reduced inflammation. Additionally, repeated muscle contraction stimulates the release of myokines—including IL-6, irisin, BDNF, FGF21, apelin, and others—that act through endocrine and paracrine routes to regulate glucose and lipid metabolism, insulin secretion, adipose tissue remodeling, neuroplasticity, and systemic inflammatory tone. Epigenetic modifications and exercise-responsive microRNAs further contribute to long-term metabolic reprogramming. Collectively, these molecular adaptations establish exercise as a systemic biological stimulus capable of restoring metabolic homeostasis and counteracting the pathophysiological processes underlying NCDs. Understanding these mechanisms provides a foundation for developing targeted, personalized exercise-based interventions in preventive and therapeutic medicine. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is characterized by progressive β-cell dysfunction and insulin resistance. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may enhance β-cell function. Semaglutide, a long-acting GLP-1 RA, improves glycemic control and weight, but its direct effects on β-cell function remain uncertain. Methods: This systematic review and meta-analysis followed PRISMA guidelines and was registered in PROSPERO (CRD420251034071). PubMed, Embase, and Scopus were searched through April 2025 for randomized controlled trials evaluating semaglutide’s effects on β-cell function in adults with T2DM. Primary outcomes included HOMA-B, HOMA-IR, and the proinsulin/insulin ratio; secondary outcomes included insulin secretion rate, insulinogenic index, and C-peptide. Two reviewers independently performed data extraction and risk-of-bias assessment using the Cochrane RoB 1 tool. Random-effects models were used for pooling. Certainty of evidence was evaluated using GRADE. Results: Sixteen trials (n = 6591) met inclusion criteria, with nine included in the meta-analysis. Semaglutide improved β-cell function (HOMA-B log ratio of means 1.50, 95% confidence interval [CI]: 1.25–1.80) and reduced insulin resistance (HOMA-IR ratio 0.82, 95% CI: 0.73–0.94) compared with placebo or active comparators. The pooled treatment ratio for proinsulin/insulin was 0.70 (95% CI: 0.63–0.79). However, risk of bias was generally high due to open-label designs, and certainty of evidence for all primary outcomes was rated very low. Conclusions: Semaglutide appears to improve β-cell function and insulin sensitivity in adults with T2DM, but conclusions remain uncertain given the very low certainty of evidence and substantial heterogeneity. High-quality trials with standardized β-cell outcomes are needed to confirm these findings. Full article

Hair loss and scalp dysfunction are prevalent concerns with limited non-medicinal long-term solutions. Growth factors and plant-derived extracellular vesicle (EV) represent promising regenerative approaches. In this exploratory randomized controlled trial, 60 healthy adults (18–60 years) were randomly assigned into five groups: (A) placebo; (B) base formula with 0.1% caffeine and panthenol; (C) base + recombinant Fc-fusion long-acting insulin-like growth factor-1 (rIGF-1) and fibroblast growth factor-7 (rFGF-7); (D) base + Centella asiatica (C. asiatica) EV; and (E) base + rIGF-1, rFGF-7, and C. asiatica EV. Participants applied their assigned product once daily for 56 days. Scalp and hair parameters, including sebum content, hair length, thickness, density, and hair loss, were assessed at baseline and Days 14, 28, 42, and 56. The combination of C. asiatica EV with rIGF-1 and rFGF-7 (Group E) showed the greatest improvements across all endpoints, including significant increases in hair thickness, density, and length, and a reduction in sebum content and hair loss by Day 56 compared with placebo. The results support further study of topical use of C. asiatica-derived EV with recombinant long-acting growth factors as a novel, naturally derived, cosmetic intervention for scalp and hair care. Full article