Search Results (727)

Depressive disorder is the most prevalent mental illness, and increasing evidence suggests its potential bidirectional relationship with metabolic disorders. Given the limited efficacy of conventional antidepressants (including Selective Serotonin Reuptake Inhibitors; SSRIs) and the growing prevalence of treatment-resistant depression, there is a significant need to identify alternative molecular pathways underlying the pathophysiology of depressive disorder, which may represent novel therapeutic targets for other agents. Emerging evidence indicates that metabolic dysfunction and depressive disorder share a common pathophysiological molecular mechanism and increase each other’s risk. Targeting peripheral metabolic pathways and their interactions with the central nervous system may alleviate depressive symptoms. Glucagon-Like Peptide-1 agonists (GLP-1 RAs) and Sodium–Glucose Cotransporter-2 (SGLT2) inhibitors, widely used in the treatment of type 2 diabetes and obesity, exhibit neurotrophic and anti-inflammatory effects, ameliorate oxidative stress, and enhance mitochondrial function, collectively contributing to the antidepressant-like effects observed in preclinical studies. Peroxisome Proliferator-Activated Receptor (PPAR) α agonists primarily regulate lipid and glucose metabolism, which may potentially improve neuronal plasticity and mood regulation. Moreover, agents such as Angiotensin Receptor Blockers (ARBs) and Angiotensin Receptor-Neprilysin Inhibitors (ARNIs), used in hypertension treatment, exert central anti-inflammatory and neuroprotective effects via the modulation of the renin–angiotensin–aldosterone system (RAAS), implicated in affective disorders. Nevertheless, long-term, head-to-head trials are required to establish their efficacy, safety, and therapeutic positioning within current treatment paradigms. The aim of this review is to summarize current evidence on metabolic modulators as potential antidepressant strategies, focusing on their molecular mechanisms, preclinical and clinical findings, and prospects for integration into future therapies for depression. Full article

Background: Sodium–glucose cotransporter-2 (SGLT2) inhibitors are widely used to manage type 2 diabetes mellitus (T2DM) because of their glucose-lowering and cardioprotective effects. However, euglycemic diabetic ketoacidosis (euDKA) is an uncommon but serious adverse event. EuDKA is characterized by metabolic acidosis and ketosis with only mild-to-moderate hyperglycemia, making diagnosis challenging. The risk of this interaction may be increased with the concurrent use of glucagon-like peptide-1 receptor agonists (GLP-1RAs), particularly during periods of reduced caloric intake or the presence of gastrointestinal symptoms. Case: A 38-year-old woman with newly diagnosed T2DM presented with five days of fatigue, poor oral intake, nausea, and vomiting. She had recently initiated semaglutide (GLP-1RA) for weight loss and practiced prolonged intermittent fasting. One week prior, she had started metformin and enavogliflozin, a selective SGLT2 inhibitor. Laboratory results showed a glucose level of 137 mg/dL, urine ketones (+++), lactate level of 4.87 mg/dL, HbA1c of 9.3%, C-peptide of 0.88 ng/mL, and high anion gap metabolic acidosis. She was diagnosed with euDKA and treated with IV fluids, insulin infusion, dextrose, and potassium supplementation. Her symptoms resolved, and she was discharged in a stable condition. Conclusion: This case highlights the importance of recognizing euDKA in patients using SGLT2 inhibitors and GLP-1RAs, particularly those with fasting or gastrointestinal symptoms. Clinicians should suspect euDKA even without significant hyperglycemia to enable prompt diagnosis and management, thereby preventing complications. Full article

Cardiovascular-kidney-metabolic (CKM) syndrome is a multifaceted, systemic disorder characterized by the interplay of cardiovascular disease (CVD), chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and obesity. This review synthesizes current and emerging therapeutic strategies aimed at addressing the shared pathophysiologic mechanisms driving CKM progression, such as insulin resistance, inflammation, oxidative stress, and neurohormonal activation. Established pharmacotherapies that include sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and nonsteroidal mineralocorticoid receptor antagonists like finerenone have demonstrated robust efficacy in reducing cardiovascular events, slowing renal decline, and improving metabolic outcomes. Additionally, novel agents targeting lipoprotein(a), interleukin-6, and hepatic fat accumulation are expanding the therapeutic landscape. RNA-based therapies, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), are designed to modulate lipoprotein(a) and PCSK9 expression. Artificial intelligence (AI) is also emerging as a transformative tool for personalized CKM management, enhancing risk prediction and clinical decision-making. The review highlights the relevance of metabolic dysfunction-associated steatotic liver disease (MASLD) as a CKM modifier and discusses the approval of resmetirom, a selective thyroid hormone receptor β agonist, for noncirrhotic MASH. By integrating evidence from clinical trials, mechanistic studies, and emerging technologies, this review provides a comprehensive resource for clinicians and researchers navigating the evolving field of CKM syndrome. Full article

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) effectively manage type 2 diabetes mellitus (T2DM) but may impair gastrointestinal motility, increasing the risk of small intestinal bacterial overgrowth (SIBO). Diagnostic evaluation of SIBO commonly involves breath testing and clinical assessment. This study aimed to assess the association between GLP-1 RAs or dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) RAs are associated with incident SIBO. Methods: We conducted a retrospective cohort study using the TriNetX global database, identifying adult T2DM patients initiating GLP-1 RA or dual GLP-1/GIP RA therapy versus other second-line T2DM agents (OSLT2DM) from 1 January 2006 to 2 December 2024. Patients with major abdominal surgery, connective tissue disorders, gastroparesis, or other high-risk conditions for SIBO were excluded. 1:1 Propensity score matching was applied. Short-term (<1 year) and long-term (up to 5 years) risks were evaluated with Kaplan–Meier curves and univariable Cox models. Results: After matching, 216,173 patients per cohort were analyzed. Short-term analysis demonstrated a higher incidence of diagnostically confirmed SIBO in patients treated with GLP-1 RA/GIP (0.177 per 1000 patient-years) compared to OSLT2DM (0.083 per 1000 patient-years; HR 2.14, 95% CI 1.13–4.07; p = 0.0491). Long-term analysis indicated a non-significant trend toward increased risk in the GLP-1 RA/GIP group (HR 2.02, 95% CI 0.98–4.12), though Kaplan–Meier analysis revealed a sustained divergence (p = 0.017). Conclusions: GLP-1 RA and dual GLP-1/GIP RA therapy are associated with increased short-term SIBO risk. Symptom-driven SIBO breath-test evaluation may be warranted in patients initiating these agents. Full article

Background/Objectives: Obesity and type 2 diabetes mellitus (T2DM) have a continuously increasing prevalence and often co-exist, exacerbating cardiometabolic risk. GLP-1 receptor agonists (GLP-1 RAs) are recommended as first-line therapy for patients with T2DM and excess weight, particularly when cardiovascular risk is present. This study assessed the real-world effectiveness of available GLP-1 RAs in Romania on glycemic control, body weight reduction (BWR), and waist circumference (WC) in T2DM patients with excess weight. Methods: A prospective observational study was conducted on 311 adults with T2DM (glycated hemoglobin (HbA1c) > 7.2%, body mass index (BMI) ≥ 25 kg/m²). Patients received exenatide, semaglutide (either oral or injectable), or dulaglutide and were monitored for a period of 6 months. Parameters assessed included HbA1c, body weight, BMI, and WC. Results: All treatments significantly improved the patients’ HbA1c, BMI, and WC (p < 0.05). Dulaglutide had the most significant impact on HbA1c (−6.69 ± 0.91%), while injectable semaglutide led to the most notable BWR (−4.60 ± 2.74 kg) and WC reduction, especially among male patients. No significant differences in treatment effect were observed concerning the patient’s age, gender, or T2DM duration. Conclusions: In real-world clinical practice, GLP-1 RAs provide significant metabolic benefits and should be considered as part of individualized treatment strategies for T2DM patients who are overweight or obese. Full article

Background: Osteoarthritis has a large and growing burden in an ageing population. Controversy exists in current management, particularly regarding opioid use due to increasing negative effects. Clinicians need guidance on the individual mortality associations for common osteoarthritis treatments when compared to a control. Aims: The aim is to undertake a structured narrative literature review comparing mortality associations for common osteoarthritis management options. Methods: A search strategy (Web of Science 23 September 2024) was performed to identify observational studies which reported all-cause mortality in a treatment group compared to a control. The control group could be either the general population or those with osteoarthritis who were treated with the following: NSAIDs (non-steroidal anti-inflammatory drugs), opioids, paracetamol, GLP-1 RAs (Glucagon-like peptide-1 receptor agonists), hip or knee arthroplasty, or exercise. Articles were screened by two authors, and each included article was assessed for adequate quality using the strengthening the reporting of observational studies in epidemiology (STROBE) framework. Results: Of 2362 studies retrieved, 39 cohort studies met the inclusion requirements. Exercise, compared to no or lower levels of exercise, had ten studies reporting substantially reduced all-cause mortality. GLP-1 RA agonists had two related studies showing all-cause mortality reduction up to 5 years. Mortality following joint arthroplasty followed a multi-phasic response. There was a short-term post-surgical increase in mortality. However, from 90 days post-surgery to 8–11 years, there were significant reductions in mortality. After 9–12 years post arthroplasty, mortality increased and became significantly higher. Opioids were associated with an increase in mortality in 6 out of 7 studies. Inconsistent trends were found for NSAIDs and paracetamol. Conclusions: Exercise and GLP-1 RA prescription are associated with reduced all-cause mortality. Arthroplasty was found to have survival benefit until 9–11 years post-operatively, whereafter mortality then increased. Opioids were found to consistently increase mortality when used for non-cancer pain at all time points. The other common osteoarthritis treatments assessed were not consistently associated with changes in mortality. Full article

Background: Overweight and obesity are currently a worldwide problem, with undesirable health consequences, such as type 2 diabetes. Therefore, much attention has been paid to preventing obesity through diet. Free fatty acids (FFAs) serve as signaling molecules in many biological processes, leading to increased energy expenditure and insulin secretion. Short-chain fatty acids (SCFAs) such as acetic, propionic and butyric acid are bioactive metabolites produced by gut microbes, and their beneficial effects on host metabolism are well studied. However, the effects of hexanoic acid on metabolism are poorly understood. Methods: Male C57BL/6J mice were fed a normal chow diet, a high-fat diet (HFD), an HFD containing 5% butyric acid or an HFD containing 5% hexanoic acid for 4 weeks, and the effects of hexanoic acid on their lipid and glucose metabolisms were examined. Results: Dietary supplementation of hexanoic acid or butyric acid for 4 weeks prevented HFD-induced obesity and fat accumulation in the white adipose tissues. Both FFAs also suppressed the elevated plasma non-esterified fatty acid (NEFA) levels and hepatic triglyceride content in the mice fed an HFD. In addition, butyric acid and hexanoic acid decreased the elevated expression of genes involved in fatty acid biosynthesis in the white adipose tissues under HFD conditions. Hyperinsulinemia induced by HFD feeding was attenuated by oral intake of butyric acid or hexanoic acid, whereas hyperglycemia under HFD feeding was improved only through oral administration of hexanoic acid. Hexanoic acid increased plasma glucagon-like peptide-1 (GLP-1) levels and the expression of genes associated with gluconeogenesis. The intraperitoneal glucose tolerance test (IPGTT) and the insulin tolerance test (ITT) revealed that the oral administration of hexanoic acid significantly enhanced glucose tolerance and insulin sensitivity. Conclusions: This study highlights the importance of hexanoic acid in improving lipid and glucose metabolisms. Hexanoic acid, as well as butyric acid, is a remarkable FFA with anti-obesity properties. Furthermore, hexanoic acid is more potent in maintaining glucose homeostasis than butyric acid. Thus, our findings provide insight into the development of functional foods which could prevent obesity-related diseases such as type 2 diabetes. Full article

Aquaglyceroporins, including human AQP7, AQP10, and E. coli GlpF, are known to facilitate movements of glycerol, water, and some other uncharged molecules across the cell membrane. In this study we focused on the transport of water molecules in the absence of glycerol for AQP7, AQP10 and GlpF using the Transition State Theory for the novel application of permeability and kinetics studies. We conducted around 500 ns of in silico simulations of the aquaglyceroporins embedded in lipid bilayer membranes with intracellular-extracellular asymmetries in leaflet lipid compositions. For the water permeability analysis, we computed the transition rate constant with correction for recrossing events where the water molecules do not completely traverse the protein channel from one side of the membrane to the other side. We also studied the hydrogen bond distributions of the single-file waters and channel residues and linear water densities along the pores of the aquaglyceroporins. Interestingly, we found that there was an inverse correlation between the number of single-file water molecules in the channel and osmotic permeability. Full article

Youth-onset type 2 diabetes (T2D) is a growing public health challenge. This narrative review aims to provide a comprehensive overview of epidemiology, pathophysiology, diagnosis, complications, and therapeutic strategies in children and adolescents with T2D, highlighting the most recent evidence and the distinctive features that differentiate youth-onset from adult-onset disease. Over recent decades, its incidence has increased worldwide, closely linked to rising rates of childhood obesity, sedentary behavior, and socioeconomic disparities. The disease typically emerges around puberty, a period marked by physiological insulin resistance, and is influenced by a complex interplay of genetic, environmental, and developmental factors. Diagnosis can be delayed or missed due to overlapping features with type 1 diabetes and limitations in current screening tools. The clinical course is often aggressive, with early onset of microvascular and macrovascular complications. Management is particularly challenging due to the limited number of pharmacologic agents approved for pediatric use and the psychological and behavioral complexities of adolescence. While metformin remains the first-line treatment, newer therapies such as GLP-1 receptor agonists and SGLT2 inhibitors show promise in improving metabolic outcomes. In conclusion, early diagnosis, multidisciplinary management, and equitable access to effective therapies are essential to improve long-term outcomes in this vulnerable population. Full article

Background and Aims: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) delay gastric emptying, raising concerns about periprocedural safety in elective endoscopy. We aimed to evaluate the association between pre-procedural GLP-1 RA use and post-procedural complications such as aspiration pneumonia. Methods: In this retrospective cohort study, adults (18–89 years) undergoing outpatient esophagogastroduodenoscopy or colonoscopy within the HCA Healthcare network from 1 July 2021 to 31 March 2024 were identified. Patients were classified as GLP-1 RA users (n = 953) or non-users (n = 3289) based on home medication records. Primary outcomes included aspiration, post-procedural oxygen requirement, hypotension, hospitalization, ICU admission, length of stay, and all-cause inpatient mortality. Multivariable logistic and negative-binomial regression models, incorporating an interaction term for anesthesia type, were adjusted for age, sex, body mass index, ASA class, and key comorbidities. Results: No aspiration events were reported in either group. GLP-1 RA use was associated with lower odds of post-procedural oxygen requirement (OR 0.43, 95% CI 0.25–0.76), hospitalization (OR 0.73, 95% CI 0.39–1.36), and mortality (0.1 vs. 0.9%, p = 0.014), and a shorter hospital stay (IRR 0.54, 95% CI 0.40–0.71). Rates of hypotension and ICU admission were similar between both groups. In anesthesia-stratified analysis among GLP-1 RA users, those receiving MAC/MS had higher odds of hospitalization compared with GA (OR 1.87, 95% CI 1.23–2.85, p = 0.003), whereas other outcomes were not significant. Conclusions: Pre-procedural GLP-1 RA therapy was not associated with increased peri-procedural complications. Although hospitalization was more frequent with MAC/MS, this difference did not extend to other clinically significant outcomes. Further prospective studies are needed to clarify the clinical implications of anesthesia choice. Full article

Epicardial adipose tissue (EAT), the visceral fat layer next to the myocardium, has become an important focus in heart failure with preserved ejection fraction (HFpEF). When enlarged and inflamed, EAT increases pericardial restraint, releases fibroinflammatory mediators, and disrupts myocardial energetics, thereby reproducing the high-pressure, exercise-intolerant HFpEF phenotype regardless of body mass index. Modern echocardiography, cardiac CT, and MRI, enhanced by artificial intelligence texture analytics, now enable precise depot-specific quantification, making EAT a measurable therapeutic target. Early interventional studies suggest that caloric restriction, bariatric surgery, SGLT2 inhibitors, GLP-1 receptor agonists, statins, PCSK9 antibodies, and colchicine can reduce EAT volume or alter its inflammatory profile, with concurrent improvements in haemodynamics and biomarkers. However, definitive outcome trials are still pending. Priority directions include standardising imaging cut-offs, mapping EAT immune–metabolic niches, and testing combined metabolic–inflammatory regimens to translate EAT modulation into precision therapy for HFpEF. This review aims to synthesise current mechanistic, diagnostic, and therapeutic insights on EAT in HFpEF and outline future research priorities. Full article

Leptin, an adipocyte-derived hormone, plays a central role in the regulation of energy homeostasis by acting on distinct hypothalamic nuclei. This review explores recent advances in our understanding of leptin’s region-specific actions within the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and lateral hypothalamus, highlighting their contributions to appetite regulation, energy expenditure, and neuroendocrine function. In the hypothalamic arcuate nucleus, leptin’s differential regulation of pro-opiomelanocortin and agouti-related peptide/neuropeptide Y neurons is now complemented by the identification of novel leptin-responsive neuronal populations—such as those expressing prepronociceptin, basonuclin 2, and Pirt—as well as a growing array of cellular and molecular modulators, including secreted factors like angiopoietin-like growth factor, zinc-α2-glycoprotein, and spexin, intracellular regulators such as Rap1, growth factor receptor-bound protein 10, and spliced X-box binding protein 1. In the ventromedial hypothalamus, leptin integrates with both peripheral (e.g., cholecystokinin) and central (e.g., pituitary adenylate cyclase-activating polypeptide) signals, while epigenetic mechanisms, such as those mediated by Jumonji domain-containing protein D3, regulate leptin receptor expression and sensitivity. The dorsomedial hypothalamus is increasingly recognized for coordinating leptin’s effects on metabolism, circadian rhythms, and respiration through distinct neuronal populations, including a subset of neurons co-expressing GLP-1 receptors that mediate leptin’s metabolic effects. In the lateral hypothalamus, leptin modulates reward-driven feeding via GABAergic neuronal populations—circuits that are particularly susceptible to disruption following early life trauma. Together, these insights reveal a sophisticated neurobiological framework through which leptin orchestrates systemic physiology. Understanding the heterogeneity of leptin signaling opens new avenues for restoring leptin sensitivity and developing personalized therapeutic strategies to combat obesity and related metabolic disorders. Full article

Type I collagen hydrogels are widely employed as scaffolds in tissue engineering due to their biocompatibility and ability to mimic the extracellular matrix (ECM). ECM viscoelasticity plays a critical role in regulating key cellular functions such as adhesion, proliferation, and differentiation. This study evaluates how collagen source and quality influence hydrogel architecture, mechanical properties, and keratinocyte behavior. Hydrogels were prepared at a concentration of 2.3 mg/mL using collagen from Advanced Biomatrix (AB, GLP grade) and Collagen Solutions (CS, GMP grade), and assessed for fibrillogenesis, rheological performance, and their ability to support stratified HaCaT keratinocyte cultures. AB-derived hydrogels exhibited higher porosity but lower mechanical resilience, characterized by a linear viscoelastic region (LVER) of 2.54%. In contrast, CS-derived hydrogels showed reduced porosity, denser fiber networks, and a higher LVER of 9.96%, indicating enhanced strain tolerance. HaCaT cells cultured on AB hydrogels showed diminished proliferation, metabolic activity, stratification, and expression of differentiation markers compared to those on CS hydrogels, which supported a more robust epidermal architecture. These findings highlight the critical role of collagen quality and mechanical characteristics on scaffold performance and epidermal tissue formation, emphasizing the need to optimize biomaterial properties for effective regenerative outcomes. Full article

Background/Objectives: The incidence of metabolic-dysfunction-associated steatotic liver disease (MASLD) is on the rise worldwide. The purpose of this paper is to review the current and emerging trends in the management and treatment of this condition. Methods: A comprehensive literature review was conducted using PubMed and GoogleScholar, focusing on articles published within the last ten years. Results: As the incidence of MASLD rises worldwide, it is becoming ever more important to call attention to disease prevention and progression. Although weight loss, diet, and exercise play a major role, certain therapies including GLP-1 receptor agonists, resmetirom, lanifibranor, and FGF-3 analogs are showing promise when treating patients with MASLD. As more drugs become available, it will be important to note how these medications change the global outlook of this disease. Conclusions: Overall, the treatment landscape of MASLD is rapidly changing. Several phase 3 trials have revealed promising data when it comes to improving liver fibrosis and histology. This shift in treatment will provide new hope for patients and clinicians when treating this challenging disease. Full article

Background: Short-chain fatty acids (SCFAs) are produced by the colon microbiome and bind to specific G-protein coupled receptors GPR 41 and GPR 43. Leptin and glucagon-like peptide 1 (GLP-1) are produced mainly in the intestinal lumen as a result of SCFAs binding to their receptors at this level. Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC), and their major complication, colorectal cancer (CRC), can disturb the dynamics of the colonic microenvironment thus influencing SCFAs production and effects. Our study aimed to investigate serum levels of SCFAs and SCFAs-mediated production of circulating leptin, GLP-1, and Nesfatin-1 in patients with IBD and CRC. Methods: A total of 88 subjects (29 with CRC, 29 with IBD, and 30 controls) were included in this pilot study. Serum SCFAs, leptin, Nesfatin-1, and GLP-1 levels were analyzed. Results: Nesfatin-1 levels were significantly higher in CRC patients (p < 0.05) compared to IBD and controls. Leptin levels were positively correlated with Nesfatin-1 levels in CRC, IBD, and control groups (CRC: R² = 0.6585, p < 0.01; IBD: R² = 0.2984, p < 0.01; Control: R² = 0.2087, p < 0.05). Serum SCFAs levels were negatively correlated with GLP-1 levels in CRC and IBD (CRC: R² = 0.3324, p < 0.01; IBD: R² = 0.1756, p < 0.05) and negatively correlated with Nesfatin-1 levels in CRC (R² = 0.2375, p < 0.05). Conclusions: These findings suggest that alterations in gut microenvironment may influence systemic metabolic regulators involved in appetite control and inflammation, potentially influencing IBD and CRC pathogenesis. This is the first study to evaluate the relationships between Nesfatin-1, leptin, GLP-1, and SCFAs in CRC and IBD patients; further research is needed to clarify their mechanistic links and therapeutic potential. Full article