Metabolic

Antipsychotic-related overweight and metabolic dysregulation are highly prevalent among patients with severe mental illness. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated substantial metabolic benefits in the general population, their efficacy and safety in antipsychotic-treated patients remain unclear. This review aimed to systematically evaluate the efficacy and safety of GLP-1RAs in patients with antipsychotic-related overweight and metabolic dysregulation. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GLP-1RAs in adults receiving antipsychotic treatment. PubMed, Web of Science, Embase, MEDLINE, the Cochrane Library, and ClinicalTrials.gov were searched from inception to September 13, 2026. Primary outcomes included changes in body weight, body mass index (BMI), HbA1c, and total cholesterol. Random-effects models were used to pool mean differences (MDs) and risk ratios (RRs). This study was registered with PROSPERO (CRD420261290294). Eight RCTs involving 535 randomized participants were included. GLP-1RAs treatment was associated with significant reductions in body weight (MD = -6.54 kg, 95% CI: -9.80 to -3.29, P < 0.001, I2 = 92%), BMI (MD = -2.34 kg/m2, 95% CI: -3.34 to -1.34, P < 0.001, I² = 85%), HbA1c (MD = -0.32%, 95% CI: -0.39 to -0.26, P < 0.001, I² = 52%), waist circumference (MD = -5.22 cm, 95% CI: -6.55 to -3.88, P < 0.001, I2 = 27%), visceral fat mass (MD = -0.31 kg, 95% CI: -0.46 to -0.16, P < 0.001, I2 = 11%), and LDL-C (MD = -0.16 mmol/L, 95% CI: -0.31 to -0.01, P = 0.03, I2 = 54%), whereas no significant effects were observed for total cholesterol, triglycerides, or HDL-C. Weight reduction was greatest with semaglutide, followed by liraglutide, and increased with longer treatment duration (both P for subgroup differences < 0.05). GLP-1RAs were associated with higher risks of nausea (RR = 1.61, 95% CI: 1.20 to 2.16), vomiting (RR = 2.10, 95% CI: 1.32 to 3.35), and constipation (RR = 2.34, 95% CI: 1.23 to 4.47), but not of diarrhea, serious adverse events (RR = 0.72, 95% CI: 0.49 to 1.06), all-cause discontinuation (RR = 1.05, 95% CI: 0.60 to 1.85), or discontinuation due to adverse events (RR = 2.14, 95% CI: 0.72 to 6.33). Psychiatric adverse events were infrequent and could not be pooled. GLP-1RAs significantly improve weight-related and glycemic outcomes in antipsychotic-treated patients, at the cost of an increased risk of gastrointestinal adverse events. Their psychiatric safety could not be established owing to sparse data. Longer-term trials with standardized safety reporting are warranted.

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterised by pulmonary vascular remodelling, right ventricular (RV) pressure overload, and ventricular metabolic reprogramming. Metformin has been proposed as a candidate therapy for PAH on the basis on encouraging preclinical results, most of which have been obtained in rat models and in single-sex cohorts. Its preventive effects in mice and its dependence on biological sex remain incompletely characterised. Based on the Sugen5416/hypoxia (SuHx) model, male and female mice were exposed to normoxia (Ctrl) or Sugen5416/Hypoxia (SuHx) conditions (PAH group) for 21 days, with two parallel groups, Ctrl + Met and PAH + Met, receiving metformin 0.25% w/v (effective dose 410-503 mg/kg/day) ad libitum in drinking water. The endpoints comprised cardiac cine and phase-contrast MRI, invasive RV systolic pressure (RVSP), Fulton index, [18F]-FDG PET, glucose and fatty acid related RT-qPCRs, histology and weekly measured body weight. These experimental data suggested that SuHx reliably induced RV mass gain and elevated RVSP in both sexes. Also, metformin did not attenuate the primary structural or haemodynamic features of the model in either sex. In fact, metformin triggers sex- and ventricle-specific responses detectable at multiple levels: a opposite transcriptional changes in RV's Glut4 between sexes, together with a coordinated downregulation of left ventricle (LV) fatty acid oxidation transcripts under both SuHx and metformin. Also, the histological analysis performed with WGA revealed that sex-specific cardiomyocyte hypertrophy phenotypes emerge only with metformin. Finally, the MRI determination of RV volumes and ejection fraction along with the pulmonary artery dilatation highlighted this sex-dysmorphism. Collectively, our data argue against a preventive benefit of metformin on the core SuHx-PAH phenotype in either male or female mice. Furthermore, they highlight cardiopulmonary and cellular markers that vary by sex and caution against the assumption that the beneficial effects of metformin in PAH models can be extrapolated without explicit confirmation stratified by sex.

This research was designed to assess the impact and underlying pathways of the root aqueous extract of Moghat root (MRE) on metabolic syndrome (MS). The extract's constituents were identified through HPLC analysis, followed by evaluation of its impact on lipid and glucose metabolism using in vitro and in vivo assays. In a high-fat high-carbohydrate diet, streptozotocin animal model-induced MS, MRE increased fat accumulation and diminished the genes expression included in lipogenesis. Moreover, the extract enhanced obesity, the resistance of insulin, the amounts of lipid, oxidative stress, and hepatic function in MS rats after a 4 weeks intervention orally with the extract at 100 and 200 mg/kg related to metformin at 200 mg/kg after verification of diabetes. MRE decreased the expression of hepatic INSR, Srebf1, mTOR, PI3K, AKT, NF-κβ, and IL-6 through the PI3K/AKT/mTOR signaling pathway to inhibit inflammation and lipid accumulation and achieve its hypolipidemic effect. Moreover, MRE decreased the expression of MYD88 and p38 MAPK which was confirmed in liver tissue by using IHC analysis. Our data proposed that MRE could improve MS by improving lipid metabolism via numerous pathways and can be progressed into dietary supplements for the correction of MS.

Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia arising from insulin resistance or impaired insulin secretion. Conventional and commercially available effective antidiabetic drugs are often associated with adverse effects and reduced efficacy over prolonged use, highlighting the need for safer and plant-based alternatives. Persea americana seed extract (PSE) has antidiabetic potential but suffers from non-specific distribution and poor bioavailability, thus limiting its clinical application. This study developed and evaluated the poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating Persea americana seed extract (PSENP) to enhance therapeutic efficacy and delivery. Nanoparticles were characterized for zeta size, zeta potential, transmission electron microscopy (TEM), stability and their phytochemical composition, with HPLC confirming the presence of bioactive compounds including quercetin, syringic acid, and gallic acid. In-vivo, forty wistar rats were allocated into five groups: normal control, diabetic control, metformin-treated, PSE-treated, and PSENP-treated. Biochemical parameters were evaluated including fasting blood glucose, insulin (serum level), lipid profile, oxidative stress biomarkers (superoxide dismutase, catalase), and inflammatory cytokines (IL-6, TNF-α). Histopathological examination of pancreatic tissue and safety evaluations for kidney and liver were performed. Moreover, In-silico study demonstrated the strong binding affinity between quercetin and α-glucosidase, thus supporting the glucose-lowering role of quercetin. The PSENP administration resulted in statistically significant glycemic control, enhanced antioxidant activity of enzymes, improved lipid profile, reduced pro-inflammatory cytokines, and preservation of architecture of pancreas, with no renal and hepatic toxicity. The findings of the study indicated that PLGA-based nanoformulation of P. americana seed extract provides a promising therapeutic strategy for diabetes management and its oxidative and inflammatory complications.

Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple local intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) as a model system, we identify the orphan transporter MCT6/SLC16A5 as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe in vitro, mediates Lac-Phe efflux in cells, and is required for maintaining normal circulating Lac-Phe levels in vivo, particularly following metformin treatment or high-intensity exercise. High-fat-diet-fed mice with global or intestinal epithelial-specific deletion of MCT6 exhibit resistance to metformin-associated weight loss. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-knockout (KO) mice. These data connect MCT6 to Lac-Phe and gut glycolytic flux and underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy characterized by a dismal prognosis and profound resistance to conventional therapies. Emerging evidence highlights systemic metabolic dysfunctions including obesity, dyslipidemia, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty pancreatic disease (NAFPD) as critical drivers of PDAC initiation, progression and chemoresistance. This review integrates current knowledge on the intricate interplay between metabolic alterations and PDAC biology, focusing on the therapeutic and chemopreventive potential of repurposed metabolic modulators (specifically statins and antidiabetic agents) and novel metabolic pathway inhibitors currently under clinical evaluation. Statins exert prominent antitumor effects in preclinical models by disrupting the mevalonate pathway, impairing Ras prenylation, and reprogramming cholesterol metabolism; however, epidemiological data regarding risk reduction remain inconsistent. Parallel to lipid pathways, glucose homeostasis dictates tumor behavior. T2DM acts as both a potent risk factor and an early paraneoplastic indicator through new-onset diabetes. Among antidiabetic drugs, metformin attenuates PDAC progression via insulin-lowering and AMPK-mediated pathways, though its survival benefits are often obscured in clinical trials by methodological challenges. Conversely, hyperinsulinemia driven by exogenous insulin or secretagogues exacerbates PDAC risk, while incretin-based therapies yield conflicting outcomes. Notably, novel strategies targeting metabolic vulnerabilities, such as SGLT2 inhibition combined with metformin, show promise in targeting chemoresistant, nutrient-deprived tumor zones. Ultimately, integrating metabolic profiling, prescription history, and molecular biomarkers into clinical practice is essential to advance risk stratification and precision oncology. Overcoming tumor metabolic plasticity in contemporary clinical trials will require a shift from single-node therapies towards rational, biomarker-guided combination strategies.

Weight loss improves obesity-associated metabolic dysfunction, yet resolution of adipose inflammation may be incomplete and can reappear during weight regain. Whether high-dose semaglutide induces sustained immunological remodeling of adipose and hepatic tissues during weight cycling remains unclear. Male C57BL/6 mice with diet-induced obesity were treated with semaglutide (60 nmol/kg, intraperitoneally, every 3 days) or vehicle for 3 weeks, followed by drug withdrawal under continued high-fat diet feeding. Body weight, body composition, and glucose homeostasis were assessed during treatment and after weight regain. Inflammatory changes in visceral and subcutaneous adipose tissue and liver were analyzed by flow cytometry, histology, immunofluorescence, and gene expression profiling. Semaglutide induced rapid fat mass-selective weight loss with preservation of lean mass and significantly improved fasting glucose, insulin levels, insulin sensitivity, and glucose tolerance. During treatment, visceral adipose tissue exhibited marked reductions in pro-inflammatory macrophages, crown-like structures, and inflammatory gene expression, whereas subcutaneous adipose tissue was minimally affected. Following withdrawal, mice rapidly regained weight and adiposity. Visceral adipose inflammation fully reverted, with macrophage infiltration and inflammatory gene expression comparable to chronically obese controls. Hepatic steatosis and inflammatory markers similarly returned to obese levels. Despite this tissue-level reversion, fasting glycemia and insulin levels remained partially improved. High-dose semaglutide induces robust metabolic improvement and transient suppression of visceral adipose inflammation during active treatment; however, these inflammatory changes are not sustained after withdrawal and largely revert with weight regain. In contrast, partial improvement in fasting glycemia persisted, suggesting differential durability between systemic metabolic adaptation and local inflammatory remodeling during pharmacological weight cycling.

Graves' orbitopathy (GO) is characterized by proliferation and differentiation of orbital fibroblasts. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for metabolic disorders and have been reported to modulate cell proliferation and differentiation. The present study aimed to examine the effects of GLP-1RAs on key fibroblast-mediated pathogenic processes relevant to GO using human orbital fibroblasts. Orbital fibroblasts were isolated from patients with GO and non-GO controls. Cells were treated with the GLP-1RAs liraglutide (100 nM) or semaglutide (200 nM). Fibroblast proliferation was assessed by nuclear counting, lipid accumulation was evaluated by Oil Red O staining of oil droplets, and myofibroblastic differentiation was assessed by α-smooth muscle actin (α-SMA) immunostaining. Hyaluronan production was measured by ELISA. GLP1R mRNA expression was examined using reverse transcription quantitative PCR. Among the outcomes assessed, liraglutide significantly reduced lipid accumulation in GO-derived orbital fibroblasts, whereas semaglutide showed a nonsignificant trend in the same direction. Neither liraglutide nor semaglutide significantly altered lipid accumulation in non-GO fibroblasts. Importantly, neither GLP-1RA increased fibroblast proliferation, TGF-β-induced myofibroblastic differentiation, or IL-1β-induced hyaluronan production in GO or non-GO fibroblasts under the tested conditions. GLP1R mRNA was not reliably detected, and the underlying mechanism remains uncertain. Taken together, this in vitro study showed a significant reduction in lipid accumulation following liraglutide treatment in GO-derived orbital fibroblasts, while semaglutide showed a trend in the same direction that did not reach statistical significance. Neither agent enhanced fibroblast proliferation, myofibroblastic differentiation, or hyaluronan production under the tested conditions. These findings suggest a potentially favorable biological profile of liraglutide in GO and warrant further studies to clarify the underlying mechanisms and assess its clinical relevance, particularly in patients with metabolic comorbidities.

Obesity represents a global public health burden with continuously increasing prevalence over recent decades. Combination regimens pairing semaglutide (Sema) with additional therapeutic agents have emerged as a major focus for anti-obesity research. In diet-induced obese (DIO) mice, we evaluated whether oxytocin (Oxt, 3 and 5 mg·kg-1), long-acting oxytocin (la‑Oxt), caffeine, or butyrate could potentiate the anti-obesity efficacy of Sema. We further compared hypothalamic neuronal activity and plasma metabolomic profiles following Sema treatment against dietary restriction (DR), an established intervention for weight loss and metabolic improvement. Whereas Oxt, la‑Oxt, and caffeine did not augment Sema-mediated body weight reduction, butyrate produced significant potentiation of Sema's anti-obesity effects. Either Sema monotherapy or Sema-butyrate co-administration elevated the number of c-Fos-positive cells in the paraventricular nucleus (PVN) of the hypothalamus. By contrast, DR decreased PVN c-Fos-positive cell number. Butyrate amplified Sema-elicited activation of PVN neuronal activity. Plasma metabolomics revealed limited overlap between the pharmacological interventions and DR, demonstrating orthogonal metabolic responses. These findings identify the Sema-butyrate combination as a promising anti-obesity strategy, and demonstrate that Sema and DR exert divergent effects on both hypothalamic neuronal activity and plasma metabolite levels.

Glucagon-like peptide-1 (GLP-1) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists show high efficacy in treating obesity and metabolic dysfunction-associated liver diseases, conditions that collectively represent one of the most challenging One Health crises of our time. However, their hepatic molecular mechanisms remain poorly understood. This study defined targeted hepatic proteomic signatures associated semaglutide (GLP-1 agonist) and tirzepatide (dual GLP-1/GIP) in diet-induced obese (DIO) male C57BL/6J mice using an liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted-proteomics approach and validated using western blotting. After 18 weeks of high-fat diet (HFD), obese mice received once-daily subcutaneous semaglutide (10 nmol/kg), tirzepatide (3 nmol/kg), or vehicle for 4 weeks. Tirzepatide produced greater systemic efficacy (24.6% body weight and 30.3% fat mass reduction, preserved lean mass, improved glucose homeostasis), yet both drugs yielded overlapping targeted hepatic proteomic signatures despite different receptor pharmacology. Both drugs significantly downregulated CD36 and CPT1A fatty acid importers for β-oxidation without altering lipogenic enzymes (FASN, ACC1, ACLY, ACSS2) or glucose-handling proteins (PDH, GLUT2). These findings suggest a substrate limitation over enhanced β-oxidation or broad lipogenesis-suppression, suggesting GLP-1 receptor activation is sufficient for the core liver response and GIP co-agonism mainly augments extrahepatic effects. From a One Health proteomics perspective, CD36/CPT1A anchored targeted proteomic signature provides a mechanistically informed benchmark for evaluating novel GLP-1 and non-GLP-1 investigational therapeutics.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by a complex pathophysiology driven by intertwined metabolic and hepatic pathways, enabling the identification of multiple therapeutic targets and a rapidly expanding drug development pipeline. This review summarizes the current and emerging therapeutic landscape for MASLD and discusses key challenges for clinical implementation. The imminent availability of several new therapies is expected to pose important clinical challenges, particularly in accurately identifying patients most likely to benefit. Currently, resmetirom and semaglutide are the only two drugs conditionally approved for patients with fibrosis stages 2-3, pending final phase 3 outcomes, and represent the main liver-directed and metabolic-focused therapeutic strategies, respectively. Treatment selection should follow a phenotype-based approach integrating metabolic profile and liver disease stage. Non-invasive tests are central for assessing treatment eligibility; however, strategies incorporating metabolic risk profiling and longitudinal monitoring will be essential to optimize real-world management of MASH.

Despite being defined pathologically by amyloid-β plaques, chronic neuroinflammation and neurofibrillary tangles, the drugs that target these processes directly (lecanemab and donanemab) have only modest effects on the clinical course of Alzheimer's disease (AD) and significant safety concerns have been identified, so there is renewed interest in upstream, systemic contributors to disease. This review aims to provide a synthesis of the latest mechanistic and clinical evidence that gut microbiota dysbiosis is associated with Alzheimer's disease with a specifically immunopharmacological focus. We will explore how the gut-brain axis pathways (vagal, immune, endocrine and microbial-metabolite signaling) converge to trigger microglial and astrocytic activation via toll-like receptor 4/NF-κB and complement-primed NLRP3 inflammasome signaling, which is also directly activated by amyloid-β and tau. Then we review the immunopharmacological interventions intended to break this axis - probiotic supplementation (some consistent benefit - although mild) and sodium oligomannate, with strong preclinical and case report signals that need human trials (in 2026) and polyphenols and GLP-1 receptor agonists, which have a persistent disconnect between mechanistic promise and clinical efficacy, including a definitive null result for semaglutide in 2026. Translative directions are addressed to nanotechnology-based delivery systems for improving bioavailability and blood-brain barrier penetration, as well as emerging precision-medicine, AI-driven approaches in the selection of treatments based on microbiome information. It is our opinion that because the gut-brain-immune axis is a mechanistically supported and potentially highly scalable therapeutic target, complementary to amyloid and tau therapies, the development of future therapies should match the inflammatory, metabolic and microbial phenotypes.

Across the full spectrum of major clinical trials evaluating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for obesity management, nausea consistently emerges as the most documented adverse effect, yet the methods used to capture it have received little scrutiny relative to their clinical importance. This narrative review traces how nausea was actually measured across the pivotal liraglutide (SCALE), semaglutide (STEP) and tirzepatide (SURMOUNT) obesity trial programmes, and situates those methods against the standards set out in the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) and the United States Food and Drug Administration's Patient-Focused Drug Development guidance. Across all three drug classes, nausea was ascertained through investigator-recorded, spontaneously reported adverse events coded to the Medical Dictionary for Regulatory Activities (MedDRA), a pharmacovigilance framework built for a different purpose than symptom characterization, rather than through any validated, symptom-specific patient-reported outcome instrument. This observation gains further importance when considered alongside a second, less widely recognized fact: these same trial programmes devoted substantial methodological effort to developing and implementing a rigorous, quality of life measure specifically for obesity, the Impact of Weight on Quality of Life-Lite Clinical Trials Version in addition to the Short Form-36 and EuroQol-5D. We argue that this asymmetry, more than any single mismeasurement, helps explain why real-world persistence with these agents falls so far short of what trial-reported tolerability figures would predict, and we outline what a fit-for-purpose metabolic nausea instrument would need to capture that adverse-event surveillance cannot.

Metformin-associated lactic acidosis (MALA) is an uncommon but potentially fatal complication of metformin therapy in which extracorporeal treatment may be required for severe acidemia or markedly elevated lactate levels. We report the case of a 47-year-old man with type 2 diabetes mellitus treated with metformin who presented with encephalopathy, profound hypoglycemia, hypothermia, and severe high-anion-gap metabolic acidosis. Lactate was 24.1 mmol/L and peaked at 25.5 mmol/L, while serum total carbon dioxide was <5 mmol/L. Despite the severity of the metabolic disturbance, serum creatinine was 1.18 mg/dL on presentation, although he had experienced recent acute kidney injury. Toxicologic evaluation did not identify an alternative major cause of the acidosis, although urine testing was positive for amphetamine/methamphetamine, suggesting a potentially multifactorial process. The patient received supportive care and repeated intravenous sodium bicarbonate before extracorporeal treatment. Lactate had already declined from 25.5 to 16.0 mmol/L before dialysis began, while acidemia partially improved after bicarbonate administration. High-efficiency intermittent hemodialysis (iHD) was initiated for severe suspected MALA as the rapid initial phase of extracorporeal treatment, followed by continuous venovenous hemodialysis to provide sustained therapy toward biochemical treatment targets; hemodynamic intolerance during iHD further supported the transition. Lactate subsequently normalized without rebound, and kidney function recovered without further renal replacement therapy. This case highlights that severe suspected MALA may warrant extracorporeal treatment despite relatively preserved creatinine at presentation and illustrates the importance of aligning biochemical trends with treatment timing when assessing the contribution of dialysis to lactate and acid-base correction.

Obesity and diabetes can increase perioperative risk, especially in posterior cervical spine surgery. Bariatric surgery provides durable weight loss but carries surgical and nutritional risks, while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are non-surgical alternatives that may optimize weight and metabolic status preoperatively. Evidence evaluating GLP-1 therapy in spine surgery is limited. To evaluate associations between preoperative GLP-1 RA use and perioperative, short-term, and long-term complications following posterior cervical spine surgery in patients with type 2 diabetes, including comparisons to matched controls and patients with prior bariatric surgery. Retrospective database analysis. Patients with type 2 diabetes treated with metformin undergoing posterior cervical spine surgery between 2010 and 2023 were identified in the PearlDiver Mariner database. Patients were stratified into GLP-1 users, non-GLP-1 controls, and patients with prior bariatric surgery. Physiologic measures included perioperative outcomes and postoperative complications assessed at 90 days and 2 years, including pneumonitis, surgical site infection, revision surgery, readmission, nutritional deficiency, and other medical and surgical complications. The PearlDiver Mariner database was queried for eligible patients. Propensity-score matching adjusted for baseline cohort differences. Outcomes included perioperative, 90-day, and 2-year complications, with BMI-stratified analyses conducted within the matched GLP-1 and control cohort. Benjamini-Hochberg false discovery rate correction was applied for multiple comparisons. GLP-1 users demonstrated lower odds of perioperative complications, including pneumonitis (OR 0.57; 95% CI 0.43-0.75; p <0.001). At 90 days, GLP-1 users experienced reduced odds of surgical site infection (OR 0.72; 95% CI 0.65-0.80; p <0.001), revision surgery (OR 0.33; 95% CI 0.29-0.36; p <0.001), readmission (OR 0.82; 95% CI 0.76-0.90; p <0.001), and other complications. At 2 years, GLP-1 users had lower odds of revision surgery (OR 0.31; 95% CI 0.28-0.34; p <0.001), nutritional deficiency (OR 0.62; 95% CI 0.59-0.66; p <0.001), and other complications. Exploratory BMI-stratified analyses suggested similar directional trends across overweight and obese patients. Comparisons to prior bariatric surgery patients showed no significant differences. Preoperative GLP-1 RA use was associated with reduced perioperative, short-term, and long-term complications following posterior cervical spine surgery in patients with type 2 diabetes. When compared with a matched bariatric surgery cohort, no significant differences in postoperative outcomes were observed. These findings should be interpreted in the context of potential residual confounding and support further prospective investigation of GLP-1 therapy as a strategy for preoperative metabolic optimization in posterior cervical spine surgery. Cervical Spine, Outcomes Research, Risk Factors, Perioperative Complications.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with reproductive, metabolic, and neurobehavioural abnormalities, including anxiety, depression, and cognitive impairment. Omega-3 fatty acids have anti-inflammatory and neuroprotective properties that may ameliorate these complications. To evaluate the effects of metformin, fish oil, and flaxseed oil on anxiety-like behaviour, depressive-like behaviour, locomotor activity, and cognitive function in a letrozole-induced PCOS mouse model. Thirty female Swiss albino mice were divided into five groups: Control, PCOS, PCOS + Metformin, PCOS + Flaxseed Oil, and PCOS + Fish Oil. PCOS was induced with letrozole (2 mg/kg, orally). These neurobehavioral tests were conducted: Open Field Test, Elevated Plus Maze, Morris Water Maze, Forced Swim Test, and Actophotometer Test. Data were analysed using one-way ANOVA followed by Tukey's post hoc test. The PCOS Group exhibited anxiety- and depression-like behaviours and impaired spatial learning and memory compared with controls. Treatment effects varied across behavioural domains. Fish oil improved selected behavioural outcomes, particularly immobility and locomotor activity, whereas effects on spatial memory and other measures were less consistent. Flaxseed oil and metformin showed moderate beneficial effects on the behaviour of PCOS mice. In letrozole-induced PCOS mice, metformin, flaxseed oil, and fish oil showed distinct impacts on neurobehavioral outcomes. The results indicate that several behavioural changes linked to experimental PCOS may be modulated by omega-3-rich oils; nevertheless, additional mechanistic and clinical research is required to determine their therapeutic significance.

Mitochondrial function is a central determinant of cardiomyocyte survival, yet mitochondrial pharmacology remains under-integrated into cardiovascular and antidiabetic drug classification, safety assessment, and therapeutic decision-making. Many cardiometabolic drugs exert direct or indirect effects on mitochondrial bioenergetics, redox balance, calcium handling, quality control, and genome stability effects that can confer protection in some contexts while precipitating toxicity in others. In diseased myocardium, where mitochondrial reserve is constrained by ischemia, metabolic stress, ageing, or heart failure, these drug-mitochondria interactions frequently dictate clinical benefit or harm beyond the nominal drug class. This review synthesises the mitochondrial actions of widely used cardiovascular and antidiabetic therapies, including statins, renin-angiotensin-aldosterone system inhibitors, β-blockers, metformin, sodium-glucose cotransporter-2 inhibitors, and incretin-based agents, across acute and chronic exposure windows. We integrate key mechanistic domains encompassing electron transport chain modulation, redox and cofactor reprogramming, calcium permeability transition coupling, mitochondrial dynamics, mitophagy, and stress signalling, and relate these signatures to clinically relevant cardiometabolic disease contexts. We propose a unifying framework in which mitochondrial reserve capacity and quality control competence function as the central decision node determining whether pharmacologic mitochondrial engagement is adaptive or injurious. Finally, we outline principles for mitochondria-conscious prescribing, risk stratification, and drug development, and propose that systematic incorporation of mitochondrial endpoints into clinical trials and safety pipelines is essential for advancing precision cardiometabolic therapy.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual incretin receptor agonists such as glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) are increasingly being prescribed for type 2 diabetes and obesity due to their efficacy in glycaemic control, weight loss and cardiovascular risk reduction. Emerging pharmacovigilance data suggest potential oral adverse effects, including xerostomia, dysgeusia, oral hypoesthesia and throat discomfort. Therefore, alterations in salivary function may compromise oral homeostasis and increase susceptibility to dental caries, periodontal inflammation and mucosal irritation. Additionally, metabolic and inflammatory changes mediated by GLP-1 and GIP may indirectly affect oral tissues. However, current evidence remains limited and inconsistently reported. Further research is needed to investigate the prevalence, underlying mechanisms and clinical significance of oral manifestations associated with GLP-1RA and GLP-1/GIP dual receptor agonist medications, as well as to explore the need for individualised management strategies and more frequent monitoring for patients receiving these therapies. This protocol describes the methodology for a future scoping review to be conducted in accordance with the JBI reporting guidelines. Studies addressing incretin-based medications and their implications for oral health will be eligible for inclusion in the review, with no restrictions on language or publication date. The following databases will be searched: Cochrane, LILACS, PubMed/MEDLINE, Scopus and Web of Science. Additional literature will be identified through Google Scholar and ProQuest Dissertations & Theses Global. The snowballing technique and consultation with experts in the field will be used to identify additional relevant studies. The findings will be presented through a narrative synthesis, supported by tables, graphs and maps. When data are available, exploratory comparisons will be performed according to therapeutic indication (type 2 diabetes or obesity) and pharmacological class (GLP-1RAs and GLP-1/GIP dual receptor agonists), with particular attention to tirzepatide and other incretin-based agents, to explore potential differences in reported oral manifestations. In particular, studies involving different GLP-1RA and GLP-1/GIP dual receptor agonists agents (eg, semaglutide, liraglutide and tirzepatide) may be compared to explore potential differences in reported oral manifestations. These comparisons will be conducted descriptively, considering variations in dosage, treatment duration and pharmacological class when such information is reported. This protocol has been registered prospectively on the Open Science Framework (DOI:10.17605/OSF.IO/NWTCS). This scoping review protocol does not require ethics approval, as it only describes the methodological aspects of a future scoping review and uses secondary data from previously published studies. The findings of the review will be disseminated through publication in a peer-reviewed journal and presentations at scientific conferences. As this study is a protocol for a scoping review and does not involve human participants or identifiable data, ethics committee approval was not required.

Obesity has reached epidemic proportions in South Asia, contributing significantly to metabolic diseases and economic burdens. Newer antiobesity medications (AOMs), such as semaglutide and tirzepatide, show promising efficacy but face barriers such as high costs and limited familiarity among healthcare professionals (HCPs) in low- and middle-income countries (LMICs). This study explored perceptions, prescribing practices, efficacy, safety concerns, and barriers to AOM use among HCPs managing obesity in South Asia. A cross-sectional online survey was conducted from May to September 2025 among 552 HCPs (physicians, endocrinologists, bariatric surgeons, nephrologists, gastroenterologists, and dieticians) specializing in obesity care, recruited via social media groups using convenience sampling. The questionnaire, developed from prior surveys and pilot-tested, assessed knowledge, attitudes, and practices regarding AOMs. Descriptive analysis was performed using SPSS version 21. Of 552 responses, 86.4% were from India. Endocrinologists (62.9%) and internists (21.6%) dominated, with varied experience levels. Key factors influencing prescriptions included efficacy (83%), affordability (75.9%), and safety (58.9%). Reported efficacy was high with 51.7% of the patients achieving > 10% weight loss. Barriers encompassed high costs (93.8%), side effect fears (46.2%), and poor adherence (41.3%). Biosimilars were available to 52.7%, with 78.6% of HCPs open to them if efficacy/safety matched originators. South Asian HCPs recognize AOMs' transformative potential but are hindered by costs, safety, and access. Biosimilars could enhance equity, but require robust data and regulation. Targeted education, reimbursement policies, and region-specific evidence are essential to optimize AOM integration in obesity management.

Explore/exploit decision-making is a crucial component of motivated behavior. Explore/exploit behaviors are related to disparate cognitive and reward-related functions and have been implicated in multiple neuropsychiatric conditions, including major depressive disorder (MDD). Several mediators of explore/exploit decision-making have been proposed; metabolic mechanisms have been theorized to potentially affect its underlying processes. Here, we examined the effects of a GLP-1 receptor agonist (GLP-1RA), semaglutide, on explore/exploit behavior in patients with MDD, using a four-armed restless bandit task. In this secondary analysis of a randomized clinical trial, 72 participants with MDD were randomized either to oral semaglutide (n = 35) or placebo (n = 37), and completed the bandit task at baseline and following 16 weeks of treatment. Explore/exploit decision-making was assessed using computational modeling of choice behavior, with a trial-by-trial reinforcement-learning model. Treatment with semaglutide resulted in increased exploitation (i.e. choosing the option with the highest expected reward) (Average Treatment Effect [ATE] = 0.0242, p < 0.001), directed exploration (i.e. exploring a choice with higher uncertainty) (ATE = 0.0619, p = 0.013), and perseveration (i.e. the value-independent tendency to repeat the previous action) (ATE = 0.3017, p = 0.013). These effects were moderated by, but ultimately independent of, baseline characteristics and weight loss during the trial. Treatment with semaglutide modulated explore/exploit behaviors in patients with MDD. These results highlight the role of metabolic mechanisms in decision-making processes in MDD and expand knowledge of the potential neuropsychiatric effects of GLP-1RAs.