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Evaluation of incretin levels in patients with prolactinoma.

Endokrynol Pol

Gökçe Altunay Vurğun, Nusret Yılmaz, Sebahat Özdem +1 more

Prolactin has been shown to play an important role in the regulation of glucose metabolism. The present study aimed toevaluate incretin hormones in patients with prolactinoma.

Clinical Advances in Heart Failure with Preserved Ejection Fraction: A Systematic Review of Therapeutic and Mechanistic Evidence.

Vasc Health Risk Manag

Razieh Parizad, Juniali Hatwal, Mohammadreza Taban Sadeghi +4 more

Heart failure with preserved ejection fraction (HFpEF) has emerged as the predominant of heart failure (HF), particularly among aging populations and individuals with a high burden of comorbidities. Its underlying pathophysiological mechanisms are complex, multifactorial and, heterogeneous.

Racial and ethnic variations of metabolic indicators associated with childhood obesity: a comparative cross-sectional study.

Int J Obes (Lond)

Jing Wu, Zhenran Xu, Li Xi +3 more

Susceptibility to adult metabolic diseases varies significantly across ethnicities. Asian adults exhibit elevated risks associated with obesity at lower body mass index (BMI) levels; whether similar patterns occur in pediatric populations remains unclear. This study aimed to evaluate how metabolic indicators associated with childhood obesity vary across diverse racial/ethnic groups.

Impact of Fibrotic Metabolic Dysfunction-Associated Steatohepatitis as a New Indication on Semaglutide Eligibility in the US Adult Population.

Gastro Hep Adv

Laurens A van Kleef, Maurice Michel, Mesut Savas +9 more

Semaglutide, a glucagon-like peptide-1 receptor agonist, is effective in the treatment of fibrotic (F2-F3) metabolic dysfunction-associated steatohepatitis (MASH) and has recently received accelerated Food and Drug Administration approval. However, the extent to which this new indication expands treatment eligibility beyond existing approvals for type 2 diabetes mellitus (T2DM) and obesity remains unclear.

Right Ventricular-Pulmonary Artery Coupling in Patients With Atrial Fibrillation and Changes After Catheter Ablation.

J Am Heart Assoc

Kazutoshi Hirose, Koki Nakanishi, Masao Daimon +17 more

Atrial fibrillation (AF) is a predominant risk factor for heart failure, even in patients with preserved left ventricular ejection fraction. Emerging evidence suggests the significance of right ventricular-pulmonary artery (RV-PA) uncoupling in heart failure occurrence. We aimed to elucidate the prevalence and associated factors of RV-PA uncoupling and the efficacy of catheter ablation (CA) for RV-PA adaptation in patients with AF without history of heart failure.

Ageing and the lymphatic system: Implications for immunity, brain health, and possible therapeutic interventions.

Ageing Res Rev

M N Rojas Velazquez, E Gousopoulos, S Wolf +2 more

The lymphatic system is essential for maintaining interstitial fluid balance, supporting immune surveillance, and clearing metabolic waste, yet its role in ageing has only recently come into focus. With age, lymphatic vessels and lymphoid organs undergo structural and functional decline, leading to impaired transport, disrupted immune cell trafficking, and chronic low-grade inflammation. These changes contribute to systemic inflammaging and are increasingly implicated in cardiovascular disease, metabolic dysfunction, and neurodegenerative disorders. In the central nervous system, deterioration of the glymphatic and meningeal lymphatic systems compromises cerebrospinal fluid circulation and the clearance of amyloid-β, tau, and other metabolites, thereby accelerating cognitive decline. In this review, we examine the molecular and cellular mechanisms that underline lymphatic ageing, including junctional remodeling, extracellular matrix stiffening, altered lymphangiogenic signaling, and endothelial senescence. We critically assess the consequences of lymphatic dysfunction for systemic and brain health, highlighting unresolved controversies such as the extent to which lymphatic changes are primary drivers of pathology, the limitations of rodent models and indirect imaging readouts, and the lack of ageing-resolved single-cell maps in human tissues. Finally, we discuss therapeutic avenues ranging from antioxidant and pro-lymphangiogenic strategies to lifestyle interventions and reconstructive microsurgery. Together these insights position the lymphatic system as a central, yet underexplored, determinant of resilience in ageing and a promising target for future gerotherapeutic interventions.

Cellular senescence and metabolic aging in type 2 diabetes: mechanistic insights and translational implications.

Front Endocrinol (Lausanne)

Ammaar Riyaz Syed, Radwan Abdulaziz Aloti, Bassam Jehad Awad +4 more

Type 2 diabetes mellitus (T2DM) is traditionally conceptualized as a disorder of insulin resistance and β-cell dysfunction driven by metabolic overload. Increasing evidence now implicates cellular senescence-a stress-induced state of durable cell-cycle arrest accompanied by a pro-inflammatory senescence-associated secretory phenotype (SASP)-as a biologically distinct contributor to metabolic dysfunction. Senolytic therapies, which selectively eliminate senescent cells by targeting senescent cell anti-apoptotic pathways (SCAPs), have therefore emerged as potential disease-modifying interventions.

[Expression of Concern] Insulin-like growth factor-1 receptor knockdown enhances radiosensitivity via the HIF-1α pathway and attenuates ATM/H2AX/53BP1 DNA repair activation in human lung squamous carcinoma cells.

Oncol Lett

Xiaoxing Liu, Haiyan Chen, Xin Xu +8 more

Dual roles of syndecan-4 in regulating chicken fibrosis in vitro.

Front Physiol

Lucie Pejšková, Nina Therese Solberg, Marianne Lunde +3 more

Wooden Breast (WB) is a myopathy affecting the skeletal breast muscle (Pectoralis major) in broiler chickens and is characterized by muscle fiber damage and varying degrees of fibrosis, ECM remodeling and inflammation. Several key factors such as pro-inflammatory cytokines like TGF-β1 and IL-1β, drive fibrosis in WB myopathy. We have previously shown that the expression of syndecan-4 (SDC4), a transmembrane proteoglycan, was increased in WB poultry skeletal muscle tissue. Furthermore, the ectodomain shedding of SDC4 by matrix metalloproteinases (MMPs) differed in the skeletal muscle satellite cells from isolated affected chickens compared with normal. While SDC4 has been previously implicated as a key driver for regulating myofibroblast activity in mechanically induced fibrosis in cardiac tissue, its specific role and shedding activity in chicken fibroblasts in relation to WB myopathy remain poorly understood.

Antimicrobial peptides in malaria and tuberculosis management: a systematic review of emerging evidence.

Int Immunopharmacol

Neha Sylvia Walter, Varun Gorki, Bikash Medhi +1 more

AMPs (Antimicrobial peptides) are small molecules that are crucial components of biological activities, viz wound healing, angiogenesis, antimicrobial activity, immune regulation, and exhibit anticancer properties. This systematic review summarizes the origin, sequence, efficacy, and structure-activity mechanisms of AMPs against tuberculosis and malaria, the world's leading killer infectious diseases, employing the AMP database (APD3) (till June 2025) and PubMed search (January 1965 to June 2025). The comprehension is well addressed by covering the inhibitory activity, SAR (structure-activity relationships), and action mechanisms of AMPs (natural and synthetic) against Mycobacterium tuberculosis and Plasmodium spp., as both pathogens exhibit multidrug resistance. The review also illustrates how these specific motifs, along with their properties such as hydrophobicity, charge, or amphipathicity, influence the AMPs activity against the pathogens. Moreover, challenges in the AMPs use and the way forward, including the recent breakthroughs employing nanocarriers, inhalable formulations for TB, and targeted erythrocyte delivery for malaria, are also highlighted. AMPs have illustrated promising anti-TB and antimalarial efficacy owing to their unique structure and novel mode of action, despite exhibiting varying extents of toxicity. Anti-malarial AMPs are grouped in defensins and cecropins, while the majority of natural anti-TB AMPs are classified as bacteriocins, defensins, and cathelicidins. Synthetic AMPs, in contrast, are designed to enhance activity and selectivity while reducing toxicity and the development of resistance. AMPs have α-helical, β-sheet, or random-coil structures and are cationic, amphipathic, and highly hydrophobic, attributes that contribute to observed anti-TB and anti-malarial potential. A comprehensive understanding of AMP's structure and function, along with the use of artificial intelligence (AI) and machine learning, can provide impetus for AMP therapy as an alternative to tackle tuberculosis and malaria.

Real-World Effectiveness and Safety of Escalating Once-Weekly Semaglutide from 0.5 to 1.0 mg in Type 2 Diabetes.

Diabetes Ther

Genki Sato, Hiroshi Uchino, Kota Takuma +5 more

Real-world data on escalation of once-weekly semaglutide from 0.5 to 1.0 mg remain limited. Therefore, we aimed to evaluate the effectiveness and safety of this dose escalation in routine clinical practice.

Emerging natural products against obesity and metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis: Direct target discovery and mechanistic insights.

Pharmacol Rev

Wei Hu, Meng Gu, Huibo Li +5 more

Obesity is a multifactorial metabolic condition characterized by dysregulated lipid accumulation and systemic energy imbalance with escalating global prevalence. This chronic disease drives a spectrum of life-threatening comorbidities, including metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), which now represent a primary cause of liver-related morbidity and transplantation. Both conditions share pathophysiological underpinnings such as insulin resistance, chronic inflammation, and mitochondrial dysfunction, creating a vicious cycle where obesity exacerbates hepatic steatosis and fibrosis. Although US Food and Drug Administration-approved antiobesity agents such as glucagon-like peptide-1 receptor agonists (eg, semaglutide) demonstrate weight loss efficacy, their long-term utility is constrained by gastrointestinal intolerance and variable effects on hepatic outcomes. Similarly, the recent approval of resmetirom for MASH, though groundbreaking, leaves unresolved challenges in durability, accessibility and some adverse effects including gastrointestinal reaction. The intricate molecular crosstalk linking adipose and hepatocyte dysfunction necessitates innovative therapeutics targeting shared pathophysiological pathways or novel molecular targets. Natural products, with inherent structural diversity and multitarget potential, offer a promising avenue for dual intervention in the obesity-MASH continuum. This review systematically evaluates emerging endogenous metabolites and plant-derived compounds, elucidating their directly validated molecular targets and preclinical evidence for metabolic reprogramming against obesity and MASLD/MASH. Furthermore, it synthesizes translational insights from natural product research and clinical trial experiences of related synthetic agonists. By integrating mechanistic discovery with a critical assessment of developmental challenges, this review aims to advance strategic frameworks for the concurrent management of obesity and MASLD/MASH. SIGNIFICANCE STATEMENT: Obesity-driven metabolic dysfunction-associated steatotic liver disease and steatohepatitis are leading causes of liver morbidity with limited treatment options. This review systematically evaluates natural products as multitarget therapeutics for these interconnected conditions. By integrating evidence of their efficacy and target mechanisms with modern discovery approaches, this study emphasizes pathways for clinical translation and aims to stimulate future research into novel, mechanism-based interventions.

Updated Global Consensus Recommendations for Risk Stratification, Treatment Initiation, and Response Monitoring in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Clin Gastroenterol Hepatol

Zobair M Younossi, Markos Kalligeros, Vincent Wai-Sun Wong +47 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) have increased in prevalence alongside the global epidemics of obesity and type 2 diabetes and now represent one of the leading causes of chronic liver disease. Patients with MASLD and significant fibrosis (≥F2) are at increased risk for adverse outcomes. With advances in noninvasive tests (NITs) and the recent approval of resmetirom and semaglutide for noncirrhotic MASH with F2-F3 fibrosis, we provide updated consensus guidance on standardized risk stratification, treatment initiation, and response monitoring.

Oral semaglutide reduces diabetes-related distress in adults with type 2 diabetes mellitus switching from DPP-4 inhibitors. The DOORS prospective real-world Italian study.

Diabetes Res Clin Pract

Andrea Giaccari, Francesca Borroni, Marco Dauriz +6 more

To evaluate glycaemic control, weight management, and patient-reported outcomes (PROs) in adults with type 2 diabetes mellitus who transitioned to oral semaglutide (OS) after inadequate glycaemic control on dipeptidyl peptidase-4 inhibitors (DPP-4i).

Genetic predictors of GLP1 receptor agonist weight loss and side effects.

Nature

Qiaojuan Jane Su, James R Ashenhurst, Wanwan Xu +39 more

The development of glucagon-like peptide 1 (GLP1) receptor agonists, including semaglutide and tirzepatide, has transformed the clinical management of overweight and obesity. However, substantial inter-person variability exists in both weight loss efficacy and the incidence of side effects1. To investigate the genetic basis of this variability, here we conduct a genome-wide association study of self-reported weight loss and treatment-related side effects in 27,885 people following GLP1 receptor agonist therapy. We identify a missense variant in GLP1R that is associated significantly with increased efficacy of GLP1 medications (P = 2.9 × 10-10), with an additional -0.76 kg of weight loss expected per copy of the effect allele. Furthermore, we identify associations linking variation in both GLP1R and GIPR to GLP1 medication-related nausea or vomiting, with the GIPR association being restricted to people using tirzepatide. We incorporate these findings into a broader model of GLP1 medication response, and demonstrate the ability to stratify patients by efficacy and side effect risk. These findings provide direct genetic evidence that variation in the drug target genes contributes to inter-person variability in response and lay the foundation for precision medicine approaches in the treatment of obesity.

Acute onset of neovascular age-related macular degeneration after initiation of tirzepatide.

Diabetol Int

Kohzo Takebayashi, Yurina Iemura, Mototaka Yamauchi +4 more

Recent retrospective cohort studies showed that use of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) increased the incident risk of diabetic retinopathy and nonarteritic anterior ischemic optic neuropathy (NAION). Furthermore, it was recently reported that use of GLP-1RAs for more than 6 months increased the risk of neovascular age-related macular degeneration (nAMD) by about twofold, although the association between a gastric inhibitory polypeptide (GIP)/GLP-1 receptor dual agonist (GIP/GLP-1RA) and nAMD is not clearly established. We describe the case of a middle-aged male patient with type 2 diabetes without apparent diabetic retinopathy. Due to poor glycemic control, tirzepatide (a GIP/GLP-1RA) was started instead of sitagliptin (a dipeptidyl peptidase-4 inhibitor). After switching from sitagliptin to tirzepatide, glycemic control rapidly improved, but the patient felt haziness with distortion of the central part of the left eye. A diagnosis of neovascular age-related degeneration (nAMD) was made by ophthalmologists in our hospital. The basis for the possible association of tirzepatide administration with onset of nAMD is unknown. However, clinicians should pay attention to potential visual impairments after achieving acute glycemic control with incretin-related drugs, including tirzepatide.

Cardiovascular adverse event reporting profile of tirzepatide: a real-world pharmacovigilance analysis of heart failure, arrhythmias, and ischemic events.

Front Pharmacol

Daqiu Chen, Zixun Wang, Zhanxiong Xie +3 more

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, is highly effective for glycaemic control and weight reduction. However, its real-world cardiovascular adverse event reporting profile remains incompletely characterised.

Incretin-Based Therapies for the Treatment of Binge Eating-A Systematic Review.

Pharmacotherapy

Raechel T White, Penelope Henriquez, Britnee Innocent +2 more

Binge eating disorder (BED) is a common psychiatric condition associated with psychological and cardiometabolic morbidity. Psychotherapy remains a core treatment modality while pharmacologic agents such as lisdexamfetamine, selective-serotonin reuptake inhibitors (SSRIs), and topiramate demonstrate variable efficacy and tolerability. Incretin therapies-specifically glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA-originally developed for type 2 diabetes mellitus (T2DM) and obesity, are an emerging therapy of interest for BED due to their effects on satiety, appetite regulation, and reward-driven eating. This systematic review examines current data surrounding the efficacy of incretin therapies in treating BED and discusses potential mechanisms underlying their effects.

Targeting Multiple Gut-Brain Pathways in Obesity: Rationale for Combination Pharmacotherapy.

Obes Sci Pract

Alexander D Miras, Muzamil Hussain

As a disease of energy dysregulation, obesity involves metabolic, hormonal, and neural factors, the interconnection of which is referred to as the "gut-brain axis."

Obesity pharmacotherapy reimagined: The era of multi-receptor agonists and next-generation metabolic modulators, perspectives and controversies.

Metabol Open

Ioannis G Lempesis, Maria Dalamaga

Obesity affects over 2 billion adults globally, with projections indicating that nearly two-thirds of adults will be affected by 2050. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed obesity treatment, achieving weight loss previously considered attainable only with bariatric surgery. However, GLP-1-based therapies have revealed important limitations, including weight loss plateaus, substantial inter-individual variability, and weight regain upon discontinuation, underscoring the need for next-generation approaches. Existing reviews have focused predominantly on approved GLP-1RAs, with limited synthesis of emerging multi-receptor agonists, oral formulations, and body composition-targeted agents, while guidance on treatment personalization and sequencing strategies remains limited. This review examines the evolving landscape of obesity pharmacotherapy beyond injectable GLP-1RAs. Oral GLP-1 agonists, including orforglipron, offer comparable efficacy to injectables while potentially improving global accessibility by eliminating cold-chain requirements and simplifying manufacturing. Multi-receptor agonists represent the most transformative developments: triple agonists such as retatrutide achieve weight reductions of 20-24%, while dual GLP-1/glucagon agonists like survodutide and mazdutide show strong efficacy with particular promise for metabolic-associated steatotic liver disease. Maridebart cafraglutide, combining GLP-1 agonism with glucose-dependent insulinotropic polypeptide (GIP) antagonism, enables once-monthly dosing. The amylin pathway has re-emerged through long-acting analogs (cagrilintide, eloralintide) and unimolecular co-agonists (amycretin), achieving weight reductions up to 24% via distinct neuroendocrine circuits. Body composition optimization through agents like bimagrumab addresses lean mass preservation during potent anorectic therapy. Personalized approaches, including setmelanotide for monogenic obesity, exemplify precision pharmacotherapy. Collectively, these advances signal a shift from appetite-centric weight loss toward integrated metabolic, neuroendocrine, and body-composition-focused disease modification. The next epoch of obesity pharmacotherapy will be defined by multi-receptor strategic combinations, targeted approaches to preserve lean mass, and personalized treatment algorithms. Critical priorities include phenotype-stratified trials, long-term safety surveillance, pediatric obesity research, and implementation science to ensure equitable global access. Balancing pharmacologic innovation with sustainable, equitable implementation remains the defining challenge ahead.