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Genomic-to-space measurements reveal large-scale ocean nutrient stress.
Sci Adv
Adam C Martiny, Lucas J Ustick, Toby K Westberry +1 more
Phytoplankton growth and ocean primary production depend on a nutrient supply that fluctuates across seasonal to millennial timescales. Because surface nutrients and phytoplankton biomass recycle rapidly, they obscure the large-scale pattern of nutrient stress. Here, we integrate a satellite-derived index of phytoplankton physiology with hydrographic observations, omics biomarkers, and nutrient-addition experiments to understand the drivers of ocean nutrient stress. A clear biogeography emerges. Nutrient stress tracks nutricline depth and is stronger in nitrogen- than phosphate-limited waters, peaking where cells exploit rarer alternative nutrients. Seasonal variability dominates, but there are also clear signatures of major climate modes. Over the past two decades, surface warming has broadly intensified nutrient stress. A key exception is in southern hemisphere oligotrophic regions, where enhanced nitrogen fixation appears to offset stratification effects. This synthesis of hydrography, genomics, and satellite physiology exposes contemporary, climate-linked shifts in the large-scale distribution of phytoplankton nutrient stress.
[Semaglutide-induced acute-on-chronic liver failure: A case report and literature review].
Zhong Nan Da Xue Xue Bao Yi Xue Ban
Rao Fu, Huizhi Wu, Haiying Huang +1 more
Semaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA), primarily used for the treatment of type 2 diabetes mellitus and obesity. Common adverse drug reactions (ADRs) include nausea, vomiting, diarrhea, abdominal pain, and constipation, whereas liver function-related ADRs are relatively rare. We report a rare and severe case of semaglutide-induced acute-on-chronic liver failure (ACLF) in a 47-year-old male patient who was successfully treated. The patient was admitted to the Department of Infectious Disease at the Second Xiangya Hospital of Central South University on December 1, 2023. He had a history of chronic hepatitis B and had discontinued antiviral therapy for more than two years without medical supervision. Due to weight loss requirements, he initiated subcutaneous semaglutide therapy. Approximately three months after treatment initiation, he developed severe liver dysfunction, which rapidly progressed to profound jaundice, coagulopathy, and hepatic encephalopathy. Drug-induced liver injury (DILI) was considered the primary precipitating factor of liver failure, and the final diagnosis was ACLF. Following confirmation of the diagnosis, semaglutide was discontinued, and comprehensive management, including hepatoprotective therapy, artificial liver support, plasma exchange, and liver transplantation, was implemented. The patient's clinical symptoms and liver function parameters improved significantly. This report describes the successful management of semaglutide-induced ACLF and reviews the relevant literature. For individuals with underlying chronic liver disease (e.g., chronic viral hepatitis), thorough baseline liver assessment should be performed prior to initiating semaglutide or similar agents. Close monitoring during treatment is essential to identify potential severe drug-induced liver injury at an early stage.
Starvation ketosis following self-administered tirzepatide obtained via online services in a young woman later diagnosed with anorexia nervosa: a case report.
J Eat Disord
Norio Yasui-Furukori, Kasumi Tasaki, Yusuke Kaiga +1 more
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, induces potent appetite suppression and substantial weight loss. Increasing access to incretin-based therapies through online services has raised concerns regarding metabolic and psychiatric complications, particularly in vulnerable individuals. We report a case of starvation ketosis associated with self-administered tirzepatide, followed by the clinical recognition of anorexia nervosa.
Rates of, Reasons for, and Reactions to Discontinuation of GLP-1 Receptor Agonists: A Narrative Review.
Diabetes Obes Metab
Henry D Heisey, L Parker Gregg, Christopher D Verrico +2 more
GLP-1RAs are increasingly used for their glucose-lowering and weight-management effects, but many patients discontinue them. In this narrative review we aim to review real-world, quantitative and qualitative GLP-1RA discontinuation, adherence, and persistence evidence as it aligns with an established conceptual framework for understanding medication adherence in noncommunicable chronic disease. Many inconsistencies exist in how discontinuation, adherence, and persistence are studied in this literature. Few qualitative studies have focused on discontinuation of GLP-1RAs. Quantitative approaches often focus on medication-related factors and more superficial aspects of socioeconomic and condition-related factors. Very few studies encompass all 5 dimensions of the medication adherence conceptual framework. Patient-related factors, especially related to patient behaviors, are understudied in relation to GLP-1RA discontinuation. Patients treated for type 2 diabetes mellitus or weight management with GLP-1RAs often discontinue the medication, but this is often nonpermanent. Improving adherence to and persistence on GLP-1RAs will require nuanced attention to care trajectories as well as an integrated understanding of GLP-1RA tolerability, expectations, and the understudied role of patient behaviors and the healthcare system. To clarify relevant mechanisms and guide targeted intervention for highest-risk individuals, further study should standardize definitions of persistence and discontinuation and implement patient-centered qualitative work, especially related to health behaviors.
Tirzepatide for weight and behavior management in a patient with Smith-Magenis syndrome.
JCEM Case Rep
X Charlene Liao, Tao Huang, David S Hong +1 more
Smith-Magenis syndrome (SMS) is a rare neurodevelopmental disorder characterized by intellectual disability, behavioral dysregulation, and hyperphagia-driven obesity. While dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated efficacy in the general population, their use in patients with SMS has not been described. We report the case of a 31-year-old woman with SMS (17p11.2 deletion) treated with tirzepatide, a dual GIP/GLP-1 receptor agonist. The patient presented with lifelong obesity (body mass index [BMI] 32.0-32.9 kg/m2 in adulthood) and aggressive behaviors refractory to standard management. Following initiation of tirzepatide, titrated to 5 mg weekly, she achieved 9.4% weight loss (7.3 kg) over 10 months, along with improvement in fasting glucose levels. Concurrently, caregivers reported notable behavioral improvements, including reduced food-seeking behavior and impulsivity. Quantitative analysis demonstrated a significant reduction in aggression. The treatment was well tolerated. This case suggests that tirzepatide may represent a promising therapeutic option for SMS, targeting both metabolic and central nervous system pathways involved in its phenotype.
Tirzepatide for Recurrent Weight Gain after Bariatric Procedures: Real-World Evidence of Efficacy and Safety.
Obes Surg
Federica Vinciguerra, Carla Di Stefano, Fabio Guccione +6 more
Recurrent weight gain after bariatric surgery (BS) or endoscopic bariatric therapy (EBT) remains a long-term clinical challenge, potentially undermining long-term treatment success. Tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has shown promising results in obesity treatment, but data regarding its use in post BS or EBT recurrent weight gain are limited.
Cohort Study: Risk of Gallstones and Biliary Complications With Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes.
United European Gastroenterol J
Mohamed H Eldesouki, Omar Alkasabrah, Mohammed Kloub +5 more
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes mellitus (T2DM) because of their benefits in glycemic control, weight reduction, and cardiovascular outcomes. This study evaluated the risk of gallbladder disease among diabetic patients treated with GLP-1 RAs.
Attitudes of nurses toward the care of older adults and associated socio - demographic factors: a descriptive cross-sectional study at Teaching Hospital, Jaffna.
BMC Nurs
A M Hazeem, M K I Mathusnka, L Kamalarupan +1 more
It is important to give more emphasis to elderly care as the population is aging. Nurses play a vital role in caring for older adults. This study aimed to assess the attitude of nurses toward caring for older adults at Teaching Hospital Jaffna; to examine nurses' attitudes while caring for adults, maintaining patient rights, and communicating with older adults; and to determine the association between socio-demographic factors (age, gender, ethnicity, religion, work unit, work experience, and educational qualification).
Enteric viral infections promote systemic accelerated aging in Drosophila.
Sci Adv
Rubén González, Mauro Castelló-Sanjuán, Maria-Carla Saleh
Do viral infections accelerate aging, and does this acceleration scale with pathogenicity? Using transcriptomic aging clocks, we measured biological age in Drosophila melanogaster infected with four enteric RNA viruses spanning a broad pathogenicity range (i.e., reduction of host lifespan). All pathogenic infections accelerated aging and the magnitude of acceleration tracked pathogenicity. This pattern held across oral and systemic infection routes and was conserved in Caenorhabditis elegans where the nonpathogenic Orsay virus produced negligible aging acceleration. Pathway analysis indicated a systemic impact across aging hallmarks with virus- and tissue-specific signatures. Acceleration was comparable in females and males, but host context modulated the acceleration: The bacterial symbiont Wolbachia mitigated the virus-induced aging. Notably, biological age remained elevated even after viral clearance. These results demonstrate that viruses act as age-distorters and link infection severity to lasting aging consequences, providing a quantitative framework for predicting long-term health effects of viral disease.
Systematic identification of human anti-mouse antibody interference causing falsely elevated B-type natriuretic peptide: A case study.
Ann Clin Biochem
Shunchang Li, Jifei Yao
B-type natriuretic peptide (BNP) is crucial for heart failure diagnosis. However, immunoassays are vulnerable to heterophilic antibody interference, which may lead to false-positive results and significant clinical mismanagement. Studies suggest such interference may account for a notable proportion of unexplained biomarker elevations. This report describes a case of a 36-year-old female with a markedly elevated BNP (2735.7 ± 54.3 pg/mL) incongruent with her clinical presentation. Therefore, we conducted a detailed analysis through a stepwise investigation, including serial dilution (showing non-linear recovery), cross-platform comparison (normal result on an alternative platform), and heterophilic blocking reagent treatment (partial correction). Ultimately, the addition of purified mouse IgG, but not anti-goat IgG or IgM blockers, normalized the BNP level in a dose-dependent manner, confirming human anti-mouse antibody (HAMA) interference. This case demonstrates that such interference is one of the potential causes of unexplained elevations in clinical immunoassay results. A systematic workflow was established in the case, ranging from suspicion to confirmation and ultimately to laboratory-adoptable conclusions. This process facilitates accurate diagnosis and helps clinicians avoid unnecessary interventions.
A rationally designed 18-amino acid peptide with potential as GLP-1 receptor agonist.
Front Pharmacol
Aditi Singh, Sucharita Shadangi, Soumendra Rana
Diabetes mellitus (DM) is a multifaceted disease etiologically characterised by dysregulation in glucose homeostasis. The World Health Organization (WHO) global report indicates that over 90% of DM cases are classified as Type 2 DM (T2DM), which is clinically characterized by chronic hyperglycemia. This systemic condition arises predominantly due to the interplay of two key components: (a) compromised insulin production by the pancreatic β-cells, and (b) the failure of insulin-sensitive tissues to react to insulin. Notably, it is well established that glucagon-like peptide-1 (GLP-1), an incretin hormone of the glucagon superfamily, contributes to glucose-dependent pancreatic β-cell insulin secretion. The insulinotropic impacts of secreted GLP-1 are facilitated by its interaction with GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR). However, GLP-1 is proteolytically cleaved by dipeptidyl peptidase 4 (DPP-4), resulting in a plasma half-life of ∼2 minutes, which limits its therapeutic efficacy in patients with T2DM. Therefore, the exogenous administration of DPP-4-resistant GLP-1R agonists (GLP-1RAs) has proven to be a successful therapeutic strategy for managing T2DM. Notably, the currently marketed GLP-1RAs, such as Semaglutide, Liraglutide, and Lixisenatide, are long-chain GLP-1 mimetic peptides, ranging in length from 33 to 39 amino acids.
Adjunctive Treatment with GLP-1 and Dual GLP-1/GIP Receptor Agonists for People with Type 1 Diabetes: Consensus Report and Practical Guidelines for Safe Use.
Diabetes Technol Ther
Satish K Garg, Halis K Akturk, Samita Garg +29 more
Among the most impactful therapeutic advances in the management of diabetes over the past two decades has been the development of incretin-based therapies, specifically glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and in combination with glucose-dependent insulinotropic polypeptide (GIP) RAs. Since the introduction of exenatide in 2005, a growing number of these drugs has transformed the management of type 2 diabetes (T2D). Their pleiotropic effects include weight loss, reduced insulin resistance, improved glucose regulation, and reductions in known risk markers for diabetic kidney disease and cardiovascular disease. To date, these important noninsulin glucose-lowering therapies have only received regulatory approval for use in T2D, obesity, sleep apnea, and metabolic dysfunction-associated steatohepatitis with moderate-advanced fibrosis, supported by randomized controlled trials (RCTs) and real-world data that demonstrate efficacy and safety. Regulatory approval for use of weekly GLP-1 and GLP-1/GIP RAs in type 1 diabetes (T1D) has not yet been achieved, in part because of the limited number of inconsistent, small-scale, RCTs and real-world studies for glycemic impacts of these agents in T1D. Larger RCTs are ongoing or planned in participants with T1D. Potential safety risks include hypoglycemia and hyperglycemia-related ketosis in T1D after initiation of GLP-1/GIP RA drugs. While RCTs are ongoing to further investigate GLP-1 and GLP-1/GIP RA agents as adjunct therapy for people with T1D, access to these drugs is already possible, based on their use to treat overweight and obesity. However, without regulatory approval for the T1D indication, access and opportunities for people with T1D to engage with important education regarding the safety of GLP-1 and GLP-1/GIP RA therapy may be limited. This precludes support from diabetes health care professionals to optimize diabetes management of these agents alongside expected insulin dose changes. The purpose of this consensus report is to review the current literature and provide guidelines for diabetes clinicians and people with T1D to facilitate the safe use of GLP-1/GIP RAs in the management of T1D. This consensus statement has been endorsed by the following professional associations: Advanced Technologies & Treatments for Diabetes (ATTD), International Diabetes Federation-Europe, American Association of Clinical Endocrinologists (AACE), Breakthrough T1D, International Society for Pediatric and Adolescent Diabetes (ISPAD), Association of Diabetes Care and Education Specialists (ADCES).
GLP-1R activation alleviated sepsis-induced cardiac dysfunction by modulating macrophage polarization via the STING/ P65 pathway.
Biochem Pharmacol
Yusha Zhang, Jiayi Zhu, Jiabao Zhou +7 more
Activated glucagon-like peptide-1 receptor (GLP-1R) could alleviate sepsis-induced cardiomyocyte pyroptosis and regulate the polarization of M1 macrophages. The direct effect and mechanism of GLP-1R-mediated macrophage polarization on cardiomyocyte pyroptosis remain unclear. In our study, Liraglutide (Lira, 100ug/kg/12 h, 3 days) pretreatment was applied to a lipopolysaccharide (LPS, 10 mg/kg)-induced sepsis mouse model to investigate its efficacy in modulating cardiomyocyte pyroptosis and macrophage polarization. Our results showed that activated GLP-1R could inhibit cardiomyocyte pyroptosis, and suppress macrophage polarization in mice heart. Conditioned medium (CM) from Lira-pretreated peritoneal macrophages (PMs) inhibited the expression of pyroptosis-related proteins in H9c2 cells. Mechanistically, activated GLP-1R downregulated STING expression in M1 PMs. Furthermore, STING knockdown enhanced the inhibitory effect of Lira on M1 macrophages and strengthened the suppression of pyroptosis in H9c2 cells by CM. Conversely, DMXAA (STING agonist) could block the inhibitory effect of Lira on M1 macrophages and partially reverse the suppression of H9C2 pyroptosis by CM. Furthermore, activation of GLP-1R on macrophages could suppress P65 nuclear translocation by modulating STING expression. Subsequent in vivo studies revealed that STING pathway activation markedly attenuated the cardioprotective effects of Lira in a murine sepsis model. These results demonstrated that activation of GLP-1R inhibited M1 macrophage polarization, thereby alleviating cardiomyocyte pyroptosis. Additionally, the regulation of macrophage polarization by GLP-1R is partially mediated through the STING/P65 pathway.
Sweet Killers: Animal Toxins that Mimic Glucoregulatory Hormones.
Toxicon
Isabela Gobbo Ferreira, Beatriz de Cássia da Silva Jacob, Emilly Regina Ramos +6 more
Glucose homeostasis is regulated by a complex interplay of endocrine signals, primarily involving insulin, glucagon, and incretin hormones, such as glucagon-like peptide-1 (GLP-1). Disruption of this balance underlies metabolic disorders like type 2 diabetes, a condition of growing global concern. In recent years, animal-derived toxins have emerged as a novel and underexplored source of bioactive compounds capable of modulating key pathways involved in glucose regulation. This review provides an overview of the endocrine control of glucose metabolism, followed by an in-depth examination of animal toxins that mimic or modulate the activity of insulin and GLP-1, as well as those that interfere with glucagon signaling, focusing on their pharmacological relevance. These naturally evolved molecules offer unique mechanisms of action and high target specificity, making them valuable leads for drug development. Several venom-derived compounds have already shown promise in preclinical and clinical studies, reinforcing their potential as templates for next-generation antidiabetic therapies. We also discuss the translational implications of these discoveries, highlight current challenges in their therapeutic development, and propose future directions for researches which crosstalk between Toxinology and Endocrinology.
Brain-derived HMGB1 mediates periodontal inflammation after ischemic stroke through the STAT3/NLRP3 inflammasome pathway.
Int Immunopharmacol
Jin Wang, Jiehua Zhang, Yingze Ye +8 more
Ischemic stroke is known to cause immunosuppression and may exacerbate peripheral conditions such as periodontitis, yet its direct impact on periodontal tissues remains unclear. Using a transient middle cerebral artery occlusion (MCAO) mouse model, we showed that stroke rapidly induced periodontal inflammation, including epithelial disruption, alveolar bone loss, increased osteoclasts, and activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Meanwhile, we found that neuronal high-mobility group box 1 (HMGB1) translocated from the nucleus and was released after stroke, coinciding with disruption of the blood-brain barrier and elevated circulating HMGB1. Fluorescent tracing with intracerebroventricular 5-FAM-HMGB1, together with longitudinal periodontal fluorescence quantification and ELISA of gingival tissue (total HMGB1 and 5-FAM-HMGB1), demonstrated that brain-derived HMGB1 contributed to the periodontal HMGB1 pool after MCAO. In parallel, stroke increased hypothalamic HMGB1 and activated the hypothalamic-pituitary-adrenal (HPA) axis, as indicated by increased corticotropin-releasing hormone (CRH) and elevated serum adrenocorticotropic hormone (ACTH) and corticosterone. In addition, recombinant HMGB1 induced inflammatory responses in gingival fibroblasts via signal transducer and activator of transcription 3 (STAT3) signaling. Treatment with the HMGB1 inhibitor Glycyrrhizin (Gly) suppressed brain and hypothalamic HMGB1, inhibited HPA axis hyperactivation, reduced STAT3 phosphorylation and NLRP3 signaling, and attenuated periodontal inflammation; these effects were partially reversed by the STAT3 activator Colivelin. These findings revealed that brain-derived HMGB1 mediated post-stroke periodontal inflammation through both direct migration and HPA axis activation, and highlighted HMGB1 as a critical link in brain-oral crosstalk and a potential therapeutic target.
Differential diagnosis of ACTH-dependent Cushing's syndrome: Biochemical, imaging, and predictive approaches.
Vitam Horm
Wilfredo Antonio Rivera-Martínez, Carlos Esteban Builes-Montaño, Alejandro Román-González +3 more
Endogenous hypercortisolism remains a high-stakes diagnostic challenge in which delays or misclassification drive excess morbidity and mortality. This chapter synthesizes an evidence-based, physiology-anchored approach to the differential diagnosis of ACTH-dependent Cushing's syndrome, integrating clinical phenotyping, first-line biochemistry, dynamic testing, imaging, and invasive confirmation. We first outline bedside features that raise or lower the pre-test probability of Cushing disease (CD) versus ectopic ACTH syndrome (EAS). Then, the initial laboratory tests (nocturnal salivary cortisol, 24-h urinary free cortisol, low-dose dexamethasone suppression, ACTH) and their pathophysiological correlates are reviewed. For dynamic tests, we summarize indications and interpretation of CRH, desmopressin, and high-dose dexamethasone suppression, highlighting their value as composites rather than stand-alone arbiters. The imaging section prioritizes 3 T dynamic pituitary MRI for CD and thin-slice CT for suspected EAS, with targeted use of ^68Ga-SSTRPET/CT (ectopic NETs), ^18F-FDG (high-grade biology), ^18F-DOPA (PPGL), and emerging pituitary-targeted PET tracers as adjuncts. When non-invasive data are discordant or indeterminate, bilateral inferior petrosal sinus sampling (BIPSS) remains the reference: verify selectivity (prolactin IPS:peripheral > 1.8) and apply ACTHIPS:peripheral cut-offs (≥ 2 basal or ≥ 3 post-stimulus), with optional optimized thresholds and prolactin-adjusted ratios in suboptimal flow. Finally, we propose a step-by-step diagnostic algorithm that sequences these elements pragmatically and discuss predictive models as complementary tools to prioritize testing and resource use.
TDP-43 Sustains Satellite Cells to Maintain and Regenerate Skeletal Muscle.
bioRxiv
Theodore E Ewachiw, Tenaya K Vallery, Shloka Dhar +4 more
Skeletal muscle satellite cells, residing between the myofiber plasma membrane and the surrounding basement membrane, maintain and repair skeletal muscle throughout life. Typically quiescent, satellite cells can transition into a reversible alert state (G Alert ) that primes them for rapid activation to maintain or repair muscle. From G Alert , SCs can either re-enter quiescence or commit to the cell cycle, expand, and differentiate to fuse with existing regenerating myofibers. Exit from quiescence requires extensive post-transcriptional remodeling, including changes in RNA processing and RNA-binding protein activity. We show that TDP-43, an RNA binding protein, is essential for SC maintenance and muscle repair. Conditional deletion of TDP-43 in SCs caused a consistent and progressive loss of G Alert SCs even in uninjured muscle, leading to depletion of the SC pool. TDP-43 haploinsufficiency was sufficient to impair SC maintenance, indicating that both alleles are required. Integrative analysis suggests that TDP-43 supports expression of stress response-associated transcripts during the quiescent-to-G Alert transition, and that failure to mount this response contributes to SC apoptosis. Thus, we identified TDP-43 as a critical regulator of satellite cell survival as satellite cells activate and establish a TDP-43 requirement for maintaining and repairing skeletal muscle.
CRISPR-mediated engineering of bovine satellite cells for Alpha-Gal Syndrome-compatible cultivated meat.
bioRxiv
Susan D'Costa, Shailesh K Choudhary, Grace E Kenney +4 more
Alpha-gal Syndrome (AGS) is a potentially life-threatening allergy caused by an IgE-mediated immune response to galactose-α-1,3-galactose (alpha-gal), a carbohydrate epitope present in most mammalian meats. Currently, strict avoidance of mammalian meat remains the primary management strategy for affected individuals, and alpha-gal-free beef is not commercially available. Here, we leverage cultivated meat as a biotechnology plat-form to address this unmet clinical need by engineering alpha-gal-free bovine muscle cells. Using CRISPR/Cas9 genome editing, we disrupted GGTA1, the gene encoding α1,3-galactosyltransferase, in immortalized bovine satellite cells (iBSCs). High-efficiency editing produced clonal GGTA1 knockout iBSCs harboring a homozygous frameshift mutation. Flow cytometry and immunofluorescence confirmed loss of the alpha-gal epitope, while bulk RNA-seq indicated minimal disruption of global gene expression and preserved myogenic differentiation capacity. Importantly, lysates from GGTA1 knockout iBSCs elicited substantially reduced basophil activation in assays using plasma from a patient with AGS, indicating reduced basophil activation consistent with reduced allergenic potential. Together, these findings establish a proof of concept for engineering AGS-compatible cultivated meat and demonstrate the potential of cultivated meat technologies to address human health challenges.
Myogenic dysregulation underlies tongue overgrowth in Beckwith-Wiedemann syndrome.
bioRxiv
Elisia D Tichy, Anna T Nguyen, Mariah A Byrne +7 more
Macroglossia is a clinically significant feature of Beckwith-Wiedemann syndrome (BWS), but the cellular basis of tongue overgrowth remains poorly defined. Here, using pediatric tongue specimens from molecularly defined BWS subtypes and age-matched nonBWS controls, we show that BWS macroglossia is characterized by skeletal muscle fiber hypertrophy rather than increased fiber number. This phenotype is not explained by expansion or increased proliferation of satellite cells in situ , and prospectively isolated tongue satellite cells do not exhibit enhanced proliferation under growth conditions in vitro . Instead, BWS progenitors adopt distinct differentiation-associated regulatory states. IC2 loss of methylation cells sustain proliferative activity during differentiation and form enlarged myotubes, consistent with a cell-autonomous hypertrophic program. In contrast, pUPD11 cells display activation of NOTCH signaling and progenitor-associated programs, together with attenuated progression toward terminal myogenic differentiation. These findings identify skeletal muscle hypertrophy as a core tissue-level feature of BWS macroglossia and reveal that epigenetically defined BWS subtypes engage divergent myogenic programs that converge on a shared hypertrophic tissue phenotype. Together, these data define subtype-specific myogenic states in a rare human disease tissue and provide a framework for understanding how distinct epigenetic changes can produce a common overgrowth phenotype.
Semaglutide in Metabolic Medicine: A Review on Clinical Applications and Emerging Therapeutics.
Saudi Med J
Abdulrahman A Aljabri
Obesity and type 2 diabetes mellitus affect over 800 million and 537 million individuals worldwide. Semaglutide, a weekly glucagon-like peptide-1 receptor agonist, has advanced treatment of pathophysiological processes linked to metabolic dysregulation. This review consolidates evidence on its mechanisms of action, clinical effectiveness across established and emerging applications, safety, and prospects for personalized therapy. Clinical studies have shown that semaglutide sustains glycemic control, promotes substantial weight loss, and provides cardiovascular and renal protection. Recent FDA clearance marks the first therapeutic alternative for metabolic dysfunction-associated steatohepatitis among the emerging applications. Pharmacogenomic insights facilitate personalized therapy; however, clinical applications remain in experimental stage. Gastrointestinal side effects are the main tolerability concern, but the risk-benefit profile underscores its increasing significance in metabolic therapy. Therapies for diabetes and obesity are cost-effective; however, global accessibility challenges persist. Future priorities include refining combination medicines, promoting precision medicine, and addressing healthcare inequities to augment population-level effects.