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Tirzepatide in Metabolic Diseases: Clinical Efficacy and Safety Beyond Diabetes and Obesity.
Med Res Rev
Shixuan Dong, Ying Xu, Ran Gan +3 more
Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has attracted substantial attention for its exceptional efficacy in managing type 2 diabetes and obesity. Emerging evidence suggests that tirzepatide may also exert broad therapeutic benefits in cardiovascular diseases, metabolic dysfunction-associated steatotic liver disease, and chronic kidney disease. However, its potential clinical risks are increasingly being recognized. This review begins by outlining the structural and pharmacological advantages of tirzepatide. We then comprehensively evaluate recent clinical evidence, including randomized controlled trials and real-world studies, based on a comprehensive literature search, to analyze its efficacy and safety for metabolic disorders. Tirzepatide exhibits considerable promise in treating multiple metabolic diseases; however, its therapeutic benefits must be carefully weighed against potential risks. Conclusions on cardiorenal benefits are supported by high-level outcome trials, while the evidence for hepatic, renal and musculoskeletal effects is exploratory or preliminary. Further large-scale, long-term studies remain essential to fully elucidate its mechanisms of action and overall clinical impact, given the current safety signals and other evidence are largely based on case reports, post hoc analyses, and non-prespecified endpoints. Continued pharmacovigilance is also crucial to identify and mitigate potential adverse drug reactions in diverse patient populations, especially for rare but serious events identified through spontaneous reporting systems.
Dose-response analysis of tirzepatide and acute pancreatitis: An international systematic review and quantitative meta-analysis of randomised trials.
Pancreatology
Olivia Benny, Anurag Agarwal, Harvey Alecock +47 more
Tirzepatide, a dual GIP/GLP-1 receptor agonist for type 2 diabetes and obesity, carries a theoretical risk of pancreatitis. Whether risk varies by dose is uncertain.
Glucagon-like peptide-1 receptor agonists reduce experimental atherosclerosis progression, inflammatory biomarkers and cardiovascular events, irrespective of hyperglycaemia and obesity.
Eur Heart J
Mohamad B Kassab, Haitham Khraishah, Andrew Thrapp +16 more
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiovascular events. However, their impact on atherosclerosis and inflammation, regardless of diabetes or obesity, is unknown. Here, GLP-1 RA effects were investigated on (i) atherosclerosis burden and inflammation in vivo in rabbits and (ii) inflammatory biomarkers and major adverse cardiovascular events (MACE) in clinical subjects, adjusted for glycaemic and obesity status.
Cardiometabolic and Antioxidant Properties of Modified C-Terminal Fragments of Apelin in Experimental Cardiac Pathology.
Kardiologiia
O I Pisarenko, I M Studneva
The development of new drugs for cardiovascular diseases based on endogenous peptide hormones is a field of significant interest, driving intensive experimental research. One promising direction is the synthesis of short bioactive peptides that mimic the effects of larger peptide molecules while offering superior physicochemical properties. Recent studies have shown that C-terminal fragments of the peptide apelin mitigate metabolic and functional impairments following cardiac injury. This review summarizes current literature alongside our own experimental findings regarding the effects of apelin-13, [Pyr1]apelin-13, apelin-12, and its chemically modified analogs on the heart during in vitro and in vivo pathophysiological modeling. The therapeutic spectrum of apelin-12 analogs in the damaged myocardium includes reduced cardiomyocyte death, decreased membrane damage, improved myocardial metabolic status, and the suppression of reactive oxygen species and lipid peroxidation products. These findings highlight the potential of molecular construction of apelin receptor (APJ) agonists with enhanced proteolytic resistance and shelf-life stability as a foundation for a new class of cardiovascular drugs.
Biomarker-Guided Versus Clinically Guided Management Strategies for Heart Failure: A Systematic Review and Meta-Analysis.
Rev Cardiovasc Med
Hao Zhou, Ting Liu, Fuxia Lan +3 more
The clinical value of B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided therapy for improving outcomes in patients with heart failure (HF) remains controversial. Thus, this meta-analysis synthesizes the available evidence from randomized controlled trials (RCTs) to determine whether a biomarker-guided strategy reduces all-cause mortality and HF-related hospitalizations compared with clinically guided management.
Prospective cohort study of TIMP-1 and myocardial fibrosis in Chagas disease at a reference clinic in Pernambuco, Brazil: PTICH trial protocol.
BMJ Open
Sílvia Marinho Martins, Carolina The Macedo, Cassio Santana Meira +7 more
Chagas disease affects millions of individuals across Latin America and imposes a substantial economic burden on healthcare systems, particularly in rural and underserved regions. Chronic Chagasic cardiomyopathy remains one of the leading causes of heart failure-related mortality in endemic countries. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has emerged as a potential biomarker of myocardial fibrosis in cardiomyopathies. This study was designed to investigate the association between TIMP-1 and myocardial fibrosis in chronic Chagas disease and to assess its potential as an early biomarker of fibrotic remodelling.
Tirzepatide and metformin effects on hunger and BMI in an adolescent with hyperphagia and severe obesity due to MC4R Deficiency: a case report.
Obes Facts
Eline E P L van der Walle, Mariëtte R Boon, Elisabeth F C van Rossum +1 more
Tirzepatide, a dual GLP-1/GIP receptor agonist, is recently approved for the treatment of type 2 diabetes and obesity in adults. Melanocortin-4-receptor (MC4R) deficiency is the most common monogenic cause of obesity and presents with hyperphagia and early onset obesity. While tirzepatide seems to be effective in inducing weight loss in adults with MC4R deficiency, its effects on hyperphagia and weight loss in pediatric patients are unexplored.
Endocrine Modulation of Inflammation: The Role of Adrenocorticotropic Hormone and Cortisol.
Endocr Pract
Maritza Vidal, Nancy E Lane
The melanocortin system, derived from pro-opiomelanocortin processing, represents a crucial neuroendocrine-immune interface that regulates inflammatory and metabolic pathways. Through its 5 melanocortin receptors (MCRs), MCR1 to MCR5, this system exerts widespread endocrine, paracrine, and autocrine functions across the central nervous system, skin, adipose tissue, bone, and immune cells. Activation of melanocortin signaling produces potent anti-inflammatory effects by modulating cytokine release, leukocyte trafficking, and transcriptional control of proinflammatory mediators. Adrenocorticotropic hormone (ACTH), via the hypothalamic-pituitary-adrenal axis and direct interaction with MCR2, stimulates both cortisol synthesis and mediates steroid-independent immunomodulation in extra-adrenal tissues. It should be taken into account that ACTH is the only ligand for MCR2 inducing steroidogenesis, cell proliferation and anti-inflammatory effects. Synthetic and natural ACTH formulations, such as repository corticotropin injection (Acthar® Gel) and Purified Cortrophin Gel, have demonstrated clinical benefit in refractory inflammatory diseases, as their efficacy may extend beyond classic glucocorticoid pathways. Recent preclinical studies of selective MCR agonists, including MCR1-targeted compounds like dersimelagon, highlight novel therapeutic possibilities for autoimmune and fibrotic disorders. Understanding the dual steroidogenic and nonsteroidogenic actions of melanocortins provides a framework for developing targeted therapies with improved safety profiles compared with conventional glucocorticoids.
Symptom management with osilodrostat in multiple endocrine neoplasia type 1 with a Cushing syndrome presentation.
JCEM Case Rep
Hasan Frookh Jamal
Multiple endocrine neoplasia type 1 (MEN1) syndrome is a rare autosomal dominant disorder characterized by predisposition to a multitude of endocrine neoplasms. Cushing syndrome (CS) within MEN1 presents complex diagnostic and therapeutic challenges. We report a case of a 36-year-old male with adrenocorticotropic hormone (ACTH)-dependent Cushing disease and MEN1 syndrome with thymic and pancreatic neuroendocrine tumors. The patient presented with weight gain, weakness and proximal myopathy. Biochemical testing confirmed ACTH-dependent hypercortisolism. Imaging revealed a pituitary microadenoma, a large anterior mediastinal mass, and pancreatic lesions. Genetic analysis confirmed a pathogenic heterozygous MEN1 frameshift variant. After thymectomy, he declined further surgery. Treatment with thymectomy and octreotide long-acting release (LAR) was ineffective. Initiation of osilodrostat (titrated to 5 mg twice daily) resulted in a 76% reduction in urinary cortisol levels and a 47 kg weight loss, with significant functional improvement. Pancreatic and pituitary lesions remained stable. This is the first reported case of successful symptom management of MEN1-associated Cushing disease with osilodrostat, establishing it as an effective therapeutic option for medically complex MEN1 cases where surgery is not feasible or is declined.
The AMP-antibiotic-microbiota triad in IBD: a mechanistic framework for dysregulated antimicrobial defense.
Front Immunol
Yuyuan Hu, Yan Li, Qiang Zhang +7 more
Inflammatory bowel disease (IBD) represents a chronic relapsing disorder driven by a loss of homeostatic balance between the host immune system and the intestinal microbiota. Endogenous antimicrobial peptides (AMPs), produced primarily by epithelial and immune cells, function in concert with commensal microorganisms to preserve mucosal integrity and barrier function. Disruption of this antimicrobial equilibrium-through genetic susceptibility such as NOD2 mutations or environmental perturbations including antibiotic overuse-can impair antimicrobial defense, distort microbial composition, and initiate chronic inflammation. Recent investigations have revealed distinct alterations in AMP expression across IBD subtypes. In Crohn's disease, Paneth cell-derived α-defensins (HD5 and HD6) are markedly diminished in the ileal mucosa, whereas colonic, segmental IBD exhibits inadequate induction of β-defensins and LL-37. Conversely, in actively inflamed regions, certain AMPs such as human β-defensin-2 (HBD2) and lysozyme are strongly upregulated, reflecting a compensatory response to inflammatory cell infiltration and microbial invasion. Beyond host-derived peptides, broad-spectrum antibiotic exposure profoundly reshapes commensal communities, attenuates basal pattern-recognition receptor signaling, and secondarily perturbs AMP regulation-creating a feedback loop that amplifies dysbiosis. Here, we conceptualize these interactions as an integrated AMP-antibiotic-microbiota triad, in which endogenous antimicrobial regulation, exogenous antimicrobial pressure, and microbial ecological resilience dynamically co-determine mucosal stability. By positioning AMPs within this tripartite regulatory framework, this review delineates how antimicrobial imbalance arises across IBD subtypes, compares emerging therapeutic strategies-including AMP enhancement, microbiota-sparing antibiotic regimens, fecal microbiota transplantation, and metabolite-guided interventions-and highlights implications for precision recalibration of antimicrobial homeostasis in IBD.
[Consensus statement of the Austrian Society for Rheumatology and Rehabilitation on the management of increased cardiovascular risk in rheumatoid arthritis, psoriatic arthritis and spondyloarthritis].
Wien Klin Wochenschr
Boris Lindner, Mathias Ausserwinkler, Christina Siess +14 more
Chronic inflammatory rheumatic diseases are associated with an increased risk of cardiovascular diseases (CVD), which significantly contribute to an increased morbidity and mortality. Although international recommendations exist, disease-specific and pragmatic guidance for the routine clinical practice are lacking due to heterogeneous evidence and incompletely understood pathophysiological mechanisms of cardiovascular events.
Activin A-Endothelin-1 Axis Governs Pulmonary Vascular Remodeling: Mechanistic Basis for Emerging Therapies in PAH.
Arterioscler Thromb Vasc Biol
Novia Nurul Faizah, Gusty Rizky Teguh Ryanto, Sagita Mega Sekar Kencana +4 more
Pulmonary arterial hypertension remains a life-threatening disease despite advances in vasodilator therapy. Vascular remodeling, partly driven by pulmonary artery endothelial cell dysfunction, is accompanied by vasoactive mediators imbalance such as ET-1 (endothelin-1). Although endothelin receptor antagonists alleviate vasoconstriction, they incompletely address the remodeling process. We previously reported how endothelial-derived activin A promotes vascular remodeling, leading to the clinical development of the activin signaling inhibitor sotatercept, which improves outcomes when added to endothelin receptor antagonists. As both activin A and ET-1 originate from endothelial cells and promote remodeling, we investigated whether activin A regulates ET-1 production and activity in pulmonary arterial hypertension.
Deconstructing senescence phenotypes in cells of the bone and bone marrow.
J Clin Invest
Lorenz C Hofbauer, Martina Rauner
Cellular senescence in osteogenic mesenchymal cells contributes to age-related bone loss. The bone marrow hosts myeloid cells, the precursors of immune cells, as well as mesenchymal cells, which give rise to osteoblasts and osteocytes. The senotype and senolytic response of bone marrow cells, particularly hematopoietic cells, in age-related bone loss is unclear. In this issue, Doolittle et al. showed that of all immune cells, myeloid cells had the strongest senescence profile, yet the relative level of senescence remained lower than that of mesenchymal stromal cells. Mesenchymal cells displayed a profound senotype, rendering them susceptible to senolytic clearance protecting against bone loss. By contrast, selective clearance of p16+ myeloid cells was not long-lasting and, hence, did not fully protect against age-related bone loss. These findings underscore the challenges of developing senolytic strategies for tissues with mixed senotypes, such as bone.
TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade.
Nat Commun
Yan Xiong, Jaiprakash Sharma, Meggie N Young +9 more
Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and cellular clearance pathways. TFEB activity is tightly controlled by multiple post-translational mechanisms, but the exact molecular mechanism controlling its stability has remained elusive. Here, we identify the IκB kinase (IKK) complex as a key regulator of TFEB protein stability through a phosphorylation-ubiquitination cascade. A high-content kinase inhibitor screen reveals that IKK inhibition increases TFEB protein levels, and genetic ablation of IKK components increases TFEB stability, upregulates lysosomal genes, and enhances lysosomal biogenesis and degradative capacity. Mechanistically, we show that IKK phosphorylates TFEB on a cluster of serine residues (423SPFPSLS429), generating a phosphodegron recognized by the E3 ligase β-TrCP2, which in turn targets TFEB for proteasomal degradation via ubiquitination of adjacent lysine residues (K430 and K431). Mutation of either the phosphosites or the ubiquitination sites stabilizes TFEB without impairing its ability to translocate to the nucleus, activate target gene expression, or promote tau clearance in a cell model of tauopathy. These findings establish IKK-β-TrCP2 as a core regulatory axis controlling TFEB protein turnover and levels and reveal a mechanistically distinct layer of TFEB regulation that may be leveraged to enhance lysosomal function in disease contexts.
Human Umbilical Cord Blood Mesenchymal Stem Cells Ameliorate Autism-Like Behaviors in a Valproic Acid-Induced Mouse Model via the IGF-1/Akt Signaling Pathway.
Brain Behav
Jie Tian, Hujing Deng, Zhoujing Hu +9 more
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that significantly impacts children's physical and mental health, yet effective pharmacological treatments remain limited. The primary objective of this study was to investigate the therapeutic effects of human umbilical cord blood mesenchymal stem cells (hUC-MSCs) on ASD, evaluate the safety profile of hUC-MSCs, and elucidate their underlying mechanisms and functional roles.
The Crucial Role of Exercise in Promoting Adolescent Muscle Development.
Adv Exp Med Biol
Xilong Hu, Haiwang Shi, Rui Duan
Skeletal muscle, as one of the largest organ system in the human body, exerts a determining influence on adolescents' mastery of motor skills and their lifelong health. Puberty represents a critical window for muscle development, during which the quality of myogenesis not only shapes athletic potential but also profoundly influences long-term health outcomes in adulthood. Under pathological conditions, such as obesity, an aberrant metabolic environment can compromise muscle function in youth, impede the progression of motor abilities, and increase susceptibility to metabolic disorders. It is well established that scientifically prescribed exercise interventions effectively unlock adolescents' muscle-building potential, thereby laying a solid foundation for enduring physical performance and overall well-being.This chapter offers a systematic overview of the key biological principles that regulate skeletal muscle development during puberty and provides an in-depth analysis of the mechanisms and signaling pathways by which structured exercise drives muscle growth and functional adaptation. In addition, it examines the challenges posed by muscle structural and functional impairments under pathological states and evaluates how targeted exercise regimens can restore and enhance muscle health. By mastering the conceptual framework presented here, coaches and parents will be better equipped to identify early warning signs of impaired muscle development, support individualized training plans that optimize motor skill acquisition while minimizing injury risk, and implement proactive interventions to prevent metabolic dysregulation and age-related muscle decline.
Telocytes in skeletal muscle: Emerging players in homeostasis and repair/regeneration.
Histol Histopathol
Irene Rosa, Eloisa Romano, Mirko Manetti
Telocytes (TCs) have recently emerged as novel components of the skeletal muscle interstitium. They are distinguished from other stromal cells by their immunophenotypic profiles and, especially, unique ultrastructural traits. Specifically, TCs feature a small cell body and very long, thin telopodes with a moniliform appearance conferred by the alternation of slender segments (podomers) and small dilated portions (podoms). Experimental evidence suggests that, as part of the skeletal muscle stem cell niche, TCs may be involved in orchestrating satellite cell activation and myogenic differentiation through both direct physical interactions and paracrine signaling. Yet, further in-depth research is needed to uncover specific immunophenotypic signatures for skeletal muscle TCs within the niche, as well as to identify the signaling pathways by which they influence neighboring satellite cells and, possibly, other cellular components of the niche. In the present review, particular emphasis is placed on the putative strategic role of TCs in maintaining skeletal muscle tissue homeostasis, their involvement in muscle pathological alterations, and, most importantly, their possible role in the coordination of the regenerative response following injury. In perspective, the promising therapeutic potential of TC-based strategies to enhance skeletal muscle tissue repair/regeneration and restrain post-injury fibrosis is also discussed.
snRNA sequencing-based skeletal muscle analysis of Jiangquan black pigs with different average daily growth rates.
Sci Rep
Hongzhen Cao, Jing Wang, Yunzhou Wang +7 more
The Jiangquan black pigs, a new breed of swine obtained by introducing traits from Duroc pigs into Yimeng black pigs, exhibits fast growth rates and high meat quality. To understand how daily weight gain influences muscle development in this breed, we analyzed longissimus dorsi muscle cell subpopulations from Jiangquan black pigs using snRNA and bulk RNA sequencing. Thirteen distinct cell types (e.g., muscle stem cells, satellite cells, fibroblasts) were identified, and marker genes (PAX7, MYOD, MYOG) were found to exhibit stage-specific expression during differentiation. Pseudotime analysis revealed the differentiation trajectories of these cell populations, while cell cycle analysis uncovered the higher mitotic activity in satellite cells of the fast-growth versus slow-growth groups. Furthermore, cell communication analysis highlighted the interactions between muscle cells and other cell types. Finally, intergroup analysis revealed that 2,466 and 2,597 genes were differentially expressed in muscle stem cells and muscle satellite cells, respectively. These genes were enriched in disease-related pathways. This study provides a single-cell resolution atlas of porcine muscle development, offering insights into the genetic regulation of growth and potential targets for breeding optimization.
Appetite, Obesity, Metabolism, and Malignancy: Do Incretin-Mimetic Drugs Reduce Cancer Risk?
Cancer Prev Res (Phila)
Andrew G Renehan, Michael N Pollak
Obesity is associated with increased risk of at least 13 adult cancer types and is the second most common cause of cancer (after tobacco) in many populations. Uncertainty about the extent to which intentional weight loss leads to reduced cancer risk represents a gap in knowledge. Evidence from bariatric surgery studies shows that sustained weight reduction of 20% to 30% in individuals with severe obesity is associated with reduced risk of obesity-related cancers over 10 years. However, in terms of population health, this is not a viable cancer prevention strategy. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RA), known to be effective antidiabetes drugs, have been shown in randomized trials to cause substantial weight loss (in the order of 15%) in obese individuals with or without diabetes. This is a rapidly evolving field, which has revolutionized the modern management of obesity. Much clinical experience has been with semaglutide (a GLP-1RA) and tirzepatide (a dual agonist of the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide receptor), but newer drugs in the class are being developed. We review available data that provide a strong rationale for evaluating incretin-mimetic drugs in a cancer prevention trial but show that the feasibility of such a trial is questionable.
Responses to GLP-1RA in White and Black Adults With Obesity: Insights From Generalized Additive Mixed Models of EHR Data.
Obesity (Silver Spring)
Jordan H Mallette, Joshua S Speed, Seth T Lirette +2 more
This study examined racial differences in weight loss and clinical response to glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy among adults with obesity using real-world data.