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Efficacy and Safety of Intensifying Once-Weekly Insulin Icodec Treatment With Once-Weekly Semaglutide in Adults With Type 2 Diabetes: A Single-Arm, Open-Label, Treat-to-Target, Phase 3b Trial (ONWARDS 8).
Diabetes Obes Metab
Krzysztof Strojek, Andreas Liebl, Neha Narendra Mumbaikar +3 more
To investigate the efficacy and safety of intensifying once-weekly insulin icodec (icodec) with once-weekly semaglutide in adults with type 2 diabetes (T2D).
Rebooting blood vessel repair: implications of the SEMA-VR CardioLink-15 trial.
Curr Opin Cardiol
Raj Verma, Meena Verma, Brady Park +4 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events (MACE), heart failure, and mortality through undetermined mechanisms independent of glycemic control. This review examines emerging evidence that GLP-1RAs overcome vascular regenerative cell exhaustion (VRCE), a pathological depletion of bone marrow-derived progenitor cells that mediate vessel repair.
Beyond weight loss: predictors of treatment satisfaction and patient-reported outcomes in incretin-based therapies. A cross-sectional study.
Front Endocrinol (Lausanne)
Ali Kapan, Othmar Moser, Richard Felsinger +1 more
Incretin-based therapies, including glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists, have demonstrated substantial efficacy in weight management. However, real-world treatment experience, tolerability, and treatment continuation remain important challenges, and the determinants of patient satisfaction are not fully understood.
Pharmacological mechanisms and clinical impacts of antidiabetic drugs on colorectal cancer risk: a systematic review.
Front Pharmacol
Yu Yang, Kan Wang
Type 2 diabetes mellitus (T2DM) significantly increases colorectal cancer (CRC) risk, driven by shared metabolic and inflammatory pathways. As lifelong glucose-lowering medications are routinely used in T2DM, their pharmacological activities and associated oncological effects have become critical for safety and repurposing. This review systematically summarizes the pharmacological mechanisms, epidemiological evidence, and clinical outcomes of eight antidiabetic drug classes in modulating CRC risk. We highlight drug-specific effects: metformin may act via AMPK/mTOR and immune reprogramming; SGLT-2 inhibitors may exert direct cytotoxicity and indirect metabolic benefits; GLP-1 RAs show class-wide neutrality except high-dose semaglutide; DPP-4 inhibitors display dual pro- and anti-tumor effects; insulin and most secretagogues elevate CRC risk via hyperinsulinemia; while TZDs and AGIs offer modest chemopreventive effects. We conclude that antidiabetic drugs possess pharmacological properties that can inform CRC risk stratification and drug repurposing. Future research should prioritize mechanistic validation and precision pharmacology to translate these findings into clinical practice.
Tirzepatide as a multi-organ integrator in metabolic diseases: a review of molecular mechanisms and clinical translation.
Endocrine
Irshad Khan, Sarasa Meenakshi, Md Abubakar +4 more
Metabolic diseases, including type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), and obstructive sleep apnoea (OSA), are characterized by a complex and interconnected pathophysiological syndrome. These conditions involve insulin resistance, chronic inflammation, and disturbances in energy homeostasis. Typically, they affect multiple organs and require comprehensive treatment.
Impact of tirzepatide on systemic arterial stiffness assessed by cardio-ankle vascular index in individuals with obesity complicated by type 2 diabetes: A retrospective cohort study in Japan.
Obes Pillars
Daiji Nagayama, Miwako Wakamatsu, Yasuhiro Watanabe +6 more
Tirzepatide, a multi-agonist incretin agent that targets body weight and metabolic parameters, has stronger weight reduction and glycemic control effects than existing agents. This study aimed to elucidate the effects of tirzepatide on vascular function in individuals with obesity complicated by type 2 diabetes (T2D).
Clinical Implications of Mounjaro (Tirzepatide) for Breast Cancer Detection and Management: A Narrative Review.
Cureus
Raafat Mady, Habib Tafazal, Haitham Soliman +2 more
Tirzepatide, marketed as Mounjaro, is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that is widely used to treat type 2 diabetes and obesity. As more women presenting to screening and symptomatic breast clinics receive tirzepatide, questions have emerged regarding how rapid pharmacologic weight loss may influence breast lump detection, mammographic density, and breast cancer risk. This narrative review summarises tirzepatide pharmacology, its effects on adiposity, expected changes in breast composition with weight loss, oncologic data on breast cancer risk and outcomes, and radiological implications for mammography, ultrasound, and MRI. Randomised-trial data and meta-analyses currently show no clear evidence of increased breast cancer incidence with tirzepatide or GLP-1 receptor agonists. Preclinical studies in obesity-associated breast cancer models have demonstrated reduced mammary tumour progression following tirzepatide-induced weight loss and metabolic improvement; however, the clinical relevance of these findings remains uncertain. In the clinic, GLP-1 receptor agonist use in women with breast cancer has been associated with clinically meaningful weight loss without short-term safety signals. Weight loss decreases breast volume and subcutaneous fat, often making pre-existing benign lesions more palpable and altering mammographic density and parenchymal patterns, but available data do not indicate reduced imaging accuracy. Clinicians should maintain standard triple assessment, recognise that new palpable nodularity may reflect unmasked benign tissue, and reassure patients that current clinical evidence has not demonstrated an increased breast cancer risk associated with tirzepatide use. High-quality prospective imaging and oncology studies are needed to define long-term effects.
Glucagonlike Peptide-1 (GLP-1) Receptor Agonists for Cardiometabolic Risk in Severe Mental Illness: A Narrative Review.
Cureus
Catarina Domingues, Maria Ferreira, Rosa Pinho
People with severe mental illness face a substantially increased cardiometabolic risk and premature mortality, largely driven by antipsychotic-associated metabolic disturbances, including significant weight gain, insulin resistance, dyslipidemia, impaired glucose homeostasis, and increased rates of metabolic syndrome. Despite existing recommendations for monitoring and early intervention, managing this risk remains a significant clinical challenge. Glucagonlike peptide-1 receptor agonists have emerged as a potential adjunctive therapeutic strategy in this context. This narrative review evaluated the efficacy and safety of these agents in adults with severe mental illness receiving chronic antipsychotic treatment. A structured search was conducted in PubMed/MEDLINE and the Cochrane Library, complemented by relevant clinical guidelines and consensus documents. Randomized controlled trials, systematic reviews, and meta-analyses published between 2015 and 2025 in English or Portuguese were included, and the strength of evidence was assessed using the Strength of Recommendation Taxonomy. Nine studies were included, comprising six randomized controlled trials and three evidence synthesis studies. Liraglutide and semaglutide consistently demonstrated clinically meaningful reductions in body weight and improvements in glycemic control, without evidence of worsening psychiatric symptoms. In contrast, exenatide did not show additional weight loss compared with placebo, although some hemodynamic benefits were observed. The most common adverse events were mild to moderate gastrointestinal symptoms. Overall, the available evidence suggests a favorable balance between cardiometabolic benefits and psychiatric safety, particularly in patients treated with high metabolic risk antipsychotics such as clozapine and olanzapine. GLP-1 receptor agonists appear to be a promising adjunctive option for cardiometabolic risk reduction in this population. These findings support their consideration as a clinically relevant strategy, especially in patients at higher cardiometabolic risk. However, current evidence is limited by small sample sizes and short follow-up periods, and further long-term studies are needed to support broader clinical implementation.
A Validated, Modifiable Proteomic Score from the EXSCEL Trial Predicts Cardiovascular Events in Diabetes.
JCI Insight
Kristin M Corey, Maggie Nguyen, Michael Y Mi +14 more
Adults with type 2 diabetes mellitus (T2DM) are at increased risk for stroke, myocardial infarction, and cardiovascular death, yet individual risk is heterogeneous and incompletely captured by clinical models. In the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), adults with T2DM were randomized to a GLP-1 RA (exenatide) or placebo and followed longitudinally for major adverse cardiovascular events (MACE). High-throughoput discovery proteomics was done in plasma collected at baseline and 12-months. Proteins associated with time-to-MACE were identified using multivariable regression and incorporated into supervised machine learning models. A multi-protein score was developed and externally validated in two independent population-based and trial cohorts, Cardiovascular Health Study and the Prospective Multicentre Imaging Study for Evaluation of Chest Pain (PROMISE). The proteomic score showed incremental improvement in cardiovascular risk discrimination beyond clinical factors alone, and several proteins were consistently prioritized across modeling approaches. The protein score and a top-ranked protein, tetranectin, were modified by GLP-1 RA treatment, and a decrease in the protein score was associated with improved outcomes, supporting modifiability of MACE risk. External validation confirmed generalizability across cohorts with and without diabetes. Together, these findings demonstrate that plasma proteomic signatures can enhance cardiovascular risk stratification and identify treatment-responsive biomarkers in T2DM, supporting their potential role in precision prevention strategies.
Examining of the mechanism by which Yin Huang Ge compound alleviates cognitive dysfunction in Alzheimer's disease mice through modulation of Aβ degrading enzymes and neurotrophic factors.
Front Aging Neurosci
Yaxuan Hao, Haoyue Yang, Jianmin Zhong +3 more
Alzheimer's disease (AD) poses a significant threat to human health, and with the number of patients increasing annually, developing effective prevention and treatment strategies has become an urgent priority. Early intervention is a viable strategy for treating AD, as biomarker changes associated with β-amyloid (Aβ) can emerge 20 or more years before cognitive impairment becomes apparent. Traditional Chinese medicine (TCM) offers a potential avenue for treatment at this early stage.
Tissue turnover and rejuvenation through mechanics.
Front Cell Dev Biol
Mizuki Uchida, Yusuke Toyama
Tissue turnover depends on the efficient removal of damaged cells to maintain structural and functional integrity. Cells respond to damage across a spectrum of outcomes, ranging from repair and recovery to senescence, apoptosis, and malignant transformation. This review focuses on apoptosis and senescence in epithelia as two outcomes with profound consequences for tissue homeostasis, one ensuring swift mechanical removal of damaged cells and the other driving persistent tissue disruption. While apoptotic cells are efficiently eliminated through coordinated mechanical processes, senescent cells resist elimination and progressively impair tissue function through chronic inflammation and mechanical remodeling of the tissue microenvironment. Restoring tissue function therefore requires strategies to efficiently clear or reverse the senescent state. Immune-mediated clearance and senolytic drugs can reduce senescent cell burden, yet their efficacy and selectivity remain limited. Emerging mechanobiological strategies, including low-frequency ultrasound and geometric confinement, offer a complementary approach by directly reversing the senescent phenotype through physical cues. Ultimately, harnessing these mechanical forces offers a promising avenue toward restoring tissue function.
Mechanical loading primes MSC-derived exosomes to promote cartilage repair.
Bioact Mater
Zeng Lin, Chao Jia, Hongwei Lu +10 more
Cartilage defects remain a major clinical challenge due to the limited efficacy of current therapies and the intrinsically low regenerative capacity of chondrocytes. Mechanical loading has emerged as a promising strategy to enhance stem cell-based cartilage repair; however, the underlying molecular mechanisms remain poorly understood. Here, we show that cyclic tensile strain primes mesenchymal stem cells (MSCs) to secrete exosomes enriched in microRNA-330-3p (miR-330-3p), which markedly enhances cartilage regeneration. Mechanistically, miR-330-3p restores mitochondrial quality control in chondrocytes by engaging an FKBP4-FoxO3a-dependent mitophagy program, leading to activation of PINK1/Parkin-mediated mitochondrial clearance. The regenerative efficacy of miR-330-3p-enriched exosomes was validated in a Sprague-Dawley rat model of cartilage defects. In vitro, miR-330-3p promotes chondrocyte proliferation and migration while suppressing apoptosis, senescence, and extracellular matrix degradation. Together, these findings identify mechanically primed MSC-derived exosomes as a mechanistically informed therapeutic strategy for cartilage repair.
Resetting the epigenetic clock: cellular senescence and regenerative strategies in intervertebral disc degeneration.
Front Aging
Minfan Li, Haitao Deng, Hongda Xu +2 more
Intervertebral disc degeneration (IDD) is the leading pathological cause of low back pain, while current clinical treatments are only palliative and cannot reverse the programmed cellular senescence driven by epigenetic dysregulation. This process is characterized by progressive loss of nucleus pulposus (NP) cell identity and establishment of a self-amplifying senescence-associated microenvironment. In this review, we synthesize recent advances elucidating how heterogeneous senescent cell populations and their secretory phenotype (SASP) orchestrate a destructive vicious cycle in IDD. We further dissect the synergistic interplay among DNA methylation, histone modifications, and non-coding RNAs that constitutes the "epigenetic aging clock" and drives premature cellular aging within the disc. Notably, we evaluate emerging therapeutic strategies aimed at clock reversal, including senolytic clearance of senescent cells, epigenetic remodeling using small-molecule inhibitors or CRISPR-dCas9 editing, and cellular reprogramming approaches ranging from iPSC differentiation to direct lineage conversion. We propose a synergistic "clear, prime, then seed" roadmap that sequentially combines these interventions for optimal regeneration. This work provides a systematic theoretical framework for the clinical translation of epigenetic-targeted therapy for IDD, and breaks through the cognitive limitation of traditional mechanical wear theory.
Acylglycerol Kinase Sensitizes Glioblastoma to Temozolomide via Limiting Mitochondrial Damage Related Cellular Senescence.
Mol Carcinog
Na Ning, Changtu Wang, Tingyu Gao +6 more
Temozolomide (TMZ) is still the first-line drug for glioblastoma (GBM) treatment though tumor cell resistance remains a major challenge. TMZ administration may induce cellular senescence (CSEN), which exerts a dual regulatory effect on tumor progression, and evidence has suggested that CSEN is closely associated with mitochondrial dysfunction. Acylglycerol kinase (AGK), a mitochondrial membrane kinase, has been reported to participate in regulating mitochondrial function and the production of reactive oxygen species (ROS). Here, we aimed to investigate the role of AGK in GBM progression and TMZ resistance, assessed whether CSEN mediates these effects, and investigated the therapeutic potential of senolytic agents. Firstly, the analysis of TCGA data revealed that the increased expression of AGK was correlated with a poor prognosis of GBM patients. Secondly, through cell experiments of AGK-knockdown and overexpression, we found that AGK suppression inhibited the proliferation of tumor cells while paradoxically promoting TMZ resistance. Mechanistically, AGK suppression amplified TMZ-induced CSEN through increasing mitochondrial ROS (mtROS) and decreasing membrane potential. Conversely, Mito-TEMPO, a mtROS scavenger, and FOXO4-DRI, a senolytic agent, both enhanced the therapeutic efficacy of TMZ by eliminating these senescent cells via apoptosis. Furthermore, the clinical analysis linked AGK levels, CSEN, and prognosis of GBM patients treated with TMZ. In conclusion, our results establish senescence induction as a novel mechanism for AGK-mediated TMZ sensitization, suggesting that co-targeting AGK and CSEN represents a promising strategy to enhance TMZ therapy.
Experience with selexipag in triple therapy for pulmonary arterial hypertension in Chinese children.
BMC Pediatr
Meng Li, Yingchun Wang, Xiaoyu Hu +4 more
Selexipag is an orally effective prostacyclin receptor agonist that has been approved for treating pulmonary arterial hypertension (PAH) in adults but is still used off-label in children. This study aimed to evaluate the efficacy and safety of selexipag as part of triple combination therapy (TCT) with endothelial receptor antagonists (ERAs) and phosphodiesterase-5 inhibitors (PDE5is) in Chinese children with PAH.
Role of Bruton's Tyrosine Kinase in mast cell driven urothelial barrier injury in an LL-37 induced model of interstitial cystitis.
Sci Rep
Guang Wang, Bin-Sen Li, Jin-Yi Chu +4 more
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic urinary disorder with unclear pathogenesis. Previous studies identified BTK as a hub gene potentially involved in IC/BPS. This study investigates BTK's role in mast cell (MC) activation and bladder inflammation. An LL-37-induced IC/BPS rat model and an in vitro MCs Co-culture system were established. BTK expression was modulated via adenoviral vectors and cell transfection. Bladder inflammation, MC degranulation, and urothelial barrier function were assessed using histology, ELISA, RT-qPCR, Western blot, IHC, TEM, and IF. MC function was evaluated via CCK-8, flow cytometry, Transwell, and TEM. LL-37 upregulated BTK in IC/BPS rats, promoting inflammation, cytokine release, collagen deposition, MC degranulation, and urothelial damage. BTK overexpression exacerbated, while knockdown alleviated these effects. In vitro, LL-37 stimulated MC proliferation, invasion, and degranulation, and reduced apoptosis. Co-culture with activated MCs decreased glycosaminoglycan (GAG) and tight junction (TJ) proteins in SV-HUC-1 cells, enhanced by BTK overexpression and reversed by knockdown. BTK promotes LL-37-induced MC activation and urothelial barrier disruption by suppressing GAGs and TJ proteins, contributing to IC/BPS pathophysiology.
Septal GLP-1 receptors control alcohol taking and seeking.
Neuron
Ginevra D'Ottavio, Kenichiro Negishi, Yavin Shaham
In this issue of Neuron, Tian et al.1 describe a lateral septum GABAergic microcircuit through which systemic administration of the GLP-1 receptor agonist liraglutide, acting via GLP-1 receptor-expressing neurons, inhibits alcohol intake in rodent models.
Effects of Retatrutide on Learning and Memory in Streptozotocin-Induced Male Diabetic Rats.
Behav Brain Res
Ulya Keskin, Eslem Altin, Melkan Kagan Kara +6 more
Diabetes mellitus is associated with cognitive impairment and neurodegenerative changes, partly through hyperglycaemia-driven neuroinflammation and disrupted neuronal signalling. Retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, has shown strong metabolic efficacy, but its effects on diabetes-associated cognitive dysfunction remain unclear. The present study investigated whether Retatrutide attenuates learning- and memory-related impairments in a streptozotocin-induced, insulin-deficient diabetic rat model. Male Sprague-Dawley rats were allocated to four groups: control (C), streptozotocin-induced diabetic (STZ), streptozotocin-induced diabetic treated with Retatrutide (STZR), and Retatrutide alone (R). Diabetes was induced with streptozotocin, and spatial learning and memory were assessed using the Morris Water Maze and Passive Avoidance tests. Metabolic parameters were monitored, while hippocampal cytokine levels (IL-1β, TNF-α), BDNF, CREB, and AKT mRNA expression, Tau protein levels, and cortical and hippocampal histopathology were evaluated using biochemical, molecular, and histological methods. Streptozotocin-induced diabetes produced persistent hyperglycaemia, marked body weight loss, and impaired behavioural performance, particularly prolonged escape latencies in the Morris Water Maze and a selective short-term Passive Avoidance deficit. Retatrutide reduced blood glucose levels but did not prevent diabetes-associated weight loss. In behavioural testing, Retatrutide-treated diabetic rats showed preserved overall Morris Water Maze performance relative to untreated diabetic rats and a limited, task-dependent attenuation of short-term avoidance deficits rather than complete normalisation across all memory measures. These effects were accompanied by a significant reduction in hippocampal TNF-α, a non-significant trend toward lower IL-1β, and partial preservation of cortical and hippocampal cytoarchitecture. Retatrutide alone did not improve behavioural performance beyond control levels, although BDNF and CREB mRNA expression were increased in the non-diabetic Retatrutide group. These findings indicate that Retatrutide is associated with a partial attenuation of streptozotocin-induced behavioural and neuroinflammatory alterations in male rats. The observed effects are consistent with actions extending beyond glycaemic control alone, although direct central exposure of Retatrutide was not established in the present study. Further studies in insulin-resistant and type 2 diabetes-like models are needed to clarify the underlying mechanisms and translational relevance.
Caffeine suppresses inflammation and subretinal fibrosis through modulation of the thrombospondin-1-Bim axis.
Exp Eye Res
Nader Sheibani, Shoujian Wang, Soesiawati R Darjatmoko +1 more
Age-related macular degeneration (AMD) in the aging population frequently leads to vision impairment. Treatment for neovascular AMD (nAMD) focuses on the tortuous leaky vessels that typify choroidal neovascularization (CNV). Subretinal fibrosis in nAMD patients is more challenging to treat, as few effective options exist. This fibrosis notably impairs vision and typically develops in patients who do not fully respond to current treatments. To gain a better understanding of pathways that could be utilized to subvert subretinal fibrosis, we examined the role Bim, a pro-apoptotic mediator in the intrinsic cell death pathway, and thrombospondin-1 (TSP1), a key regulator of ocular angioinflammatory processes, have in moderating fibrosis. Here we show caffeine treatment significantly reduced subretinal fibrosis in the mouse laser photocoagulation model consistent with its known ability to enhance mononuclear phagocyte (MP) clearance and reduce CNV. Since the TSP1-Bim axis facilitates MP clearance, suppresses inflammation, prevents subretinal fibrosis and CNV, we assessed its necessity for the mitigation of fibrosis by caffeine. We show that caffeine did not prevent subretinal fibrosis or CNV in mice lacking Bim or TSP1. Thus, caffeine utilizes the intrinsic death pathway though TSP1-Bim axis to subvert subretinal fibrosis, likely by suppressing inflammation during CNV.
Multi-omics profiling reveals systemic rejuvenation of the aged kidney through senolytic therapy.
NPJ Regen Med
Shilin Chen, Chenglin Zhang, Pengxu Cang +14 more
Cellular senescence is a key driver of kidney aging, leading to functional decline and increased susceptibility to chronic kidney disease. While the senolytic combination of dasatinib and quercetin (D + Q) has shown promise in mitigating age-related pathologies, its long-term effects and underlying multi-level systemic mechanisms in the aging kidney remain poorly defined. Here, we systematically evaluated the long-term effects of D + Q in naturally aged mice using multi-omics approaches. We show that D + Q treatment reduces senescence markers (p16, p21, SA-β-gal), restores the anti-aging protein Klotho, and attenuates renal fibrosis and inflammation. Proteomic profiling reveals that D + Q enhances apoptotic clearance of senescent cells and promotes proliferative and regenerative pathways. Moreover, D + Q reactivates PPARα signaling, improves fatty acid oxidation, and reduces lipid accumulation in aged kidneys. Single-cell transcriptomics further demonstrates that D + Q reverses transcriptional aging signatures across multiple renal cell types and remodels cell-type-specific pathways associated with metabolism, inflammation, and fibrosis. Cell-cell communication analysis reveals that D + Q normalizes the hyperconnected intercellular network in aged kidneys, particularly by modulating inflammation-related signaling. Our findings offer a comprehensive, systems-level understanding of how senolytic therapy restores renal homeostasis, emphasizing its potential as a multifaceted intervention to combat kidney aging.