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Hemodynamic and metabolomic responses to infusion of GLP-1 agonist exenatide in pulmonary arterial hypertension.
JCI Insight
Chinthaka B Samaranayake, Marili Niglas, Nicoleta Baxan +10 more
Preclinical studies suggest beneficial effects of GLP-1 agonists in pulmonary arterial hypertension (PAH). This first-in-disease study evaluated acute hemodynamic effects of GLP-1 agonist, exenatide administered i.v. in patients with idiopathic PAH and CTEPH as well as in a PAH rodent model. Seventeen patients (9 idiopathic PAH) received an exenatide infusion during right heart catheterization, which included multisite sampling for circulating metabolites. Acute effects of exenatide were also assessed by cardiac magnetic resonance imaging in monocrotaline (MCT) PAH and control rats. In the clinical study, exenatide was well tolerated, reduced mean pulmonary artery pressure (45 ± 15 mmHg versus 40 ± 18 mmHg), and improved cardiac index (2.1 ± 0.6 L/min versus 2.4 ± 0.9 L/min/m2) and pulmonary vascular resistance (7.8 ± 8.0 WU versus 5.9 ± 5.0 WU) across all patients. Right ventricular (RV) contractility and afterload improved in a subset of patients undergoing pressure-volume measurements. In an exploratory metabolomics analysis, 47 metabolite levels changed after exenatide infusion, predominantly in free fatty acid pathways. Six metabolites with prognostic relevance in PAH within myocardial glycolytic and lipid oxidation pathways were also altered after exenatide. In MCT rats, exenatide improved RV stroke-volume, RV ejection fraction, and RV-arterial coupling. These findings support the further evaluation of exenatide within chronic studies as a potentially novel pulmonary vasodilator therapy.
A PUFA-rich diet increases endogenous genotoxic stress and mitochondrial DNA damage in mice.
Genes Environ
Masatomi Shimizu, Ayako Daizo, Kenichi Kawada +2 more
Substitution of dietary saturated fat with seed oils highly enriched in n-6 polyunsaturated fatty acids (PUFAs) has been advocated as healthy strategy to offset elevated cholesterol levels. However, both n-6 as well as n-3 PUFAs, considered essential because vertebrates lack the enzymatic apparatus for their de novo synthesis, are the main source of endogenous DNA damage during the aging process due to their high oxidizability. The membrane pacemaker theory of aging is an extension to the oxidative theory of aging and postulates that higher PUFA content in membrane lipids determines the lifespan of different species.
Endometrial senescence: inevitability and conditional occurrence in female fertility.
Reprod Fertil
Chunxue Niu, Xiuying Lin, Lei Liu +9 more
The endometrium is the primary site of embryo implantation. Cellular senescence within the endometrium can be broadly categorised into normal cyclical senescence and pathological excessive senescence. Normal cyclical senescence occurs as a normal component of the female reproductive cycle and contributes to endometrial receptivity for embryo implantation. In contrast, pathological excessive senescence arises in response to excessive external stimuli. This process may propagate between cells, impair immune-mediated clearance, and reduce the efficacy of senolytic therapies. This review aims to summarise the physiological and pathological endometrial cell senescence, as well as current therapeutic strategies targeting this process, thereby providing a theoretical framework and directions for future clinical research.
Diagnostic and management challenges of severe heart failure with reduced ejection fraction in a patient with extreme morbid obesity: a case report.
J Med Case Rep
Mafaz Mansoor, Peyton Matt, Monica Mohanty +2 more
Morbid obesity is a growing global health crisis that significantly increases cardiovascular morbidity and mortality. Patients with extreme obesity present unique diagnostic and therapeutic challenges, particularly in the management of heart failure with reduced ejection fraction (HFrEF).
Differences in physiological response to an oral glucose tolerance test in adult Maasai men and women.
Acta Diabetol
Dirk Lund Christensen, Cathrine Olesen Emborg, Kaushik Laxmidas Ramaiya +9 more
Rural, agro-pastoralist Maasai in East Africa exhibit low prevalence of diabetes, yet little is known about their physiological response to glucose loads and whether sex has an impact on glucose metabolism, including incretin hormones.
Cyclic Cushing syndrome as a clinical enigma and diagnostic dilemma in advanced endocrinology.
J Endocrinol Invest
Yeva Ilkiv, Kateryna Potapova, Viktoriia Yerokhovych +1 more
Cyclic Cushing's syndrome (CCS), a rare and atypical form of endogenous hypercortisolism, remains a very relevant problem from a diagnostic point of view. To confirm this disease, it is necessary to record two episodes of hypercortisolism alternating with period of normocortisolism. Intercyclic phase is characterized not only by negative laboratory test results but also by the absence of pronounced symptoms, making the pathology hidden and, presumably, undiagnosed in certain cases. Some causes remain undetermined and require further investigation. The process of diagnosing and verifying CCS is often lengthy and requires repeated testing at certain intervals. However, none of the currently available methods are 100% accurate. Therefore, a step-by-step approach with confirmation by several highly sensitive tests is recommended for the differential diagnosis of ACTH-dependent and ACTH-independent cyclic hypercortisolism. The risk of false results cannot be ruled out even when the most reliable methods available today are used. Thus, the diagnostic algorithm for each individual case will be specific and will depend on the phase of the disease, the patient's condition, and concomitant pathology. Our review summarizes current data on the mechanisms of cyclic hypercortisolism known to date and provides a comparative and critical analysis of modern diagnostic methods that help identify this pathology and indicate its origin.
Causes and consequences of discontinuation of GLP1RAs or tirzepatide.
Nat Rev Endocrinol
Antonio Ceriello, Francesco Prattichizzo, Abdul Raouf Mastan Sheik Abdullah +7 more
Glucagon-like peptide 1 (GLP1) receptor (GLP1R) agonists and tirzepatide, a dual GLP1R and glucose-dependent insulinotropic polypeptide receptor agonist, have become fundamental in managing type 2 diabetes mellitus (T2DM) and obesity due to their potent glycaemia-lowering and weight-lowering effects as well as their cardiovascular and renal benefits. However, data from the past 2 years suggest that real-world persistence on these drug classes is often suboptimal, with many people discontinuing these medications, even within their first year of therapy. Reasons for treatment discontinuation include, but are not limited to, gastrointestinal adverse effects, less-than-desired efficacy, high cost, and fear about uncommon or rare adverse effects. When treatment is discontinued, weight regain and the deterioration of multiple cardiometabolic risk factors are common. Repeated cycles of initiation, interruption and re-initiation of these drugs might induce body weight and HbA1c fluctuations - two risk factors for cardiovascular and microvascular events. These phenomena, coupled with the re-development of overweight or obesity and poor glycaemic control when not on therapy, might increase the long-term risk of complications. The lack of anti-atherosclerotic and plaque-stabilizing effects of incretin-based medications might contribute to elevated cardiovascular risk, especially acutely following their discontinuation. However, at present, few data are available regarding the incidence of hard outcomes in people discontinuing such drugs. In this Review, we discuss common reasons for GLP1R agonist and tirzepatide discontinuation and examine available evidence related to potential cardiometabolic consequences. We also discuss long-term implications for T2DM care, weight management and, ultimately, cardiorenal disease prevention in patients with T2DM and/or overweight or obesity.
Dysesthesia associated with GLP-1 agonist therapies: data-mining analysis and literature review.
Eur J Clin Pharmacol
Marie-Laure Laroche, Hélène Géniaux, Manon Jardou
An increasing number of anecdotal reports on social media platforms and medical blogs describe dysesthesia, particularly burning skin sensations, in association with glucagon-like peptide-1 receptor (GLP-1R) agonists. We performed a pharmacovigilance data-mining analysis to characterise cases of dysesthesia related to GLP-1R.
ALDH2 alleviates diabetes-induced myocardial cell senescence and electrical remodeling by regulating SIRT1.
Free Radic Biol Med
Lei Wang, Hui-Hui Wang, Qing Chen +19 more
There is a significant association between cardiomyocyte senescence and cardiac insufficiency. Senescent myocardial cells increase the susceptibility to cardiomyopathy and arrhythmia, while diabetes accelerates myocardial cell senescence. This study aims to explore whether ALDH2 can improve diabetes-induced myocardial cell senescence and electrical remodeling and reveal the underlying mechanism. In vivo, we found that ALDH2 overexpression effectively alleviated diabetes-induced cardiomyocyte senescence and the electrical remodeling of Nav1.5. Importantly, in vivo programmed electrical stimulation revealed that ALDH2 significantly reduced ventricular tachycardia (VT) susceptibility and duration in diabetic mice. In vitro, molecular docking confirmed the binding mode between ALDH2 and SIRT1. Using high glucose-induced H9C2 cardiomyocytes, we demonstrated that ALDH2 activation restored Nav1.5 protein expression and alleviated cellular senescence via SIRT1 upregulation. This protective mechanism is closely associated with SIRT1-mediated cellular ROS clearance and mitochondrial homeostasis. In conclusion, our study provides robust in vivo evidence that targeting the ALDH2/SIRT1 axis effectively prevents diabetic myocardial senescence and fatal electrical instability. These findings highlight a promising translational strategy to reduce the risk of malignant arrhythmias and improve cardiovascular health outcomes in diabetic patients.
Modulation of aggression by neuropeptide Y: receptor pharmacology, neural circuitry, and psychiatric relevance.
Neuropeptides
Sanjay Awathale, Akshay Chaudhari, Gajendra Pardeshi +3 more
Violence and aggression arise from dynamic interactions among genetic liability, neurobiological regulation, and environmental stressors, mediated by a distributed "core aggression circuit" encompassing the prefrontal cortex, amygdala, hypothalamus, and brainstem. Neuropeptide Y (NPY), a highly conserved 36-amino acid neuromodulator, has emerged as a key stress-buffering and emotion-regulatory agent with relevance to impulsive and reactive aggression. This review synthesizes translational evidence linking NPY biology to aggression and violence by integrating molecular mechanisms, receptor pharmacology, neural circuitry, and clinical phenotypes across psychiatric disorders. Evidence from animal models, neuroimaging, cerebrospinal fluid and plasma studies, and genetic investigations indicates that reduced central NPY signaling is generally associated with heightened stress sensitivity and impulsivity, well recognized risk factors for aggression, and, in paradigms using direct aggression measures, with aggressive behavior itself, whereas preserved or elevated NPY supports resilience. Mechanistically, postsynaptic Y1 receptor signaling dampens excitability in corticolimbic and amygdala-hypothalamic pathways and restrains stress-driven autonomic/endocrine escalation via modulation of hypothalamic corticotropin-releasing hormone and hypothalamic-pituitary-adrenal-axis activity. In contrast, presynaptic Y2 receptor limits NPY availability and, when overactivated, may promote vulnerability to anxiety and emotional dysregulation. Genetic variants and disorder-linked alterations further support clinical relevance, with indirect implications for intermittent explosive disorder, borderline personality disorder, oppositional defiant disorder, and disruptive mood dysregulation disorder. Despite inconsistent study designs and limited aggression-specific clinical data, NPY represents a candidate biomarker and potential therapeutic target for stress-related conditions involving aggression, though most therapeutic findings remain preclinical or disorder-general, underscoring the need for aggression-focused clinical trials, dimensional refinement of anger/aggression constructs, and cautious translational framing.
The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models.
J Neuroinflammation
Hyun-Ju Lee, Jaewoo Seok, Sora Kang +5 more
BMS-754807 is a dual inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) that is in phase II clinical trials for the treatment of HR-positive and HER2-negative breast cancer. Because IGF-1R signaling regulates inflammatory responses, pharmacological modulation of IGF-1R may have therapeutic potential for Alzheimer's disease (AD); however, the effects of BMS-754807 on neuroinflammatory responses/AD pathology and cognitive function have not been fully investigated.
Regulation of Satellite Cells and Myogenesis in Response to Eccentric Resistance Exercise in Hypoxic Conditions in Healthy Young Men.
FASEB J
Sophie van Doorslaer de Ten Ryen, Geoffrey Warnier, Nancy Antoine +5 more
Satellite cells participate in myogenesis and contribute to skeletal muscle regeneration and hypertrophy. Amongst other stimuli, satellite cells can be activated by exercise and hypoxia. However, the cumulative effect of exercise on hypoxia on myogenesis is not well understood, certainly in humans. Furthermore, whether satellite cell activation and myogenesis differ between environmental hypoxia and blood flow restriction is not known. The purpose of this study was to analyze satellite cell and myogenic markers in response to acute eccentric resistance exercise in normoxia, normobaric environmental hypoxia, and with blood flow restriction (local hypoxia). Thirty-eight healthy young men were allocated to one of the three experimental conditions: normoxia (n = 13), normobaric environmental hypoxia (n = 12), and blood flow restriction (n = 13). They all performed 5 series of 15 repetitions at 60°/s for the knee extension and 30°/s for the knee flexion on an isokinetic dynamometer. Vastus lateralis muscle biopsies and blood samples were taken before, 1, 24, and 72 h after exercise. Myogenic regulatory factor expression was upregulated after exercise similarly in the normoxic and hypoxic groups and attenuated in the blood flow restriction group. Despite differential regulation of myogenic regulatory factor expression and circulating creatine kinase levels after eccentric resistance exercise, none of the investigated hypoxia markers and immediate early genes, inflammatory markers, growth factors, except insulin-like growth factor-1, and mitogen-activated protein kinase members were differently regulated between the groups. Contrary to our hypothesis, satellite cell activation and myogenesis were not potentiated by the combination of eccentric resistance exercise and hypoxic conditions.
Genomic structural equation modeling reveals the shared genetic architecture of osteosarcopenia across five musculoskeletal phenotypes.
Mamm Genome
Weiqiang Lai, Kaiqin Gong, Ronghao Zhong +9 more
Osteosarcopenia-the concurrent presence of osteoporosis and sarcopenia-affects approximately 18.5% of older adults globally, yet its shared genetic basis remains poorly understood. We applied genomic structural equation modeling (Genomic SEM) to integrate genome-wide association study (GWAS) summary statistics across five phenotypes spanning the pathophysiological spectrum of osteosarcopenia: appendicular lean mass (ALM), bone mineral density (BMD), handgrip strength (HGS), walking pace, and fracture. Fine-mapping, transcriptome-wide association study (TWAS), pathway enrichment, cell-type enrichment, and spatial transcriptomic mapping were performed to functionally annotate the identified loci. A single-factor model (CFI = 0.976) captured the shared genetic liability, with HGS and ALM loading most strongly. A two-factor sensitivity analysis confirmed partial separability of muscle and bone dimensions, though the single common factor was retained for integrated downstream annotation. We identified 58,696 genome-wide significant single-nucleotide polymorphisms (SNPs) condensed into 1078 independent lead variants, including 29 novel loci. Fine-mapping prioritized 317 high-confidence causal variants, encompassing key genes including BMP6, ACAN, IHH, LRP5, and SOX5. TWAS and MAGMA converged on IGF1R, FOXO3, and IRS1 as dual susceptibility genes. Pathway analysis revealed significant enrichment in endochondral ossification and growth hormone/insulin-like growth factor-1 signaling. Cell-type enrichment localized genetic risk to mesenchymal stem cells and skeletal muscle satellite cells, while spatial mapping identified cartilage primordium as the most enriched developmental context. This study systematically elucidates the shared genetic architecture of osteosarcopenia, highlighting developmental, endocrine, and stem cell-related pathways as core mediators. These findings provide a theoretical foundation for precision geroscience and the development of dual-target therapeutic strategies.
Weight trajectories after last tirzepatide or semaglutide prescription across a federated health network.
Biol Methods Protoc
Karthik Murugadoss, Gowtham Varma, A J Venkatakrishnan +2 more
GLP-1 receptor agonist (GLP-1RA) discontinuation has been associated with weight regain. However, weight trajectories following the last documented GLP-1RA prescription in the real-world clinical setting have not been explored. Here, we assessed weight trajectories of 4182 patients in the 6 months following their last semaglutide or tirzepatide prescription. Approximately two-thirds of patients showed stable weight or continued weight loss during this period. In a representative subset of 300 patients whose clinical notes were curated using a large language model, treatment discontinuation was documented for 119 patients (40%) around the time of the last prescription. Among these 119 patients, a similar pattern of weight trajectories was observed, with 72% of patients not demonstrating weight regain. Exercise counseling was documented more frequently among patients with durable weight loss after the last GLP1-RA prescription than among those with weight regain (26.2% vs. 14.7%; P = .04). Further studies are warranted to evaluate the mechanisms underlying these real-world patterns.
Glucagon-like peptide-1 receptor agonists for weight loss in end-stage heart failure patients considered for heart transplantation.
JHLT Open
Sambavan Jeyakumar, Ragavi Jeyakumar, Hunter Eckford +11 more
Severe obesity is a relative exclusion criterion for heart transplantation. This study assessed glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for weight loss as a bridge to heart transplantation candidacy. A retrospective study of end-stage heart failure (ESHF) outpatients commenced on semaglutide compared demographic, metabolic, and transplant listing data pre- and post-treatment. Nine patients (median pre-GLP-1 RA body mass index [BMI]: 35.9 kg/m2 [IQR 1.3]) received semaglutide for a median of 4 months (IQR 9). Seven patients (78%) had an initial BMI >35 kg/m2; an exclusion criterion for transplantation. Post-treatment, median BMI decreased to 32.2 kg/m2 (IQR 4.1), representing a 5.0 kg (IQR 6.3) median weight loss. All patients were subsequently transplant-listed, and 7 (78%) patients underwent transplantation. No significant adverse effects were reported. These preliminary findings suggest semaglutide may facilitate heart transplantation eligibility in ESHF patients with severe obesity, warranting larger studies to guide GLP-1 RA use in transplant protocols.
ICER report demonstrates both the value and challenges in financing of weight loss medications.
J Manag Care Spec Pharm
Sujith Ramachandran, Ben Urick, Tara Thomas
Two out of 5 US adults live with obesity, generating substantial clinical and economic burden. Recent glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including semaglutide and tirzepatide, demonstrate significant weight loss and cardiometabolic benefits and were found by the Institute for Clinical and Economic Review (ICER) to be cost-effective compared with lifestyle modifications alone. However, even limited uptake exceeds ICER's annual budget impact threshold, prompting access concerns. The latest real-world evidence demonstrates that persistence for these drugs is lower than in clinical trials, resulting in frequent weight regain after discontinuation, tempering expectations of long-term medical cost offsets. Evidence on medical spending impact is mixed, with cost-offset signals only observed among patients with obesity and diabetes receiving high-potency injectable agents, whereas obesity-only populations often show spending increases. Given current coverage restrictions, this commentary recommends combining drug coverage with lifestyle management programs, avoiding arbitrary duration limits, using targeted prior authorization, and exploring innovative payment models to improve access while managing budget impact.
Semaglutide-associated risk of nonarteritic anterior ischemic optic neuropathy in patients with type 2 diabetes: A systematic review and meta-analysis of observational studies.
PLoS Med
Jędrzej Chrzanowski, Magdalena Walicka, Jacek Burzyński +3 more
Semaglutide, a glucagon-like peptide-1 receptor agonist, is widely used for the management of type 2 diabetes (T2DM). Recent case reports have raised concerns about a potential association between semaglutide use and the development of nonarteritic anterior ischemic optic neuropathy (NAION), a rare but vision-threatening condition. We aimed to evaluate whether semaglutide use is associated with an increased risk of NAION in patients with T2DM.
[Obesity and type 2 diabetes mellitus (Update 2026)].
Wien Klin Wochenschr
Johanna M Brix, Martin Clodi, Jürgen Harreiter +9 more
Obesity is a chronic disease with a variety of metabolic, mechanical and psychosocial complications, including a high risk of developing prediabetes and subsequently type 2 diabetes mellitus. The choice of antidiabetic treatment as well as concomitant treatment, increasingly takes this into account. Modern glucagon-like peptide 1 (GLP-1) analogues and the combined gastric inhibitory polypeptide (GIP)/GLP‑1 agonist tirzepatide play an important role in the combined treatment of obesity and type 2 diabetes mellitus. Metabolic surgery is currently indicated for people with type 2 diabetes mellitus and a body mass index (BMI) > 30 kg/m2 and can contribute, at least in part, to diabetes remission but it must be integrated into an appropriate lifelong care plan. Every obesity therapy is always based on lifestyle modifications. Due to the large number of new drugs and the many new studies in which an attempt was made to cite the most relevant ones, major changes were made to this chapter compared to 2023. The indications for metabolic treatment were also adjusted.
The Paradox and Future of GLP-1/GIP Combination Therapies: Efficacy and Mechanisms.
Annu Rev Nutr
Iona Davies, Jens J Holst, Mette M Rosenkilde +1 more
Glucagon-like peptide-1 (GLP-1)-based obesity pharmacotherapies have revolutionized obesity treatment. In this review, we discuss the discovery of GLP-1 and evaluate the efficacy of marketed and investigational GLP-1 receptor (GLP-1R) agonists (GLP-1RAs), most notably semaglutide, as well as their potential central mechanism of action. We highlight the GLP-1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual agonist tirzepatide and the GLP-1RA/GIPR antagonist maridebart cafraglutide, discussing how both methods of GIPR targeting can produce beneficial metabolic effects. The lack of evidence for the anorectic effects of GIPR agonism or antagonism alone in humans is noted, and the review concludes with an evaluation of other reasons for the greater efficacy of GIPR/GLP-1R dual targeting compounds over semaglutide.
Incidence of Barrett's esophagus and esophageal cancer following sleeve gastrectomy versus liraglutide therapy.
Ann Gastroenterol
Edward Butt, Juliana Yang
Sleeve gastrectomy has consistently been linked to gastroesophageal reflux disease and Barrett's esophagus. At the same time, the long-term effects of glucagon-like peptide-1 receptor agonists, particularly short-acting agents such as liraglutide, are less well understood. We compared the incidence of Barrett's esophagus and esophageal cancer among patients treated with liraglutide vs. those who underwent sleeve gastrectomy.