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Glucagon Agonist Therapies and Vision Loss: Balancing Promise with Prudence in India.

J Assoc Physicians India

Abhyuday Saxena, Anupam Prakash

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual incretin therapies such as tirzepatide have transformed the management of type 2 diabetes mellitus and obesity, with expanding cardiometabolic indications and rapid market growth globally and in India. However, emerging postmarketing evidence has raised concerns regarding ocular safety. Pharmacovigilance analyses, cohort studies, and case reports suggest an association between GLP-1-based therapies and ophthalmic adverse events, including early worsening of diabetic retinopathy and, more concerningly, nonarteritic anterior ischemic optic neuropathy (NAION)-a potentially irreversible cause of sudden vision loss in adults over 50 years. Although the absolute risk appears very low, regulatory agencies, including the WHO and European Medicines Agency, now recognize NAION as a very rare adverse effect of semaglutide, and similar signals are being explored for other agents, suggesting a possible class effect. Proposed mechanisms include altered optic nerve head perfusion, sympathetic-mediated vasoconstriction, and rapid glycemic shifts affecting vascular autoregulation; however, causality remains unproven. In India, where over 100 million adults live with diabetes and obesity rates are rising, even rare adverse events may translate into substantial public health impact, particularly given limited access to ophthalmic care and increasing unsupervised drug use. We advocate a balanced approach: baseline ophthalmic evaluation in high-risk individuals, informed consent regarding visual symptoms, early referral for visual complaints, strengthened pharmacovigilance, and coordinated endocrinology-ophthalmology surveillance systems. As newer triple agonists approach clinical use, integrating ocular safety into prescribing frameworks is imperative. Metabolic gains must not come at the cost of preventable vision loss.

Semaglutide-Induced Sarcopenia via GLP-1R-mTOR-Satellite Cells Axis and Muscle-Glucose Feedback Loop Potentially Leading to Refractory Hyperglycemia in Type 2 Diabetes: A Case-Driven Hypothesis.

Probl Endokrinol (Mosk)

Amr Ahmed, Sharifa Rodini, Fahad Alrubyea +1 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide have transformed type 2 diabetes mellitus (T2DM) management, yet emerging concerns highlight potential risks of accelerated sarcopenia and subsequent metabolic disruptions. This case-driven hypothesis explores a 53-year-old male with T2DM diagnosed in 2014, who experienced progressive glycemic failure despite standard therapies, including metformin, glipizide, sitagliptin, and empagliflozin. Transition to dulaglutide 1.5 mg for 1.5 years followed by semaglutide (titrated from 0.25 to 1 mg weekly starting September 2024) resulted in weight loss from 84 kg to 70 kg by September 2025, accompanied by sarcopenic symptoms (muscle weakness, reduced mobility) and refractory hyperglycemia (fasting glucose 300 mg/dL, HbA1c 9%), persisting post-discontinuation on September 1, 2025, despite metformin and empagliflozin. We posit that semaglutide may precipitate acute sarcopenia via unexpected GLP-1R-mTOR-satellite cells axis crosstalk, disrupting AMPK-mTOR balance to suppress anabolic mTORC1/IGF-1 signaling (potentially by 25-35%) while enhancing catabolic FOXO/ubiquitin-proteasome and excessive autophagy pathways. This could extend to myokine reprogramming (elevated myostatin/GDF15, reduced irisin/IL-15), glucagon/α-cell compensation inducing hyperglucagonemia (15-25% rise), microbiome-bile acid shifts fostering low-grade inflammation (IL-6/TNF-α upregulation by 10-15%), mitochondrial mass reduction (20-25% via AMPK), and NMJ disassembly, collectively impairing muscle as the primary glucose sink (reducing GLUT4-mediated uptake by 35-45%) and initiating a «muscle-glucose feedback loop» with hepatic gluconeogenesis amplification, yielding treatment-resistant hyperglycemia.Supporting evidence from cohorts (e.g., 24-month study showing ASMI/grip strength declines in 432 patients), longitudinal analyses (NMJ degradation with CAF22/NfL elevations in 141 men), secondary trials (9.3% psoas volume loss in 51 MASLD cases), and case reports (fatigue in a 74-year-old, rhabdomyolysis in a 47-year-old) aligns with this framework, as does in vitro data linking GLP-1 excess to kinesin-1/GLUT4 inhibition and ATP depletion (20-30%). This novel hypothesis underscores sarcopenia's role in GLP-1RA-induced metabolic paradoxes, urging prospective studies on muscle-preserving interventions like resistance training or GLP-1R modulators to refine T2DM paradigms and inspire multidisciplinary research into endocrine-muscle interactions.

GLP-1 receptor agonists in hip, knee and shoulder arthroplasty: Implications for obesity, osteoarthritis, metabolic optimisation and complications.

Knee Surg Sports Traumatol Arthrosc

George M Avram, Pier Francesco Indelli, Bruno Violante +7 more

Glucagon-like peptide-1 receptor agonists and related incretin-based therapies are rapidly changing the management of obesity and metabolic disease. Their increasing use also among patients with osteoarthritis has important implications for hip, knee and shoulder arthroplasty. Beyond weight loss, these drugs may influence systemic inflammation, glycemic control, osteoarthritic symptoms, perioperative complications and surgical candidacy. Recent retrospective studies suggest that preoperative GLP-1 receptor agonist use may be associated with lower risks of periprosthetic joint infection, hospital readmission and other adverse outcomes after total joint arthroplasty. Beyond the perioperative setting, GLP-1 receptor agonists have also been associated with reductions in blood pressure and significant improvements in cardiovascular risk among patients with chronic kidney disease or preexisting cardiovascular disease. However, the current evidence remains largely observational and is limited by residual confounding, indication bias, heterogeneity in treatment timing, and inconsistent reporting of drug class, dose, and duration. This editorial argues that GLP-1 receptor agonists should not be viewed simply as weight-loss agents before arthroplasty, but as part of a broader movement toward metabolic optimisation. Prospective studies are needed before these therapies can be incorporated into standardised arthroplasty optimisation pathways.

Atypical Anorexia Nervosa Developed in a Patient with Severe Obesity and Type 2 Diabetes Following Sleeve Gastrectomy and Postoperative Treatment with Semaglutide and Tirzepatide.

Intern Med

Chiaki Saito, Masahiro Saito, Masatoshi Nakagawa +7 more

We describe an unusual case of a 60-year-old Japanese woman who developed atypical anorexia nervosa (AN) after undergoing bariatric surgery and postoperative semaglutide and tirzepatide therapy. At 57 years of age, due to severe obesity with a body weight of 113 kg (BMI 47.0), she underwent laparoscopic sleeve gastrectomy, and semaglutide and tirzepatide were started one month after surgery. Three years post-surgery, her weight drastically decreased to 50.3 kg (BMI: 20.9). Her rapid weight reduction, intense fear of weight gain, obsession with her body image, and normal weight (BMI >18.5) led to the diagnosis of atypical AN according to the DSM-5.

Protecting Musculoskeletal Development and Physical Function in Adolescents on GLP-1 Therapy.

Child Obes

Webb A Smith, Ahlee Kim, Timothy J Khalil +2 more

Glucagon-like peptide-1 receptor agonists (GLP-1s), including semaglutide and liraglutide, are effective pharmacologic options for pediatric obesity, producing significant weight loss, cardiometabolic improvements, and reductions in barriers to physical activity. By alleviating pain, mechanical load, and psychosocial burden, these agents can also create a window to initiate sustainable health behaviors in adolescents. However, use during critical developmental periods raises concerns regarding long-term effects on musculoskeletal maturation. Adolescence is marked by rapid accrual of muscle and bone mass, and GLP-1-associated weight loss may attenuate this process, potentially reducing peak musculoskeletal capacity and increasing future frailty risk. This perspective piece advocates for integration of tailored exercise prescription with GLP-1 medication therapy. Given limited longitudinal pediatric data, a balanced approach is necessary. GLP-1s should be integrated within a multimodal framework emphasizing resistance training, weight-bearing activity, and optimized nutrition particularly adequate protein intake to preserve lean mass. Exercise may also synergize with GLP-1-mediated metabolic improvements to enhance functional outcomes. Clinicians should provide individualized, developmentally appropriate guidance that addresses access barriers and patient preferences while reinforcing that pharmacotherapy is not a substitute for lifestyle intervention. Integrated care models that prioritize musculoskeletal integrity and functional health are essential to maximizing long-term outcomes, underscoring the need for longitudinal research in pediatric populations.

Effects of liraglutide on gut bacterial community dynamics.

Microbiol Spectr

Jami Bull, Paul L Durham, Babur S Mirza

Liraglutide, a GLP-1 receptor agonist, is used to induce weight loss. However, limited information exists on liraglutide's effects on the gut bacterial community and their restoration after washout. We investigated liraglutide's effect on the gut bacterial community in diet-induced obese (DIO) mice and whether these changes persist after washout. Twenty-four male C57BL/6J mice on high-fat (HFC) or low-fat (LFC) diets were monitored for 21 days. A subgroup of high-fat mice received daily liraglutide for 14 days (HFL), followed by a 7-day washout. Liraglutide induced significant weight loss by Day 4, which persisted during treatment and partially reversed post-treatment. For bacterial community analysis, 7.1 million 16S rRNA gene sequences were retrieved using Illumina paired-end sequencing. We observed distinct shifts in the gut bacterial community structure during liraglutide treatment, which mostly returned to baseline after the 7-day washout. Using Similarity Percentages analysis, 21 amplicon sequence variants (ASVs) were identified as major contributors. Nine ASVs, related to Lactobacillus gasseri, L. paragasseri, L. johnsonii, and Leptogranulimonas caecicola, significantly increased during treatment and declined post-washout. The remaining 12 ASVs, associated with protein- and carbohydrate-fermenting bacteria (Romboutsia, Faecalicatena, and Oscillibacter), decreased during treatment. Comparison across all groups identified 29 ASVs, clustering into seven phylogenetic groups, highlighting liraglutide's enrichment of bile acid- and mucin-associated taxa and suppression of carbohydrate-fermentative genera. These findings demonstrate that liraglutide induces rapid, diet-dependent, yet reversible shifts in the gut microbiome, favoring lactic acid-producing bacteria while reducing fermentative taxa. Such microbial changes may contribute to liraglutide's metabolic effects and provide insight into host-microbiome interactions in obesity treatment.IMPORTANCEObesity and overweight states are intricately linked to the gut bacterial community; however, the effects of common obesity treatments such as GLP-1 receptor agonists on gut bacteria remain unclear. Here, we show that liraglutide, a GLP-1 analog, reshapes the gut bacterial community in diet-induced obese mice relative to untreated obese and lean controls. By including baseline samples when mice were at a normal weight, we distinguished bacterial changes due to the drug from those due to obesity progression, as well as how the community structure is affected during a washout period. Liraglutide treatment selectively increased beneficial gut bacteria (e.g., Lactobacillaceae) under high-fat conditions. These bacterial shifts during GLP-1 therapy may contribute to its metabolic benefits and broaden our understanding of host bacterial interactions in the context of diet and weight management.

Liraglutide affects mitochondrial function and histone acetylation through the NQO1/SIRT3 pathway in diabetic kidney disease.

Mol Cell Biochem

Jie Gao, Xiaoyu Lv, Pingping Zhao +2 more

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes. The glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide exerts renoprotective effects beyond glucose control; however, the underlying mechanisms remain incompletely understood. The protective effects and mechanisms of liraglutide were investigated using in vitro (HK-2 cells under glucolipotoxic conditions) and in vivo (DKD rat) models. Key molecular and functional assessments included the evaluation of oxidative stress, apoptosis, mitochondrial function (dynamics (MFN1, MFN2, FIS1, and DRP1), mitophagy (PINK1, PARKIN, LC3II/I, and P62), and ultrastructure), and histone acetylation (H3K9/14/18/27ac). The critical role of the NQO1/SIRT3 pathway was validated using pharmacological inhibition and genetic silencing (shRNA/AAV). Both in vitro and in vivo, a multifaceted injury phenotype, including oxidative stress, apoptosis, mitochondrial dysfunction, and histone hyperacetylation, was induced, accompanied by downregulation of the NQO1/SIRT3 pathway. Disruption of this pathway further exacerbated these injuries. Conversely, liraglutide treatment effectively counteracted this phenotype, improving metabolic parameters (blood glucose, blood insulin, and blood lipids), renal function (blood urea nitrogen, serum creatinine, and urine albumin-to-creatinine ratio) and histopathology. Liraglutide attenuated oxidative stress and apoptosis, restored mitochondrial function and mitophagy, and reduced histone hyperacetylation. These protective effects were consistently associated with the restoration of NQO1/SIRT3 expression. Genetic or pharmacological disruption of the NQO1/SIRT3 axis significantly attenuated the efficacy of liraglutide, and combined inhibition completely abolished its effects. Our findings demonstrate that liraglutide attenuates DKD by activating the NQO1/SIRT3 pathway, which coordinates the enhancement of mitochondrial function and the restoration of epigenetic homeostasis. This study revealed that the NQO1/SIRT3 pathway is a critical mechanistic mediator of the renoprotective effect of liraglutide.

Reversible disruption of proresolving lipid mediator pathways and erythroid homeostasis by PM2.5.

Toxicol Sci

Haley Asplund, Heinrich H Dreyer, Timothy E O'Toole +4 more

Ambient particulate matter (PM2.5) exposure is a major environmental risk factor for cardiopulmonary disease, but its effects on erythroid homeostasis remain incompletely understood. Although prior in vitro work indicates that PM2.5 can damage circulating red blood cells (RBCs), whether exposure alters erythropoiesis and the coordinated clearance of senescent RBCs has not been fully explored. Using a mouse model of whole-body exposure to concentrated ambient PM2.5 (CAP), we investigated associations between inhaled PM on erythroid output, splenic macrophage function, and lipid mediator signaling. CAP exposure was associated with suppressed erythropoietin levels, reduced circulating reticulocytes, and decreased erythroid precursor populations in the bone marrow, consistent with impaired erythropoiesis. Despite preserved splenic architecture, CAP-exposed mice exhibited reduced splenic iron and heme content, consistent with diminished erythrocyte turnover and processing. Targeted lipidomic profiling revealed broad suppression of proresolving lipid mediators in the spleen, with lipoxin A4 (LXA4) among the most consistently reduced species. Expression of the LXA4 receptor, ALX/FPR2, was also downregulated with prolonged exposure. Importantly, removal of CAP and return to filtered air resulted in normalization of splenic lipid mediator profiles, restoration of LXA4 levels, and recovery of erythroid parameters, including reticulocyte abundance and RBC stress markers. Together, these findings suggest that altered resolution signaling contributes to PM2.5-induced disruption of erythroid homeostasis and implicate macrophage-lipid mediator pathways in the hematologic response to environmental stress.

SDF-1 Attenuates Oocyte Quality Decline During Reproductive Aging Through Autophagy-Enhanced Stress Granule Scavenging.

Adv Sci (Weinh)

Rui Long, Meng Wang, Ruolin Mao +10 more

The age-related decline in oocyte quality constitutes a major cause of reduced female fertility. In this study, we investigated the potential of stromal cell-derived factor-1 (SDF-1) to counteract oocyte deterioration during reproductive aging. We observed a significant negative correlation between SDF-1 levels and aging in both human follicular fluid/oocytes and murine ovarian tissues. Utilizing aged mouse models, we found that SDF-1 supplementation, both in vitro and in vivo, was associated with the amelioration of multiple aging-associated oocyte defects, including restored meiotic spindle morphology, improved chromosomal alignment, normalized distribution of cortical granules and mitochondria, enhanced mitochondrial membrane potential, and reduced oxidative stress. Consequently, SDF-1 treatment improved fertilization competence, embryonic developmental potential, and fertility restoration in aged female mice. Mechanistically, transcriptomic and functional analyses suggested that SDF-1 ameliorates oocyte aging primarily by enhancing autophagic activity, which was associated with clearance of accumulated stress granules and mitigation of oxidative damage. Pharmacological inhibition of autophagy attenuated the beneficial effects of SDF-1. In conclusion, our findings point to a previously underexplored role for SDF-1 in alleviating age-related oocyte decline, potentially through autophagy-enhanced stress granule scavenging, positioning SDF-1 as a promising candidate for therapeutic intervention in reproductive aging, although further investigations are warranted in the future.

Calreticulin as a stress-responsive integrator of ER proteostasis, calcium homeostasis, and immune clearance.

Mol Biol Rep

Arsene Mutombo Menga, Xin Hong, Rui Shi

Calreticulin (CALR) is a multifunctional endoplasmic reticulum (ER) protein that couples lectin-like chaperone activity in the calnexin/calreticulin cycle with high-capacity Ca²⁺-binding, thereby linking ER proteostasis to luminal calcium homeostasis. Although classically viewed as an ER-resident chaperone, CALR is increasingly recognized as a stress-responsive regulator whose functions extend beyond the ER lumen. Under stress, CALR can relocalize to the cell surface or extracellular space, where it functions as an immune-recognition and pro-clearance signal for damaged or dying cells. Across aging and chronic degenerative conditions, persistent ER stress, altered calcium handling, and defective clearance of stressed or senescent cells may reshape CALR expression, localization, and stress-responsive functions. However, CALR has not been widely conceptualized as an integrative regulator linking ER proteostatic stress, calcium dysregulation, senescence-associated remodeling, and immune surveillance. In this review, we examine CALR as a stress-responsive integrator of ER proteostasis, calcium homeostasis, senescence-associated stress adaptation, and immune-mediated clearance, and discuss how this framework may inform mechanistic studies and therapeutic strategies in chronic degenerative diseases.

Myocardial fibrosis in patients with coronary artery disease and diabetes mellitus assessed by cardiovascular magnetic resonance T1 mapping.

Int J Cardiovasc Imaging

Jia Deng, Bihong Liao, Hong Huang +4 more

This study aimed to investigate the severity of myocardial fibrosis in patients with coronary heart disease (CHD) combined with diabetes mellitus (DM) using cardiovascular magnetic resonance (CMR) T1 mapping technique. This study enrolled 146 patients with CHD who underwent CMR. 96 patients had CHD without DM [CHD(DM-)], and 50 patients had CHD with DM [CHD(DM+)] according to whether they had DM or not. CMR-related parameters were also measured, including left ventricular (LV) cardiac function, T1 mapping, global strain, and late gadolinium enhancement. Patients were further divided into four subgroups based on the presence or absence of heart failure (HF): CHD (DM+) with HF, CHD (DM+) without HF, CHD (DM-) with HF, and CHD (DM-) without HF. The determinants of myocardial fibrosis in patients with CHD and CHD(DM+) were determined by multivariate linear regression analysis. Both native T1 and extracellular volume fraction (ECV) were significantly higher in patients with CHD (DM+) compared with those with CHD (DM-) [native T1: 1263.52 ± 69.19 vs. 1237.62 ± 62.11 and ECV: 33.95 (31.49, 37.62) vs. 32.21 (28.63, 35.7), respectively, p < 0.05]. While LV functional parameters, global peak strain, and late gadolinium enhancement were not significantly different between CHD (DM+) and CHD (DM-) patients. DM is an independent determinant of elevated native T1 and ECV in patients with CHD. In CHD and CHD (DM+), native T1 and ECV were significantly correlated with N-terminal pro-brain natriuretic peptide and LV ejection fraction. Meanwhile, native T1 and ECV were higher in patients with CHD (DM+) with HF than in those with CHD (DM+) without HF (p < 0.05). Elevated CMR native T1 and ECV values indicate that DM acts as an independent determinant in exacerbating myocardial fibrosis among CHD patients. Moreover, in patients with CHD combined with DM who developed HF, native T1 and ECV values were further increased, suggesting that the combination of DM and HF further aggravates myocardial fibrosis severity in CHD patients.

[Study on mechanism of Zhenwu Decoction against heart-kidney Yang deficiency-induced heart failure via cAMP/PKA signaling pathway].

Zhongguo Zhong Yao Za Zhi

Ya-Shu Li, Jing Zhao, Jian-Bei Li +6 more

This study aimed to investigate the effects of Zhenwu Decoction(ZWT) on cardiac fibrosis in mice with heart-kidney Yang deficiency-induced chronic heart failure(CHF). The research further explored the therapeutic mechanisms of ZWT in CHF treatment in the hope of providing novel insights for TCM approaches to managing heart-kidney Yang deficiency-induced heart failure. Sixty C57BL/6 mice were randomly divided into the following groups: the control group(normal untreated mice),the DOX group(doxorubicin-induced CHF model),the low-dose ZWT group(ZWT-L,4.7 g·kg~(-1)),the medium-dose ZWT group(ZWT-M,9.3 g·kg~(-1)),the high-dose ZWT group(ZWT-H,18.6 g·kg~(-1)),and the dopamine group(DA,positive control). The CHF mouse model was established over a 4-week period, which was followed by an additional 4-week treatment regimen. After 8 weeks, the spontaneous locomotor activity of mice was assessed, and TCM syndrome scoring was performed. Mouse serum samples were collected and analyzed to measure the levels of cardiac-specific biomarkers including cardiac troponin Ⅰ(cTn-Ⅰ),brain natriuretic peptide(BNP), creatine kinase-MB isoenzyme(CK-MB), creatine kinase(CK),lactate dehydrogenase(LDH),triiodothyronine(T3),succinate dehydrogenase(SDH) and myocardial cyclic adenosine monophosphate(cAMP). Cardiac tissue was collected for pathological examination. Western blot and real-time quantitative polymerase chain reaction(RT-PCR) were used to detect the expression of myocardial cAMP-dependent protein kinase catalytic subunit(PKA C),protein kinase A(PKA),ryanodine receptor 2(RyR2),phospholamban(PLB),B-cell lymphoma-2(Bcl-2),caspase-3,cleaved caspase-3 and Bcl-2-associated X protein(Bax). The experimental results indicated that, compared with the control group, the DOX group exhibited significantly elevated TCM syndrome scores accompanied by decreased heart rate, reduced body weight, and increased cardiac index(P<0.05); serum levels of CK, CK-MB, BNP, cTn-Ⅰ, LDH and myocardial cAMP were significantly increased(P<0.05), while SDH and T3 levels were decreased(P<0.05); meanwhile, myocardial interstitial fibrosis was aggravated and myocardial hypertrophy appeared; the expression of PKA C, PKA, caspase-3, cleaved caspase-3, Bax and phosphorylation of RyR2 were increased(P<0.05), the expression of Bcl-2 and phosphorylation of PLB were decreased compared with the DOX group, the ZWT treated groups demonstrated reduced TCM syndrome scores, increased heart rate, improved body weight, and decreased cardiac index. Additionally, serum levels of CK, CK-MB, BNP, cTn-Ⅰ, LDH and myocardial cAMP were decreased(P<0.05), while SDH and T3 levels were increased(P<0.05); myocardial hypertrophy and fibrosis were also improved; the expression of PKA C, PKA, Bax, caspase-3, cleaved caspase-3 and phosphorylation of RyR2 was reduced(P<0.05), and the expression of Bcl-2 and phosphorylation of PLB were increased(P<0.05). These findings suggested that ZWT may exert therapeutic effects on CHF by regulating sarcoplasmic reticulum calcium-related proteins, reducing apoptosis, and improving cardiac function.

Effects of BPC-157 and TB-500 on Achilles tendon healing in rats: A histopathological and biomechanical study.

Jt Dis Relat Surg

Ozancan Biçer, Oktay Adanir, Yiğit Güleryüz +5 more

This study aims to evaluate the effects of BPC-157, synthetic thymosin beta-4 (TB-500), and their combination on Achilles tendon healing using biomechanical, histopathological, histochemical, and immunohistochemical analyses in a rat model.

Case report: Tirzepatide-associated morbilliform drug eruption and implications for rising glucagon-like peptide-1 agonist use.

JAAD Case Rep

Dorothy S Peng, Amy Shen, Chandra Smart +1 more

Safety of glucagon-like peptide-1 receptor agonists in neuroendocrine neoplasms.

Eur J Endocrinol

Lakshmipriya Thandiyekkal Rajan, Johannes Hofland, Eskeatnaf Mulugeta +1 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been in use for twenty years. There have been concerns about their safety in patients with neuroendocrine neoplasms (NENs). The reports of GLP-1 receptor (GLP-1R)-driven proliferation of C-cell neoplasms in rodent studies had led to the black-box warning against their use in patients with medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2). In this review, we have attempted to evaluate the physiological and pathological expression of GLP-1 receptors (GLP-1R) in various endocrine organs and summarise the preclinical and clinical evidence regarding the effect of GLP-1RA exposure and risk of NENs. GLP-1R expression has not only been found in nonneoplastic tissues such as neurohypophysis, duodenal glands and pancreatic islets but also in neuroendocrine tumours (NETs). Preclinical studies have demonstrated the proliferative effects of GLP-1RA in cell lines representing pancreatic NETs (panNETs) and small intestinal NETs. The available data from retrospective studies, randomized trials and cancer registries provide conflicting data and does not support a generalized increase in NENs with the use of GLP-1RA. Some epidemiological studies have even shown survival benefits associated with GLP-1RA use. In addition, significant gaps in evidence remain, such as lack of data regarding certain tumour subtypes, long-term prospective studies with NENs as the clinical endpoint and uncertainty regarding patients with multiple endocrine neoplasia type 1 (MEN1). Hence, the initiation of GLP-1RA therapy in patient with predisposition to NEN where a contraindication does not exist, should be approached cautiously with careful monitoring for long-term adverse effects.

Effects of GLP-1 Receptor Agonist Exenatide on Mitochondrial Dysfunction After Spinal Cord Injury.

Neurotrauma Rep

Tatsuya Kishi, Hiroyuki Katoh, Kaori Suyama +3 more

Spinal cord injury (SCI) triggers secondary pathological processes, including inflammation, oxidative stress, and mitochondrial dysfunction, that contribute to progressive neuronal damage. Because mitochondria play a central role in cellular homeostasis, mitochondrial impairment is considered an important component of SCI pathophysiology. We investigated the effects of exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, on mitochondrial dysfunction after SCI using a rat contusion model and C6 glioma cells. Exenatide was associated with increased OPA1 expression and enhanced Drp1 phosphorylation at Ser637, suggesting a shift in mitochondrial dynamics toward fusion-dominant regulation. Exenatide also tended to increase the expression of Bcl-2, HO-1, and p62. In vitro, exenatide attenuated H2O2- and CCCP-induced reductions in cell viability, preserved mitochondrial membrane potential, and reduced the proportion of dead cells. These findings suggest that exenatide may mitigate secondary injury after SCI in association with mitochondrial protective responses.

Effects of Liraglutide on Energy Intake in Adolescents With Persistent Obesity After Vertical Sleeve Gastrectomy.

Pediatr Obes

Bao-Vi C Tran, Anna Zenno, Nazrat M Mirza +12 more

In adolescents with obesity ≥ 1-year post-vertical sleeve gastrectomy (VSG), a pilot trial of liraglutide demonstrated a 4.3% BMI reduction. This secondary analysis evaluated energy intake changes (∆EI) and associations of ∆EI with oral glucose tolerance test (OGTT) outcomes and end-of-trial liraglutide plasma concentrations.

Efficacy and Safety of Tesamorelin in People Living With HIV (PLWH) With Lipodystrophy: A Systematic Review and Meta-Analysis.

J Int Assoc Provid AIDS Care

Aqsa Mohammed Ditta, Ruqaiya Muhammad Naeem, Muhammad Mohsin Sami +9 more

BackgroundHIV-associated lipodystrophy, a complication of combined antiretroviral therapy (CART), causes significant physical and psychological distress in people living with HIV (PLWH), compromising treatment adherence. Tesamorelin, a growth hormone-releasing hormone (GHRH) analogue, has emerged as a therapeutic option.ObjectiveTo systematically evaluate the efficacy and safety of tesamorelin in HIV-infected individuals with lipodystrophy receiving CART, incorporating GRADE assessment.MethodsWe searched PubMed, https://ClinicalTrials.gov, and Scopus from inception to February 9, 2026, for randomized controlled trials evaluating tesamorelin in HIV-associated lipodystrophy. Mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CI) were calculated using random-effects models with heterogeneity assessed by I2.ResultsFour RCTs (909 patients) were included. Tesamorelin 2mg significantly reduced visceral adipose tissue (MD= -21.47, 95%CI[-34.73,-8.22],I2=74%,p=0.002), waist circumference (MD-1.61cm,95% CI[-2.28,-0.95],I2=0%,p<0.00001), trunk fat (MD-1.20kg, 95%CI[-1.47,-0.93],I2=0%,p<0.00001), and increased lean body mass (MD1.42kg,95% CI[1.13,1.71],I2=0%,p<0.00001). Modest lipid improvements occurred in total cholesterol (MD-0.16mmol/L,95%CI[-0.27,-0.06],I2=0%,p=0.003). Growth hormone-related adverse effects and higher discontinuation rates (RR2.25,95%CI[0.98,5.17],p=0.06) were observed.ConclusionsTesamorelin demonstrates efficacy in reducing visceral adiposity in PLWH with lipodystrophy on CART. However, limited data on long-term safety, optimal dosing strategies, and durability of treatment effects warrant caution. Future research should evaluate extended treatment duration, dose-response relationships, and patient-reported outcomes to establish comprehensive clinical utility.

Galangin attenuates UVB-induced skin photoaging through SIRT1-dependent LC3 deacetylation and autophagy modulation.

Phytomedicine

Su-Ying Wen, Shang-Chuan Ng, Mei-Hsin Su +4 more

Ultraviolet B (UVB) irradiation is a major contributor to skin photoaging by promoting oxidative stress, extracellular matrix degradation, and cellular senescence. Sirtuin 1 (SIRT1), an NAD⁺-dependent deacetylase, is a key regulator of cellular homeostasis and autophagy and represents an important target for phytochemical-based interventions.

Microfluidic liver-chip to predict clinical drug-drug interaction net effects for precipitant drugs with dual CYP3A4 inhibition and induction potential.

Drug Metab Dispos

Lina Mettler, Justine Badée, Felix Huth +7 more

Accurate predictions of complex clinical drug-drug interactions (DDIs), arising from dual induction and time-dependent inhibition (TDI) of CYP3A4, has remained challenging with conventional in vitro and static/dynamic modeling approaches. In this work, we aimed to anticipate the hepatic DDI effects of 6 CYP3A4 precipitant drugs using a liver-chip coupled to microfluidic perfusion, which enabled simulating clinically relevant pharmacokinetic (PK) time-concentration profiles. Midazolam clearance was measured in the liver-chip to determine the CYP3A4-mediated DDI net effect following exposure to precipitants under either dynamic or constant concentration conditions. For direct comparison, hepatic DDI reference values were generated based on clinical DDI studies by physiologically based PK modeling. Under microfluidic perfusion, CYP3A4 activity in the liver-chip was retained for 3 days and inducible by rifampicin. Although most precipitant drugs induced CYP3A4 mRNA levels, CYP3A4 activity net effects showed either induction or inhibition, in line with clinical observations. Compared with a mechanistic static net effect model and physiologically based PK simulations, liver-chip predictions showed closer alignment and higher accuracy relative to hepatic reference values. Although constant exposures offered the strongest quantitative performance, the ability to apply dynamic PK profiles represents a distinctive feature of this platform. Collectively, these findings position the human liver-chip as a novel translational platform for predicting complex hepatic CYP3A4 DDIs arising from dual TDI and induction in a single, holistic in vitro model. This approach aligns with the broader global regulatory shift toward human-relevant new approach methodologies. SIGNIFICANCE STATEMENT: Complex CYP3A4-mediated drug-drug interactions (DDIs), driven by concurrent time-dependent inhibition and induction, remain difficult to anticipate using conventional in vitro and modeling frameworks. This study establishes a human liver-chip model capable of capturing dual CYP3A4 inhibition and induction within a single experiment, and evaluates how clinical exposure regimes shape the quantitative prediction of hepatic DDI effects. Relative to modeling approaches, this platform demonstrates superior accuracy against hepatic DDI references, supporting more translational DDI risk assessments.