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Oral Delivery of Liraglutide Formulated with PLGA for Sustained Obesity Management.
Int J Mol Sci
Nipeng Chen, Zhipeng Zeng, Xiaoyu Ji +3 more
Liraglutide (Lira), a glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated substantial efficacy in improving glycemic control and reducing body weight. However, subcutaneous injection is poorly adherent for patients. To improve treatment compliance, we developed a poly(lactic-co-glycolic acid) (PLGA)-based nanovesicle (PLGA-Lira-NV) system for the oral delivery of Lira using a double-emulsion solvent evaporation technique. The optimized formulation yielded a narrow size distribution and high encapsulation efficiency (>95%). In vitro release studies showed that PLGA-Lira-NVs remained relatively stable under acidic conditions (pH 1.2 to 6.8) and exhibited sustained drug release in a neutral environment (pH 7.4), enabling protection of the fragile peptide in the stomach and controlled release after crossing the intestine. Following oral administration to obese mice (10 mg/kg), PLGA-Lira-NVs achieved prolonged glycemic control for up to 72 h. Notably, body weight decreased to 83% of baseline after 12 days, outperforming the subcutaneous injection (free Lira) group (88%). The consistent trend toward weight reduction confirms the sustained-release properties of PLGA nanocarrier for Lira, highlighting its potential to reduce dosing frequency and improve patient compliance. Collectively, these findings underscore the promising potential of PLGA nanovesicles as an oral delivery platform for peptide therapeutics.
GV1001 Reprograms CD47 Immune Checkpoint to Restore Macrophage Antitumor Activity in Oral Squamous Cell Carcinoma.
Int J Mol Sci
Wei Chen, Seojin Kim, Cheyenne Beheshtian +3 more
Cluster of Differentiation 47 (CD47) functions as a key "don't-eat-me" signal that enables cancer cells to evade macrophage-mediated immune clearance. GV1001, a 16-amino-acid peptide derived from human telomerase reverse transcriptase (hTERT), has been reported to exhibit antitumor and anti-inflammatory properties and to downregulate CD47 expression in human cells. In this study, we investigated whether GV1001 modulated CD47 expression and enhanced antitumor immunity in oral squamous cell carcinoma (OSCC). In vitro, GV1001 significantly reduced CD47 expression in both murine and human OSCC cells in dose- and time-dependent manners, resulting in a marked increase in macrophage-mediated phagocytosis. Mechanistically, GV1001 suppressed CD47 promoter activity and inhibited multiple upstream regulator expression in murine and human OSCC cell lines, while exerting minimal effects on normal human keratinocytes and fibroblasts. In vivo, GV1001 significantly inhibited tumor growth, suppressed CD47 expression, increased macrophage infiltration, and induced tumor cell necrosis and apoptosis in both murine OSCC syngeneic graft model and human OSCC xenograft model. GV1001 administered alone or in combination with cisplatin produced antitumor effects. Collectively, these findings demonstrate that GV1001 functions as a potent immunomodulatory anticancer peptide that downregulates CD47 expression and restores macrophage-mediated tumor clearance, highlighting its potential as a therapeutic strategy for OSCC.
Cellular Microenvironment Triggered Ferroptosis and Photodynamic Therapy for Selective Senescent Cell Clearance.
ACS Appl Mater Interfaces
Hang Wang, Yuli Kang, Qiqiang Zhang +7 more
Biomedical strategies based on the cellular microenvironment often lead to significant improvements in diagnosis and therapy. In this study, based on the elevated reactive oxygen species (ROS) microenvironment of senescent cells, we designed Fe3+ coordinated nitrogen doped graphene quantum dots (Fe@N-GQDs) with both photodynamic and ferroptotic activity. The results demonstrated that Fe3+ modulated the electronic structure of nitrogen doped graphene quantum dots (N-GQDs) and enhanced their photodynamic activity. Meanwhile, the high ROS levels in endoplasmic reticulum and mitochondria enabled accumulated Fe@N-GQDs to synergistically amplify oxidative stress through the Fe3+/Fe2+ redox cycle and activate the ferroptosis related process. Under the synergistic photodynamic and ferroptosis effects, the clearance efficiency of senescent cells reached 98%. More importantly, leveraging the senescent cell microenvironment, Fe@N-GQDs showed minimal impact on healthy cells without targeting modifications, significantly improving therapeutic safety.
Clearance of Senescent Cells by BCLXL-PROTAC: A Novel Approach to Treat COPD?
Aging Cell
Justine V Devulder, Peter S Fenwick, Ewa Kolosionek +9 more
Ageing and cellular senescence significantly contribute to the progression of age-related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro-inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study examines the senolytic potential of BCLXL-PROTAC, a novel proteolysis-targeting chimera designed to degrade BCLXL, in small airway epithelial cells and fibroblasts from patients with COPD. Treatment of COPD small airway epithelial cells and fibroblasts with BCLXL-PROTAC led to their apoptosis through the activation of caspase 3, along with a reduction in senescence markers such as p21CIP1, p16INK4a and senescence-associated β-galactosidase. The effects of BCLXL-PROTAC were selective for senescent cells and did not affect non-COPD cells. The clearance of COPD small airway epithelial cells and fibroblasts by BCLXL-PROTAC was associated with an increase in the proliferation marker Ki67 and enhanced cell proliferation. Additionally, in precision-cut lung slices obtained from COPD patients, BCLXL-PROTAC significantly reduced p21CIP1 expression in the airway epithelium, validating its effectiveness in a more complex tissue environment. These findings demonstrate that BCLXL-PROTAC is a potent and selective senolytic agent that may promote lung cell rejuvenation, supporting its potential as a novel therapeutic strategy for age-related diseases, including COPD.
Growth Differentiation Factor 15 as a Biomarker of Cardiovascular Burden and Mortality in a Population-Based Cohort.
Int J Mol Sci
Beatriz Martín-Carro, Leticia Nieto-García, Clara Sánchez-Pablo +18 more
Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine strongly associated with aging, multimorbidity, and cardiovascular disease. Although prior studies have established its prognostic value in high-risk populations, its role in the general population remains less defined. The aim of this study was to determine if there is an association between plasma GDF15 levels, heart disease and mortality in a representative population-based cohort. We analyzed 1532 participants (mean age 55 years; 54.6% women) with available baseline plasma GDF15 concentrations. Participants were stratified according to an optimal cutoff of 1081 pg/mL, derived from ROC curve analysis for mortality. Associations with prevalent heart disease were assessed using multivariable logistic regression models adjusted for cardiovascular risk factors and NT-proBNP. Mortality was analyzed using Cox proportional hazards models, with model performance evaluated by C-index and time-dependent ROC curves. Individuals with GDF15 > 1081 pg/mL were older and exhibited a more adverse cardiometabolic profile with higher prevalence of comorbidities. Elevated GDF15 was independently associated with ischemic cardiomyopathy (OR 3.34, 95% CI: 1.38-8.11), particularly in men (OR 4.26, 95% CI: 1.40-12.96), but not in women. No independent associations were observed with arrhythmias, valvulopathy, or heart failure after adjustment for NT-proBNP. During a median follow-up of 6.2 years, 51 deaths occurred. Elevated GDF15 independently predicted all-cause mortality (HR 2.47, 95% CI: 1.19-5.13), though the effect was attenuated after adjustment for NT-proBNP. GDF15 improved model discrimination (ΔC-index = +0.01; LRT p = 0.011) and showed robust time-dependent predictive ability, with AUCs of 0.76, 0.82, and 0.85 at 2, 4, and 6 years, respectively. In this population-based cohort, elevated GDF15 identified individuals with an adverse health profile, was independently associated with ischemic cardiomyopathy in men, and predicted mortality. Although its incremental predictive value over NT-proBNP was modest, GDF15 could provide complementary biological information and may enhance multimarker strategies for cardiovascular risk stratification in the general population.
Novel Small Molecule GLP-1R Agonists Based on 1H-Benzo[d]imidazole-5-Carboxylic Acid Scaffold.
Molecules
Elena V Tolkacheva, Tagir L Salakhov, Alexandr Yu Saliev +7 more
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal endocrine L cells that activates the GLP-1 receptor (GLP-1R), leading to glucose-dependent insulin secretion and suppression of glucagon release. In recent years, GLP-1R agonists (GLP-1RAs) have become one of the leading therapeutic options for the treatment of type 2 diabetes mellitus; however, for a long time clinically approved GLP-1RAs were limited to peptide drugs unsuitable for oral administration. The discovery of the "first-in-class" small molecule agonist danuglipron in 2018 demonstrated the feasibility of orally available GLP-1RAs and stimulated the development of numerous danuglipron-like compounds, some of which showed increased efficacy over the prototype. In this study, we report the design and synthesis of novel GLP-1RAs based on a regioisomeric danuglipron scaffold, 1H-benzo[d]imidazole-5-carboxylic acid. A series of 35 compounds was synthesized and evaluated in vitro for cytotoxicity and GLP-1R agonistic activity using a cAMP accumulation assay. A potent lead compound 12r (pEC50 = 7.72, pCC50 < 3.60) was found which is a close structural analog of danuglipron with reduced cytotoxicity and excellent selectivity over two other class B GPCRs, including GCGR and GIPR. Despite decreased potency compared to danuglipron, the obtained results hold promise for further optimization and provide valuable structure-activity relationship insights.
Effects of Fan Noise on Growth Performance, Blood Parameters, Feeding Behavior, and Slaughter Performance of Geese Aged 21-70 Days.
Animals (Basel)
Qun Xie, Xiaofeng Huang, Zuolan Liu +10 more
We conducted this experiment with the aim of investigating the effects of different noise levels from ventilation fans on the growth and slaughter performance, meat quality, blood parameters, and feeding behavior of geese from 21 to 70 days of age. A total of 108 male geese (21-day-old) were randomly assigned to one of three conditions: a control group (no additional fan noise), low-noise treatment (65-75 dB), and high-noise treatment (85-95 dB). Each treatment included six replicates, with six geese per replicate. The results showed that neither ventilation fan noise level significantly affected growth performance, feeding behavior, slaughter performance, or major meat quality traits (p > 0.05). Compared with the control group, noise exposure significantly reduced circulating adrenocorticotropic hormone and corticosterone concentrations (p < 0.05), and the low-noise group exhibited significantly reduced cortisol concentrations (p < 0.05), while the high-noise group had increased cortisol concentrations. Under noise exposure conditions, no statistically significant effects were observed on superoxide dismutase, total antioxidant capacity, malondialdehyde concentration, catalase, and glutathione peroxidase activities compared with the control group (p > 0.05). Overall, prolonged noise stimulation (65-75 dB and 85-95 dB) alleviated stress responses in commercial geese aged 21-70 days, without negatively affecting their growth performance, slaughter performance, meat quality, or feeding behavior.
Diagnostic Utility of ACTH, Cortisol, DHEAS, and Their Derived Ratios in Cushing's Syndrome Subtypes.
J Clin Med
Ekin Yiğit Köroğlu, Abbas Ali Tam, Sevgül Faki +6 more
Background/Objectives: Differentiating Cushing's disease (CD) from adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome (AICS) remains challenging in patients with equivocal ACTH levels. While dynamic testing is frequently required, baseline hormonal measurements may offer a simpler diagnostic approach. We aim to evaluate the diagnostic value of baseline plasma ACTH, cortisol, and dehydroepiandrosterone sulfate (DHEAS) levels and their derived ratios for differentiation between ACTH-dependent and ACTH-independent Cushing's syndrome, and to propose a diagnostic algorithm based on these parameters. Methods: This retrospective single-centre study included adult patients with endogenous Cushing's syndrome aged 18-75 years who were followed at our institution. Patients with ectopic/paraneoplastic Cushing's syndrome were excluded. The AICS group comprised overt adrenal CS and mild autonomous cortisol secretion cases. Morning baseline plasma ACTH (pg/mL), serum cortisol (µg/dL), and serum DHEAS (µg/dL) levels were measured and ratios calculated: cortisol-to-ACTH ratio (CAR), DHEAS-to-cortisol ratio (DCR), and CAR-to-DHEAS ratio (CAR/D). ROC analysis assessed diagnostic performance with age and sex adjustments. Results: A total of 100 patients were included, comprising 43 patients with CD and 57 with AICS. Plasma ACTH demonstrated high diagnostic accuracy for identifying CD with a cut-off of ≥14.65 pg/mL (sensitivity 100%, specificity 98.25%, AUC 0.998). Serum DHEAS showed strong discriminative power with a cut-off of ≥67.15 µg/dL (sensitivity 88.37%, specificity 91.23%, AUC 0.925), achieving high discriminative power after age-sex adjustment at ≥85.59 µg/dL (sensitivity 100%, specificity 100%, AUC 0.999). CAR showed good performance in identifying CD with a cut-off of ≤0.75 µg/dL per pg/mL (sensitivity 93.02%, specificity 98.25%, AUC 0.980). CAR/D demonstrated high diagnostic power with a cut-off of ≤1.54 (sensitivity 95.35%, specificity 98.25%, AUC 0.974), improving after age-sex adjustment to ≤2.36 (sensitivity 97.87%, specificity 96.23%, AUC 0.992). Conclusions: Baseline plasma ACTH, serum cortisol, and serum DHEAS measurements, along with derived ratios-especially CAR and CAR/D-provide highly accurate differentiation between ACTH-dependent and ACTH-independent Cushing's syndrome. These widely available measurements may reduce dependence on dynamic testing and improve diagnostic accuracy in patients with equivocal findings.
Capsule and PspA Cooperatively Confer Resistance of Streptococcus pneumoniae to the Human Defensin HNP-1.
Int J Mol Sci
Maria Eduarda Pereira Mendes, Thalita Bastos de Freitas E Silva, Rebeca Faria +9 more
Streptococcus pneumoniae resists host defenses through multiple surface factors, yet their specific contribution to protection against antimicrobial peptides remains incompletely understood. We examined the role of pneumococcal surface protein A (PspA) and the polysaccharide capsule in protection against the human defensin HNP-1. PspA conferred increased resistance to HNP-1-induced killing, shown by a decreased killing in the presence of purified recombinant PspA and an increased sensitivity when PspA was deficient from the surface of strains of two different genetic backgrounds or when anti-PspA antibody was present. The capsule also conferred protection against HNP-1, which was serotype-dependent, with type 2 protecting better than type 4, and free polysaccharides acted as decoys by sequestering HNP-1. Removal of surface PspA from capsule-deficient mutants revealed additive contributions of both factors to survival. Molecular docking analysis suggests a potential electrostatic interaction between PspA and HNP-1. These findings highlight the independent and complementary roles of PspA and the capsule in pneumococcal resistance to HNP-1 and provide novel insights that may inform future vaccine design and antimicrobial strategies.
Treatment of Pulmonary Arterial Hypertension in Lithuania: Current Situation and Analysis of Survival of Patients Treated with Different Treatment Regimens.
J Clin Med
Skaidrius Miliauskas, Deimante Hoppenot, Ieva Dimiene +5 more
Background/Objectives: Since 2015, pulmonary arterial hypertension (PAH)-specific medications have been fully reimbursed in Lithuania. To describe the current situation of PAH treatment in the country and to determine survival during different PAH treatment regimens. Methods: The data from the Institute of Hygiene and the State Data Agency of Lithuania cases with administrative codes I27.0 and I27.8 have been evaluated. Results: In 2025, 225 confirmed cases of PAH were treated with PAH-specific medications in two PH centers. At least one PAH-specific medication was prescribed to 163 (72.4%) female and 62 (27.6%) male patients. Among these, 96 (42.7%) received sildenafil monotherapy, 82 (36.4%) received a combination of sildenafil and an ERA, 36 (16.0%) were on triple PAH-specific therapy (including selexipag or treprostinil), and 11 (4.9%) received other regimens due to specific medical considerations. The age of adults treated with sildenafil monotherapy vs. other therapies was 63.9 ± 14.8 (n = 117) and 51.5 ± 17.3 (n = 116) years, respectively (p < 0.05). A total of 191 PAH patients who received targeted therapy died during the observational period 2017-2025. Of these, 105 received monotherapy, 57 sildenafil and endothelin receptor antagonist and 29 triple therapies (treprostinil [n = 19], selexipag [n = 6], or inhaled iloprost [n = 4] were prescribed as the third drug). Patients who died and received triple therapy were younger than those on mono- and dual therapy (age at diagnosis 45.0 ± 21.6, 67.2 ± 14.7 and 61.6 ± 16.3 years, respectively, p < 0.01). Survival was longer in patients on dual therapy compared with monotherapy (43.1 ± 28.1 vs. 31.7 ± 25.0 months, p = 0.04), and the longest was in those receiving triple therapy (59.9 ± 29.4 months; p < 0.05). Conclusions: The availability of reimbursed medications dramatically increased the number of treated PAH cases in Lithuania. In 2025, most of the PAH patients received sildenafil monotherapy. Patients treated with sildenafil only were significantly older than the rest of cohort. In the survival analysis, combination PAH therapies were more often prescribed to younger patients and were associated with longer duration of life than monotherapy.
Ceftazidime-avibactam-based regimens for the treatment of central nervous system infections caused by carbapenem-resistant Klebsiella pneumoniae in a pediatric patient.
J Glob Antimicrob Resist
Liming He, Wanzhen Li, Weiming Chen +8 more
Carbapenem-resistant Klebsiella pneumoniae (CRKP) central nervous system (CNS) infections are difficult to treat in children because effective and safe therapeutic options are limited. We report a pediatric case of CRKP meningitis successfully treated with ceftazidime-avibactam (CZA) combination with intraventricular polymyxin B (PMB).
High Expression of PAPP-A Predicts Poor Outcomes in Oestrogen Receptor-Positive Breast Cancer Patients.
Cancer Med
Zeanap Mabruk, Esme Bullock, Xue Xiao +10 more
Insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) signalling is activated in breast cancer and associated with disease progression. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that can cleave IGF binding proteins leading to the release of bioactive IGF-1 and the subsequent activation of IGF-1 signalling. Here, we aimed to assess the prognostic significance of PAPP-A in breast cancer.
Molecular and Cellular Effects of Therapies for Thyroid Eye Disease on Ocular Surface and Adnexal Homeostasis.
Cells
Monika Sarnat-Kucharczyk, Wojciech Luboń, Dorota Wyględowska-Promieńska +1 more
Thyroid eye disease (TED) is an autoimmune inflammatory disorder primarily affecting orbital tissues, but ocular surface and adnexal involvement represent a frequent and clinically significant component of disease burden. Beyond mechanical exposure resulting from eyelid retraction and proptosis, TED-associated ocular surface disease arises from complex interactions between immune activation, epithelial stress, glandular dysfunction, and altered neuro-epithelial signaling. Increasing use of systemic immunomodulatory therapies, biologics, and orbital radiotherapy has improved control of orbital inflammation; however, their molecular and cellular effects on ocular surface homeostasis remain incompletely defined. This review summarizes current evidence on the cellular and molecular mechanisms underlying ocular surface dysfunction in TED and examines how disease-modifying therapies influence epithelial integrity, tear film stability, meibomian and lacrimal gland function, and local immune signaling. Key pathways discussed include cytokine-mediated inflammation, thyroid-stimulating hormone receptor and insulin-like growth factor-1 receptor crosstalk, pro-fibrotic signaling, neuro-inflammatory mechanisms, and epithelial stress responses involving mitogen-activated protein kinase and nuclear factor kappa B pathways. We further highlight the challenge of disentangling therapy-induced molecular effects from persistent exposure-related mechanical stress. Understanding how TED therapies modulate ocular surface and adnexal homeostasis is essential for optimizing integrated management strategies that address both orbital inflammation and long-term ocular surface stability.
Effects of Glial Cell Line-Derived Neurotrophic Factor and Ciliary Neurotrophic Factor on Extraocular and Limb Muscle Precursor Cells.
J Histochem Cytochem
Austin J Winker, Laura L Johnson, Linda K McLoon
SummaryMyogenic precursor cells within skeletal muscles are responsible for the maintenance of skeletal muscle over a lifetime. Neurotrophic and growth factors play critical roles in this maintenance and in responses of myogenic precursor cells. Both glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) play roles in the maintenance and/or development of strabismus, yet few studies have examined their roles in the control of myogenic precursor cell proliferation and differentiation. Two populations of myogenic precursor cells were isolated from extraocular and leg muscle by fluorescence-activated cell sorting: EECD34 cells, largely PITX2-positive, and PAX7-positive cells. Cultures were treated with GDNF or CNTF and processed immunohistochemically to determine proliferation and differentiation rates. Neither GDNF nor CNTF affected cell proliferation rates for either muscle. Both treatments impacted cell differentiation by increasing multinucleated cell number, with TA-derived precursor cells producing cells containing large numbers of nuclei and EOM-derived precursor cells producing shorter multinucleated fibers with fewer nuclei. These differences may explain the presence of extremely short myofibers within normal adult EOM compared with limb muscle. As GDNF and CNTF are downregulated in strabismic muscles, data suggest that myofiber length homeostasis may be disrupted in strabismic EOM and suggest possible approaches for strabismus treatment.
Differential Impact of Metabolic Bariatric Surgery Versus Semaglutide on Adverse Hepatic and Extrahepatic Outcomes in Individuals With Metabolic Dysfunction-Associated Steatotic Liver Disease and Type 2 Diabetes.
Diabetes Obes Metab
Weronika Stupalkowska, Alex E Henney, David R Riley +3 more
We compared the impact of metabolic bariatric surgery (MBS) versus semaglutide on clinical outcomes in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D).
Association of Semaglutide Treatment With Liver Cirrhosis and Hepatocellular Carcinoma in Type 2 Diabetes: A Population-Based Cohort Study.
Diabetes Obes Metab
Assaf Issachar, Talish Razi, Ilya Borochov +2 more
Metabolic dysfunction-associated steatotic liver disease is common among individuals with type 2 diabetes mellitus and substantially increases the risk of liver cirrhosis and hepatocellular carcinoma. Effective therapies that improve metabolic control while preventing advanced liver outcomes are limited.
SemaGBA: A System Dynamics Model of the Semaglutide-Responsive Gut-Brain Axis A Model of How the Brain and Semaglutide Regulate Appetite and Weight.
Diabetes Obes Metab
Vivan C W Kennis, Natal A W van Riel
Semaglutide is a GLP-1 receptor agonist for the treatment of type 2 diabetes and obesity. Its clinical effects are well established, but the underlying mechanisms remain unclear. This study aims to use computational modelling to generate hypotheses about semaglutide's long-term metabolic (body weight, net energy intake, blood glucose, insulin, insulin sensitivity, glucotoxicity, leptin, leptin sensitivity, lipotoxicity, GLP-1 and βcell function) and neural (AgRP, POMC, and dopamine neural activity) effects.
Real-world use of semaglutide in patients with type 2 diabetes and end-stage renal disease: a multicenter retrospective cohort study.
Front Endocrinol (Lausanne)
Omar Alkhezi, Lama Alfehaid, Amal Alanezi +2 more
Semaglutide and other Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular and renal benefits in patients with type 2 diabetes mellitus (T2DM); however, individuals with end-stage renal disease (ESRD) have been systematically excluded from landmark outcome trials. Consequently, real-world data evaluating the safety and effectiveness of GLP-1 RAs in this high-risk population remain limited.
Pharmacologic Treatment of Obesity in the Context of Type 2 Diabetes.
Curr Diab Rep
Caterina Conte, Anastassia Amaro
To examine the role of pharmacologic obesity treatment in people with type 2 diabetes (T2D), with a focus on efficacy, safety, and clinical positioning in the context of T2D-specific metabolic and therapeutic challenges.
Clinical Potential of GIP in Type 2 Diabetes and Obesity.
Diabetes Care
Michael Nauck, Fiona Gribble, Frank Reimann +2 more
Incretin-based pharmacology has revolutionized the medical treatment of type 2 diabetes and obesity. The most effective drug to date is tirzepatide, a dual incretin receptor agonist that engages both the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). While the relative contributions of GIPR and GLP-1R actions to the clinical effects of tirzepatide have not been established, the potency of this agent has reignited interest in the clinical potential of GIPR agonism. Here, we discuss incretin biology as it relates to metabolic pharmacology and contextualize the mechanisms by which GIPR activity could contribute to the development of new and effective drugs. We explore current and future applications of GIPR agonists and antagonists, to underscore the potential that this signaling system could add to treatment of type 2 diabetes and obesity.