Peptide Research Database

Urinary-free cortisol-based thresholds for differentiating ACTH-dependent Cushing: a Spanish validation study.

In a case report, severe hypercortisolism and hypokalemia strongly predict EAS, supporting a pragmatic diagnostic approach that prioritizes whole-body imaging in high-risk patients and pituitary-centered evaluation in mild cases.

Biagetti B, Marques P, Soto-Moreno A, García-Centeno R, González-Fernández L, Ollero García MD, Irigaray Echarri A, Cardona-Arias A, Moure Rodríguez MD, Paja M, Castro A, Manzano Valero L, Guerrero-Pérez F, Lamas C, Alcázar Lázaro V, Gracía P, Sanchis-Pascual D, Álvarez-Escolá C, Lozano-Aida C, Hanzu FA, Araujo-Castro M

Differentiating ectopic ACTH secretion (EAS) from Cushing disease (CD) remains one of the most challenging steps in the diagnostic workup of ACTH-dependent Cushing syndrome (CS). Urinary-free cortisol (UFC) expressed as times above the upper limit of normal (ULN) has been proposed as a simple, noninvasive discriminator, but external validation in independent populations is lacking. To validate the diagnostic performance of UFC × ULN for distinguishing EAS from CD and explore complementary biochemical markers, including late-night salivary cortisol (LNSC × ULN) and hypokalemia. Multicenter retrospective study from the Spanish Cushing Registry including 269 patients with ACTH-dependent Cushing's syndrome (208 CD, 61 EAS) diagnosed and managed in tertiary referral centers. Diagnostic accuracy of UFC × ULN and LNSC × ULN for discriminating EAS from CD, expressed as area under the ROC curve (AUC), sensitivity, specificity, and predictive value. EAS patients were older (median 59.0 vs 44.9 years; P < .001) and showed higher UFC × ULN (16.6 vs 3.6; P < .001) and LNSC × ULN (9.3 vs 1.5; P < .001). UFC × ULN and LNSC × ULN achieved excellent discriminative performance (AUC 0.90 and 0.92). No EAS occurred with UFC × ULN < 3 × ULN, while 40.5% of patients with UFC ≥ 10 × ULN had EAS. The combination of severe hypercortisolism (UFC ≥ 10 × ULN and LNSC ≥ 9 × ULN) plus hypokalemia identified 75% of EAS with 98% specificity. UFC × ULN thresholds reliably stratify the probability of EAS vs CD. Severe hypercortisolism and hypokalemia strongly predict EAS, supporting a pragmatic diagnostic approach that prioritizes whole-body imaging in high-risk patients and pituitary-centered evaluation in mild cases.

[GLP-1 Receptor Agonists in Urology and Andrology: Indications, Opportunities and Clinically Relevant Adverse Effects].

In a research review, prospective controlled trials with urological endpoints are needed.

Klotz T

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have evolved rapidly from an antidiabetic drug class into one of the most influential pharmacological groups in internal medicine. The approved agents - semaglutide, liraglutide and the dual GIP/GLP-1 agonist tirzepatide - achieve weight reductions of up to 22% of body weight. The close pathophysiological link between obesity, metabolic syndrome and urological-andrological disease creates direct clinical relevance for urology.This narrative review summarises a systematic PubMed search (2020-2026) covering erectile dysfunction, hypogonadism, male fertility, nephroprotection, prostate cancer, lower urinary tract symptoms and perioperative considerations in the context of GLP-1 RA therapy.GLP-1 RAs show clinically relevant effects in several urological domains: increase in total testosterone and improvement in erectile function in men with obesity-related hypogonadism, nephroprotection with reduction of albuminuria and slowing of eGFR decline, signals of reduced prostate cancer risk in epidemiological studies, and indirect benefit for stress incontinence and overactive bladder via weight loss. At the same time, clinically relevant warning signals exist: a 4.5-fold increased risk of new-onset erectile dysfunction in non-diabetic obese men on semaglutide, novel urological adverse effects in case reports, perioperative aspiration risk through delayed gastric emptying, and a near-complete absence of data in women.GLP-1 RAs represent both a therapeutic opportunity and a clinical challenge for urologists. Systematic andrological and nephrological monitoring as well as proactive patient education on urogenital and perioperative implications is recommended. Prospective controlled trials with urological endpoints are needed.

When dose follows response: Interpreting lower-dose semaglutide effectiveness in clinical practice.

Kılınç S

GLP-1 Receptor Agonists in Pulmonary Hypertension: Mechanistic Rationale, Preclinical Evidence, and Clinical Knowledge Gaps.

In an animal study, future cardiometabolic and HFpEF trials should incorporate standardized PH and right ventricular measures, and dedicated prospective studies with haemodynamic classification are required before GLP-1-based therapies can be considered for PH.

Allaham L, King B, Ali F, Gupta I, Metuku R, Nieto I, Lurie A, Amer FN, Reddy R, Alzghoul B

Pulmonary hypertension (PH) frequently coexists with type 2 diabetes mellitus, obesity, and heart failure with preserved ejection fraction (HFpEF), particularly in World Symposium on Pulmonary Hypertension (WSPH) Group 2 disease. Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists improve several cardiometabolic conditions and have anti-inflammatory and vascular effects. Whether these agents directly modify pulmonary haemodynamics or clinical outcomes in PH remains unknown. A structured narrative review was conducted using PubMed/MEDLINE and Google Scholar from database inception through March 2026, with additional studies identified by reference-list screening. Search terms encompassed GLP-1 receptor agonists, dual GIP/GLP-1 receptor agonists, pulmonary hypertension, pulmonary vascular remodelling, endothelial dysfunction, inflammation, and HFpEF. The structured search yielded 491 unique PubMed/MEDLINE records. Of these, 189 were assessed at full-text level alongside 40 additional articles identified through reference-list screening; 67 publications were included in the final synthesis. Evidence was organized by mechanism, experimental model, WSPH group, and whether PH evidence was direct or indirect. GLP-1 receptor expression has been demonstrated in pulmonary arterial smooth muscle in human and non-human primate tissue and in selected alveolar cell populations in rodent studies; however, available studies do not establish greater expression in pulmonary than systemic vascular smooth muscle. GLP-1 receptor signalling modulates inflammatory, endothelial nitric oxide, endothelin-1, and mitochondrial pathways relevant to PH. In monocrotaline- and hypoxia-induced models that primarily resemble Group 1 pre-capillary pulmonary arterial hypertension (PAH), liraglutide reduced right ventricular pressures or hypertrophy and pulmonary vascular remodelling, while semaglutide improved right ventricular mitochondrial and functional measures in an experimental pressure-overload model. By contrast, available human evidence is observational or derived indirectly from HFpEF studies, involves populations likely enriched for Group 2 or unclassified PH, and lacks prespecified, catheterization-confirmed PH endpoints. Consequently, these studies do not establish that GLP-1-based therapy prevents or treats PH. Current evidence supports a mechanistic hypothesis and a preclinical signal, not clinical efficacy in PH. Future cardiometabolic and HFpEF trials should incorporate standardized PH and right ventricular measures, and dedicated prospective studies with haemodynamic classification are required before GLP-1-based therapies can be considered for PH.

From Gila Monster Venom to Dermatology: The History of GLP-1 Receptor Agonists.

In a research review, have explored how observations from a venomous desert lizard has translated into one of the most important therapeutic advances in metabolic medicine with evolving therapeutic applications in dermatology.

Dyson S, Hoenig L, Levell NJ

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have evolved from novel therapies for type 2 diabetes mellitus into widely used treatments for obesity and metabolic disease. Their origins can be traced to the Gila monster (Heloderma suspectum), a venomous lizard native to the deserts of the southwestern United States and northwestern Mexico. The discovery of exendin-4, a peptide isolated from the venom of the Gila monster, led to the subsequent development of longer acting GLP-1RAs. Long before its contribution to modern medicine would be recognized, the Gila monster was revered in Navajo culture and folklore. We have examined the historic development of GLP-1 RAs, from the natural history and cultural significance of the Gila monster to the discovery of exendin-4 and the subsequent development of modern therapeutics. We describe the scientific advances that led to the translation of a venom-derived peptide into a major therapeutic class, including the development of exenatide, liraglutide and semaglutide. The history of GLP-1 receptor agonists demonstrates how observations in nature can lead to major therapeutic advances. What began with a view of a venomous desert lizard has evolved into one of the most important therapeutic classes in modern metabolic medicine, with expanding therapeutic applications in dermatology. The Gila monster (Heloderma suspectum) is a venomous lizard native to the deserts of the southwestern United States and northwestern Mexico. Long revered in indigenous cultural traditions, the Gila monster made an unexpected contribution to modern medicine. The discovery of exendin-4, a peptide within its venom, ultimately led to the development of glucagon-like peptide-1 receptor agonists (GLP-1RAs), representing one of the most significant therapeutic advances in modern metabolic medicine. GLP-1RAs are synthetic polypeptides that mimic the actions of the endogenous incretin hormone glucagon-like peptide-1. Initially developed for the treatment of type 2 diabetes mellitus, they have transformed obesity management and are now among the most widely prescribed therapies worldwide. As recognition of obesity has emerged as a major global public health challenge, GLP-1RAs have provided an effective pharmacologic approach to weight management. According to the World Health Organization, more than 1 billion people worldwide have been living with obesity as of 2022 [1]. The success of GLP-1RAs can be traced to the discovery of exendin-4, a peptide isolated from Gila monster venom that shares key biologic properties with human GLP-1 while demonstrating greater resistance to enzymatic degradation. Emerging evidence suggests that GLP-1RAs may influence inflammatory skin disease through a combination of weight reduction, improvements in metabolic health, and modulation of inflammatory and immune pathways [2]. This has generated increasing interest in the potential applications of GLP-1RAs within dermatology. In this review, we have examined the cultural significance and physiologic adaptations of the Gila monster, the discovery of exendin-4 and the subsequent development of GLP-1 RAs from venom-derived peptide to an expanding modern therapeutic class. We have explored how observations from a venomous desert lizard has translated into one of the most important therapeutic advances in metabolic medicine with evolving therapeutic applications in dermatology.

Adjunctive GLP-1 receptor agonists for cardiometabolic risk in antipsychotic-treated patients: A GRADE-assessed meta-analysis of randomized trials.

In a combined analysis of multiple studies, larger RCTs with longer follow-up are needed to confirm these findings.

Moubarak ES, Elgendy MS, Elkoumi O, Ibrahim AA, Manasrah A, Ahmad J, Hassan MA, Rageh OE, Mohamed AA, Elzahaby A, Abuelazm M

Patients with schizophrenia spectrum or bipolar disorders have reduced life expectancy due to cardiometabolic risk. We conducted this meta-analysis to evaluate glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for their effects on cardiometabolic outcomes. We systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane up to May 2026 for randomized controlled trials (RCTs). We pooled continuous outcomes as mean differences (MDs) and dichotomous outcomes as risk ratios (RRs) using random-effects models with 95% confidence intervals (CIs). We included 8 RCTs with 664 patients. Compared with control, GLP-1 RA significantly reduced body weight (MD: -6.74, 95% CI: -10.05 to -3.43), body mass index (BMI; MD: -2.37 kg/m2, 95% CI: -3.52 to -1.23), waist circumference (MD: -4.27 cm, 95% CI: -6.65 to -1.89), HbA1c (MD: -0.61%, 95% CI: -1.06 to -0.17), and fasting glucose (MD: -6.82, 95% CI: -11.89 to -1.76). Subgroup analyses by GLP-1 RA type showed that semaglutide produced the greatest reductions in body weight (MD: -11.06 kg) and BMI (MD: -3.60 kg/m2), with significant between-subgroup differences (p < 0.05). Adverse events (AEs; p = 0.77), serious AEs (p = 0.09), and discontinuation due to AEs (p = 0.20) were similar between groups. However, GLP-1 RA was associated with a significantly higher risk of gastrointestinal (GI) AEs, including nausea, vomiting, and constipation (all p < 0.01). GLP-1RA, particularly semaglutide, was associated with clinically meaningful improvements in antipsychotic-related cardiometabolic outcomes without compromising psychiatric stability or treatment adherence. However, the significant increase in GI AEs necessitates careful clinical titration. Larger RCTs with longer follow-up are needed to confirm these findings.

Melatonin testicular synthesis and its role in reproductive physiology in seasonal and non-seasonal breeders.

In an animal study, therefore, suggesting that MT serves as a conserved but diversified intratesticular signal that integrates photoperiodic, metabolic, and cell-protecting regulation of male fertility.

Cesauri M, Ventrella D, Fanelli D, Elmi A

Melatonin (MT) is an indoleamine primarily produced by the pineal gland in a light-dark-dependent manner; however, it is also locally synthesized in the testis, where it influences male reproductive physiology upon interaction with its receptors (MT1/MT2), the binding started the bio-signaling inside the cells mediated by MT. This review outlines the intratesticular effects of MT, addressing seasonal and non-seasonal mammals. In rodents, Leydig, Sertoli, and germ cells contain enzymatic machinery to produce MT, with MT1/MT2 signaling influencing androgen production through cAMP-dependent and independent pathways and interacting with local Corticotropin-Releasing Hormone (CRH), serotoninergic, and catecholaminergic systems to regulate steroidogenesis and testicular plasticity. In non-seasonal species, Sertoli cells express MT1/MT2 and react to melatonin through alterations in proliferation, expression of spermatogenesis-related genes, and restructuring of glycolytic and acetate metabolism, thus modifying energetic support to germ cells. In seasonal breeders like rams and roe deer, MT1/MT2, N-acetyltransferase (AANAT), and acetylserotonin O-methyltransferase (ASMT) are found in testicular cells, spermatozoa, and the epididymis. Exogenous MT treatments are linked to advancements in the breeding season, increased testicular size and enhanced testosterone secretion in rams. MT1/MT2 were reported in spermatozoa from several seasonal and non-seasonal mammalian species and MT frequently was detected in seminal plasma, where they are involved in motility, capacitation, cryotolerance, and antioxidant protection. Therefore, suggesting that MT serves as a conserved but diversified intratesticular signal that integrates photoperiodic, metabolic, and cytoprotective regulation of male fertility.

Efficacy and Safety of Semaglutide According to Frailty Status: A Post Hoc Analysis of the SELECT Randomized Clinical Trial.

In a randomized trial, benefits of semaglutide on health-related quality of life appeared greater with higher FI.

Ostrominski JW, Plutzky J, Scirica BM, Hovingh GK, Jeppesen OK, Lincoff AM, Lingvay I, Hoffmann Morville T, Quiroga M, Sofer Y, Urina-Triana M, Aroda VR

Whether frailty influences the benefit-risk balance of glucagon-like peptide-1 receptor agonists (GLP-1 RA) is uncertain. To evaluate whether frailty modifies the efficacy and safety of the GLP-1 RA semaglutide in adults with cardiovascular disease and overweight/obesity. In this secondary analysis of a randomized clinical trial, participants were adults with a body mass index of 27 or higher and established cardiovascular disease without diabetes. A 31-item frailty index (FI) was constructed using the Rockwood cumulative deficit approach; participants were categorized as not frail (FI ≤0.210), more frail (FI 0.211-0.310), and most frail (FI ≥0.311). Semaglutide, 2.4 mg, once weekly or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Key secondary clinical outcomes, health-related quality-of-life (assessed by EuroQol 5-Dimension 5-Level [EQ-5D-5L] score), and safety events were additionally examined. Of 17 604 participants, the mean (SD) age was 61.6 (8.9) years; 12 732 patients (72.3%) were male and 4872 were female (27.7%). A total of 5432 patients (31%) had an FI up to 0.210, 8349 (47%) had an FI of 0.211 to 0.310, and 3823 (22%) had an FI 0.311 or higher. The incidence of the primary outcome increased with higher baseline FI. Benefits of semaglutide vs placebo on the primary outcome appeared consistent across the FI categories (hazard ratio [HR], 0.84; 95% CI, 0.65-1.07, if the FI was ≤0.210; HR, 0.70; 95% CI, 0.59-0.82, if the FI was 0.211-0.310; HR, 0.92; 95% CI, 0.76-1.10, if the FI was ≥0.311; P = .09 for interaction). Similar findings were observed when the FI was examined continuously (P = .30 for interaction). Semaglutide additionally reduced the composite heart failure outcome (P = .82 for interaction), all-cause hospitalization (P = .71 for interaction), and all-cause mortality (P = .28 for interaction) regardless of FI category. Benefits of semaglutide on EQ-5D-5L scores appeared larger with higher FI (P = .02 for interaction). Between baseline and week 104, FI category was more likely to improve (odds ratio [OR], 2.46; 95% CI, 1.80-3.37), and less likely to worsen (OR, 0.47; 95% CI, 0.34-0.65) with semaglutide vs placebo. The HRs for adverse events leading to permanent discontinuation of semaglutide vs placebo appeared lower among participants with higher baseline FI (P < .001 for interaction). This study found that semaglutide demonstrated beneficial effects on a broad range of clinical outcomes in SELECT, without detectable heterogeneity by baseline FI. Benefits of semaglutide on health-related quality of life appeared greater with higher FI. ClinicalTrials.gov Identifier: NCT03574597.

Benzalkonium chloride disrupts human placental progesterone synthesis via locking NAD+ pocket in 3β-Hydroxysteroid dehydrogenase 1 and rat homolog: docking evidence and 3D-QSAR, and experiment risk assessment.

In a rat study, these findings revealed BAC-mediated endocrine-disrupting mechanisms and support structure-based optimization of inhibitors. Investigates the inhibitory effects of 9 BACs on h3β-HSD1 and rat placental (r3β-HSD4) homolog.

Chen N, Zhu H, Chi C, Xu Y, Tang Y, Ying Y, Ge RS

Benzalkonium chloride (BAC) disinfectants are widely used, but their potential to disrupt reproductive endocrine systems remains known. Human placental 3β-hydroxysteroid dehydrogenase 1 (h3β-HSD1) plays a key role in progesterone biosynthesis and is the potential target. This study investigates the inhibitory effects of 9 BACs on h3β-HSD1 and rat placental (r3β-HSD4) homolog. Kinetic analyses revealed h3β-HSD1 exhibited a Michaelis constant Km of 0.261 μM, while r3β-HSD4 showed similar Km (0.254 μM). Screening identified C12-C18 BACs as potent inhibitors (IC50: 1.15-20.43 μM for h3β-HSD1; 1.90-20.75 μM for r3β-HSD4), with mixed/noncompetitive inhibition confirmed by Lineweaver-Burk plots. A BAC mixture demonstrated antagonistic effects. Functional cell assays in JAr cells showed that C12-C18 suppressed progesterone biosynthesis, with potency influenced by membrane permeability and inhibitory strength. Structure-activity relationship (SAR) and 3D-QSAR models highlighted hydrophobicity, alkyl chain length as well as steric features as key determinants, validated by pharmacophore mapping. Molecular docking revealed conserved NAD+-binding interactions, with C18 exhibiting the highest affinity via hydrogen bonds and hydrophobic contacts as well as van der Waals. Molecular dynamics simulations confirmed stable enzyme-ligand complexes. Pharmacokinetics prediction profiling indicated variable solubility (C12 > C14 > C16 = C18). These findings elucidate BAC-mediated endocrine-disrupting mechanisms and support structure-based optimization of inhibitors.

Lead-guided prodrug development of small molecules as GLP-1R agonists.

In lab experiments, these findings suggest that the ester derivatives might represent a potential approach for modulating the how the body processes the drug properties of these compounds, and the resulting prodrugs could potentially provide more sustained systemic exposure and possibly offer safety-related advantages; however, these hypotheses require further validation through appropriate in living animals how the.

Lentschat H, Aboelfotouh HG, Nabil P, Abdallah M, Khalifa H, Stichel J, Abdel-Halim M, Abadi AH, Beck-Sickinger AG

The glucagon-like peptide-1 receptor (GLP-1R) is a well-established target for treating obesity and T2DM. To date almost all approved therapies targeting this receptor are peptide-based. The small-molecule GLP-1R agonist danuglipron, developed by Pfizer, demonstrated strong GLP-1 agonistic properties, reductions in body weight and improved glycemic control. Yet, its short duration of action, gastrointestinal side effects, and a potential case of drug-induced liver disease led to discontinuation in clinical trials. In this study, we designed and synthesized a series of acid and ester analogs of danuglipron, incorporating diverse substitution patterns and deliberate modifications, including variable substitutions and key moiety replacements. The corresponding acid forms retained activity comparable to the lead compound and the peptide drug tirzepatide. Notably, the ester compound 4 exhibited a controlled and sustained conversion to its active metabolite 4a in human plasma, as confirmed by mass spectrometry and in vitro GLP-1R activity assays. These findings suggest that the ester derivatives might represent a potential approach for modulating the pharmacokinetic properties of these compounds, and the resulting prodrugs could potentially provide more sustained systemic exposure and possibly offer safety-related advantages; however, these hypotheses require further validation through appropriate in vivo pharmacokinetic and toxicological studies.