Peptide Research Database
Access 6,710 peer-reviewed studies, clinical trials, and research papers on peptides. Filter by key research, study type, compound, and category. Direct links to full PubMed entries for comprehensive, evidence-based exploration.
GLP-1 Receptor Agonists and Musculoskeletal Outcomes: A Systematic Literature Review and Meta-Analysis.
In a combined analysis of multiple studies, further studies in this field, including those looking at muscle function, strength or performance and using multivariate models considering confounding are needed to better reinforce the models and final findings.
Beaudart C, Malréchauffé Y, van Heden S, Sanchez-Rodriguez D, Scheen A, Bruyère O, Mobasheri A, Duque G, Rizzoli R, Reginster JY, Thiyagarajan JA
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for the treatment of type 2 diabetes and obesity, but their effects on musculoskeletal health remain completely misunderstood. This systematic review/meta-analysis aims to synthesise clinical data on the effects of GLP-1 RAs on key relevant bone, muscle, and joint outcomes. MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) (both via Ovid® platform) and Embase were searched from inception to March 2025 to identify relevant randomised controlled trials (RCTs) or real-world evidence (RWE) studies to be included. This bibliographic search was completed manually. A random-effect model meta-analysis was performed for any outcome reported in at least 2 studies. Subgroup analyses were performed on the type of GLP-1 RAs, type of comparator used and study design. Sensitivity analyses (i.e., leave-out sensitivity analyses and analyses restricted to the most adjusted effect estimate) were performed to test the robustness of the data. The strength of evidence was assessed using GRADE. This work has been performed in adherence with PRISMA statement. (PROSPERO Record ID: CRD420251024082). From 1148 potentially relevant references, 60 articles (46 RCTs, 13 RWE studies and 1 pharmacovigilance study, comprising 1,250,717 individuals) met our inclusion criteria. Different GLP-1 RAs were represented across the panel of studies, i.e., semaglutide, liraglutide, exenatide, dulaglutide, tirzepatide (dual agonist gastric inhibitory polypeptide [GIP]/GLP-1) and others. No effect on bone outcomes (i.e., bone mineral density [all sites] and fractures [all sites]) were observed when the meta-analytical models included the most adjusted effect size. Regarding muscle outcomes, a significant decrease of lean body mass/fat-free mass was consistently observed with GLP-1 RAs in the global model (k = 28, standardised mean difference [SMD] 0.52, 95% confidence interval [CI] -0.8; -0.23, I2 88%, p-value for heterogeneity <0.0001), which remained robust in all sensitivity analyses. Subgroup analyses showed that the effect was mainly driven by liraglutide and semaglutide, with a decrease in lean body mass/fat-free mass observed when GLP-1 RAs were compared with placebo. No publication bias was found. Regarding joint outcome, models revealed no significant change in The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, physical function and stiffness. This meta-analysis is the first to investigate the effects of GLP-1 RAs on a large panel of musculoskeletal health outcomes. While no significant effects were observed on bone- or joint-related outcomes, GLP-1 RAs were associated with reductions in lean body mass/fat-free mass, although the certainty of evidence was low and these changes appeared largely related to weight loss. Whether these changes translate into clinically meaningful impairments in muscle function or physical performance remains uncertain. Further studies in this field, including those looking at muscle function, strength or performance and using multivariate models considering confounding are needed to better reinforce the models and final findings.
Calmodulin-tagging prevents aggregation and facilitates the proteolytic release of the recombinant human cathelicidin LL-37 by accommodating its hydrophobic regions.
In a mouse study, these results imply that CaM-tagging provides a practical and mechanistically rational platform for producing aggregation-prone antimicrobial peptides in a soluble, detergent-free, and enzymatically processable form.
Shibagaki M, Chrisnanto JO, Tefera DA, Kumeta H, Maeda K, Tsukioka K, Ueda W, Hirai F, Kumaki Y, Tsuda S, Arai T, Aizawa T
The human cathelicidin LL-37 is a widely studied 37-residue antimicrobial peptide with diverse biological functions. However, its strong aggregation propensity hinders the efficient recombinant production of this peptide. Previously reported expression strategies often face limitations such as low solubility, inefficient tag removal, and/or the need for detergents, which complicate downstream sample preparation. Here, we developed a detergent-free method for producing recombinant LL-37 in Escherichia coli as a fusion protein with calmodulin (CaM), a protein capable of binding to amphiphilic peptides. CaM-tagged LL-37 exhibited markedly improved solubility compared with LL-37 fused to conventional tags, such as thioredoxin. The CaM segment was efficiently cleaved from the CaM-LL-37 fusion protein by enterokinase (EK), enabling effective purification of LL-37 in its native form. Nuclear magnetic resonance (NMR) spectroscopy demonstrated that the CaM and LL-37 regions of the fusion protein interact with each other in both the Ca2+-bound and Ca2+-free states through distinct interaction modes. The linker region containing the EK recognition site in the CaM-LL-37 fusion protein was also revealed to be solvent-exposed and flexible, which explains the enhanced cleavage efficiency. Molecular dynamics (MD) simulations further suggested that CaM forms extensive hydrophobic contacts with LL-37, which may effectively cover its aggregation-prone surfaces from the solvent. The present strategy was also applicable to the mouse ortholog of LL-37, mCRAMP, supporting its broader utility. These results imply that CaM-tagging provides a practical and mechanistically rational platform for producing aggregation-prone antimicrobial peptides in a soluble, detergent-free, and enzymatically processable form.
Improvement of small fiber neuropathy assessed by corneal confocal microscopy following semaglutide treatment: a case report and literature review.
In a case report, further studies are urgently needed to determine whether semaglutide has a therapeutic role in the management of DPN.
Anastasiou IA, Tentolouris N, Rebelos E
Diabetic peripheral neuropathy (DPN) is the most common chronic complication of type 2 diabetes (T2D) and a major predisposing factor for the development of diabetic foot, one of the most devastating diabetes-related conditions associated with substantial morbidity and mortality. To date, no pharmacological therapy has been shown capable of preventing, halting, or reversing neuropathic damage. We report the case of a 57-year-old man with T2D and obesity (BMI 35.2 kg/m²) who presented with symptoms and signs of DPN, including a neuropathy symptom score (NSS) of 3/9, a neuropathy disability score (NDS) of 3/10, and a vibration perception threshold (VPT) of 22 volts (V) bilaterally. In vivo corneal confocal microscopy (CCM) was performed to further evaluate small fiber involvement. Despite adequate glycemic control (HbA1c 6.6%), semaglutide was initiated to optimize metabolic status and promote weight loss. After 6 months of treatment, both BMI and HbA1c had improved, while NSS, NDS, and VPT remained unchanged. Repeat CCM demonstrated improvement across all corneal nerve parameters. This case suggests that semaglutide-associated metabolic improvement, or a direct semaglutide effect on small fiber integrity, may contribute to early regeneration of small nerve fibers in DPN. Further studies are urgently needed to determine whether semaglutide has a therapeutic role in the management of DPN.
Metabolic Effects of a GLP-1 Analog Combined with Aerobic Training in Ovariectomized Rats.
In a rat study, these results suggest that SEM and EXE exert complementary effects on glycemic and lipid metabolism, with partially distinct metabolic outcomes that may involve different underlying mechanisms. In this study, ovariectomized female Wistar rats were divided into four experimental groups: sedentary plus saline (SED + SAL), sedentary plus semaglutide (SED + SEM), exercise (EXE + SAL), and EXE + SEM.
Selau B, Bastos LM, Normann RS, Cubas GK, Herrmann ROCDC, Barros LDAO, de Amaral M, Trapp M, Kucharski LC, Vogt ÉL, Model JFA, Vinagre AS
Menopause is associated with visceral obesity, low-grade chronic inflammation, and increased risk of dyslipidemia, insulin resistance, and type 2 diabetes. Although exercise (EXE) and GLP-1 receptor agonists, such as semaglutide (SEM), have demonstrated beneficial effects on metabolic regulation, their combined impact in menopause models has been less investigated. In this study, ovariectomized female Wistar rats were divided into four experimental groups: sedentary plus saline (SED + SAL), sedentary plus semaglutide (SED + SEM), exercise (EXE + SAL), and EXE + SEM. The aerobic exercise protocol consisted of treadmill running at moderate intensity for four weeks, during which the rats received either SEM or SAL weekly. At the end of the protocol, metabolic parameters were assessed in blood, liver, soleus and gastrocnemius muscles. Both SEM groups had lower body weight, weight gain, relative subcutaneous white adipose tissue (scWAT) mass, glucose, total proteins, and triglycerides in serum and liver, while LDL cholesterol, glycogen in liver and gastrocnemius, and AMPK and HSF1 expression in gastrocnemius increased. EXE decreased total and LDL cholesterol, liver triglycerides and HSF1 expression in both tissues, while glycogen in liver and gastrocnemius, liver HSF1 expression and relative mass were increased. The combination of SEM + EXE increased glycogen content in the gastrocnemius and AMPK expression in both gastrocnemius and liver. This combined treatment reduced HDL levels, hepatic triglycerides and scWAT relative weight. These results suggest that SEM and EXE exert complementary effects on glycemic and lipid metabolism, with partially distinct metabolic outcomes that may involve different underlying mechanisms.
A multiscale PBPK-PD model of oxytocin-induced uterine excitation and contraction.
This study found this work provides a quantitative framework for studying how naturally occurring oxytocin can induce uterine excitation and contraction, and offers a basis for investigating abnormal uterine activity such as preterm labour and uterine atony. Developed a multiscale dynamic model.
Yang Y, Bradley C, Zhang X, Clark A, Gao M, Li G, Yang L, Monfort-Ortiz R, Meng Y, Hao D, Ye-Lin Y
Coordinated excitation of uterine smooth muscle cells (USMCs) is the physiological basis of labour, and several mathematical models have been developed to understand the function of USMCs. However although the key role of oxytocin in parturition has been established, most existing USMC models still rely on external electrical stimulation to initiate action potentials rather than including oxytocin as a stimulus. This study developed a multiscale dynamic model. First a pregnancy physiologically based pharmacokinetic (PBPK) model was built to describe pulsatile oxytocin release, systemic transport and clearance. This PBPK model was coupled to a cell-level model via local myometrial oxytocin exposure. This model explicitly captures oxytocin binding to and dissociation from the oxytocin receptor (OXTR), as well as downstream OXTR signalling. The cell-level model incorporates excitation-contraction coupling, enabling the simulation of USMC excitation and contractile responses without external electrical stimulation. The model aligns with published data across multiple key endpoints, including oxytocin pharmacokinetic parameters, maternal venous and umbilical arterial and umbilical venous concentrations, and the duration and amplitude of cellular excitation and contraction. The results also show that an increased oxytocin association rate constant k on lowers the half-maximal effective concentration (EC50) and is a key determinant of USMC sensitivity to oxytocin. This model provides a quantitative framework to explain oxytocin's role in uterine excitability during pregnancy and to investigate pathological conditions such as preterm labour and uterine atony. KEY POINTS: Oxytocin is a major physiological regulator of labour contractions, but most existing uterine smooth muscle cell models still require external electrical stimulation to trigger excitation, rather than recapitulating oxytocin-induced myometrial activity. We developed a multiscale physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model that links pulsatile endogenous oxytocin release, maternal-fetal distribution, oxytocin receptor binding, IP3-mediated Ca2+ signalling and excitation-contraction coupling in uterine smooth muscle cells. The model reproduced published ranges for key pharmacokinetic and pharmacodynamic endpoints, including oxytocin half-life and clearance, maternal and fetal oxytocin concentrations, intracellular Ca2+ responses, membrane potential, contraction duration and active stress. Simulations showed that the oxytocin association rate constant and oxytocin receptor abundance strongly influence the oxytocin dose-response relationship, shifting EC50 and modulating uterine excitability. This work provides a quantitative framework for studying how endogenous oxytocin can induce uterine excitation and contraction, and offers a basis for investigating abnormal uterine activity such as preterm labour and uterine atony.
Structural Overview of GLP-1 Analogs.
In a research review, this review synthesizes current insights into structural determinants of GLP-1 analogs and highlights future directions in the field.
van der Velden WJC, Andresen AF, Rosenkilde MM
Glucagon-like peptide-1 (GLP-1) analogs exert potent metabolic effects through structural features that govern receptor engagement, signaling, and pharmacokinetics. Key structural determinants include N-terminal modifications that confer resistance to dipeptidyl peptidase-4 degradation, as well as C-terminal and backbone elements that stabilize peptide helicity and enhance GLP-1 receptor affinity. Lipidation and albumin-binding strategies prolong systemic exposure by increasing circulating half-life, forming the basis of long-acting agents such as liraglutide and semaglutide. Structural variation further modulates signaling bias between G protein pathways and β-arrestin recruitment, potentially influencing therapeutic efficacy. Emerging multi-receptor agonists extend these principles across incretin receptor families and are increasingly supported by computational approaches to peptide optimization. Collectively, these advances illustrate how rational design drives the development of next-generation incretin therapeutics. This review synthesizes current insights into structural determinants of GLP-1 analogs and highlights future directions in the field.
Side effects of lower dose compounded semaglutide paired with a behavioral management program: A real-world retrospective study
This study found conclusions: Lower doses of compounded semaglutide alongside a behavioral companion are associated with fewer side effects in the first 16 weeks compared to a higher dose program.
Owen EC, Moulder RG, Morse JL, Ainsworth MC, Fabry A, Merner AR.
Objective: Evaluate differences in side effects between a low and standard dose compounded semaglutide paired with a behavioral companion in the first 16 weeks of treatment using a real-world, retrospective cohort. Methods: Side effects were compared between the low dose protocol (Noom Microdose GLP-1 Rx Program; NMGP, up to 0.6mg/weekly compounded semaglutide) and Noom's standard dose of compounded semaglutide (Noom GLP-1 Rx Program; NGP, up to 1.2mg/weekly). Users were propensity score matched on side effect rate in the first 8 weeks when dosing protocols were identical, and longitudinal side effect trajectories were compared via logistic regression. Analyses were conducted on a second cohort with additional matched baseline characteristics. Results: The full sample included 7,682 NGP and 2,877 NMGP users. NMGP users had 34% lower and 29% lower relative odds of reporting GI side effects (p=0.001) and any side effects (p=0.001) by week 16, respectively (n=2,481 per group). Results of the second cohort demonstrated 38% lower odds of any side effect by week 16 among NMGP users (n=958 per group, p=0.019). Conclusions: Lower doses of compounded semaglutide alongside a behavioral companion are associated with fewer side effects in the first 16 weeks compared to a higher dose program.
Assessing the Association Between GLP-1 Receptor Agonists and Diabetic Foot Complications Using Real-World Pharmacovigilance Database and Mendelian Randomization.
This study found these results remained strong after conducting secondary and sensitivity analyses, further supporting their consistency and reliability.
Zhang T, Luo X, Chen C, Zhang Y, Xu B, He Z, Zhou J
BackgroundLimited studies to date have yielded inconsistent results regarding the association between glucagon-like peptide-1 receptor agonist (GLP-1RA) use and diabetic foot complications. We conducted a comprehensive analysis of the FDA Adverse Event Reporting System (FAERS) database and performed drug target Mendelian randomization (MR) studies to explore the association between GLP-1RAs and diabetic foot complications.MethodsWe mined the FAERS database from 2005q2 to 2024q2 using AERSMine. Additionally, a two-sample MR analysis was conducted to investigate the causal relationship between GLP-1R agonism and diabetic foot complications.ResultsA total of 1819 adverse event reports were recorded for GLP-1RAs, compared to 17,206 reports for other ATC-A10 class drugs. The frequency of diabetic foot reports in the GLP-1RA group was significantly lower than in the control group (6.38 vs 11.31/1000 reports), with a proportional reporting ratio (PRR) of 0.56 (95% confidence interval [CI], 0.54 to 0.59; P < 0.001). This trend was consistently observed across individual GLP-1RA molecules, including semaglutide (PRR, 0.45; 95% CI, 0.39 to 0.51), dulaglutide (PRR, 0.49; 95% CI, 0.45 to 0.54), and liraglutide (PRR, 0.30; 95% CI, 0.26 to 0.35). These results remained robust after conducting secondary and sensitivity analyses, further supporting their consistency and reliability. MR results generally corroborated the findings from the retrospective analyses of the AE records in the FAERS database.ConclusionsPharmacovigilance and drug target MR suggested a potential association between GLP-1RA use and diabetic foot complications, but the evidence is preliminary and requires further real-world prospective validation.
Oestrogen modulates stress-induced vagally-dependent gastric responses to oxytocin.
In a rat study, in female rats, parasympathetic control of gastric functions involved non-adrenergic, non-cholinergic vagal efferent pathways, with recruitment of distinct pathways dependent on oestrous stage and stress history These findings suggest a sex-specific organization of vagal neurocircuits regulating gastric functions, which may underlie female-specific variability and susceptibility to stress-related.
Bhagat R, Travagli RA, Browning KN
The brain-gut axis is central to gastrointestinal regulation and disorders of gut-brain interaction are more prevalent and often more severe in females. The aim of the present study was to test the hypothesis that brain-gut neurocircuitry is influenced by stress and ovarian hormone levels. Gastric emptying in Sprague-Dawley female rats was slower when oestrogen levels were high, but stress had no further effect. Whole-cell recordings revealed that, unlike previous reports in male rats, the 'anti-stress' peptide, oxytocin (OXT), suppressed GABAergic transmission to dorsal motor nucleus of the vagus (DMV) neurons under non-stressed conditions regardless of oestrogen level. Application of astressin, an antagonist of the 'pro-stress' neuropeptide, corticotrophin-releasing factor (CRF), showed that some presynaptic effects of OXT were dependent upon ongoing CRF1 receptor activity in female vagal neurocircuits. In vivo recordings showed that DMV microinjection of OXT decreased gastric tone and motility via vagal efferent pathways involving the release of vasoactive intestinal peptide and nitric oxide onto myenteric neurons, with recruitment of distinct efferent pathways dependent on oestrous stage and stress history. These findings reveal that the oestrous stage and stress do not affect the OXT modulation of inhibitory input to DMV neurons but do determine peripheral effector recruitment. The dissonance between central synaptic modulation and peripheral implementation provides a mechanistic framework for female-specific variability in gastric motor function and susceptibility to stress-related gastrointestinal dysfunction. KEY POINTS: Disorders of gut-brain interaction (DGBI) are more prevalent in females. Dorsal motor nucleus of the vagus (DMV) neurons provide extensive extrinsic parasympathetic innervation to the gastrointestinal tract. In male rats, the anti-stress neuropeptide oxytocin (OXT) is known to modulate inhibitory GABAergic transmission to DMV neurons only following stress or activation of pro-stress corticotrophin-releasing factor (CRF) receptors. The present study demonstrates that, in female rats, OXT suppressed GABAergic transmission to DMV neurons under basal (non-stressed) conditions in a manner that was independent of oestrous stage, and that CRF receptors were tonically active, even under basal conditions. In female rats, parasympathetic control of gastric functions involved non-adrenergic, non-cholinergic vagal efferent pathways, with recruitment of distinct pathways dependent on oestrous stage and stress history These findings suggest a sex-specific organization of vagal neurocircuits regulating gastric functions, which may underlie female-specific variability and susceptibility to stress-related DGBI.
Effects of high frequency administration of GnRH or kisspeptin on LH pulse and surge profiles in ovariectomized Bos taurus and Bos indicus heifers†.
This study found in conclusion, the high-frequency GnRH stimulation did not enhance LH surge response to a GnRH challenge.
eSilva LO, West S, Garza V, Sustaita-Monroe J, King L, Sellers H, Weynand M, Feist H, Perry G, Sartori R, Cardoso RC
We hypothesized that high-frequency stimulation with kisspeptin or GnRH, mimicking increased GnRH pulsatility, would amplify the GnRH-induced LH surge in heifers. Additionally, LH pulse and surge parameters were compared between Bos taurus and Bos indicus heifers. Ovariectomized estradiol-replaced Hereford (n=6) and Brahman (n=8) heifers received two intravaginal progesterone devices on d -5. On d -0.5, jugular catheters were placed and on d 0 blood samples were collected every 15 min for 12 h. In a crossover design, each heifer received all three treatments in separate replicates, administered hourly during the first 8 h: Control = saline; Kisspeptin = 0.4 μg/kg of kisspeptin; or GnRH = 0.005 μg/kg of gonadorelin acetate. At 8 h, 100 μg of gonadorelin acetate was administered to induce an LH surge. Both kisspeptin and GnRH treatments effectively induced high-frequency LH pulses. Regardless of the genetic group, 75% of kisspeptin and 87.5% of GnRH injections resulted in detectable LH pulses. LH pulsatility was greater (P<0.01) in kisspeptin- and GnRH-treated heifers compared to controls (6.1±0.6, 7.0±0.4, 2.3±0.5 pulses/8 h; respectively). Nevertheless, neither endogenous nor treatment-induced LH pulse parameters differed between breeds. The GnRH-induced LH surge was not enhanced by the high-frequency stimulation, however, it was markedly reduced in Brahman compared to Hereford heifers (P<0.01). In conclusion, the high-frequency GnRH stimulation did not enhance LH surge response to a GnRH challenge. Although LH pulsatile secretion was similar, differential pituitary responsiveness to a GnRH ovulatory stimulus may contribute to differences in reproductive function between Bos taurus and Bos indicus heifers.