Research Hub
The living record of
peptide science.
PubMed studies synced daily. Active clinical trials. Evidence updates when the science materially changes. Monthly synthesis for practitioners.
Layer 1
Study feed
Molecular, genetic, and pharmacological advances in type 2 diabetes (2015-2025).
Biomol Concepts
Ricardo Romero
Type 2 diabetes (T2D) is a multifactorial metabolic disorder driven by the interplay of insulin resistance, β-cell dysfunction, and complex genetic and epigenetic factors. Over the past decade (2015-2025), advances in molecular biology, genomics, and pharmacology have reshaped our understanding of its pathogenesis and treatment. Large-scale GWAS and functional genomics have clarified genetic risk loci and epigenetic mechanisms, while novel biomarkers, including circulating microRNAs and metabolomic signatures, offer potential for early detection and risk stratification. Therapeutically, incretin-based drugs, especially GLP-1 receptor agonists and dual agonists, as well as SGLT2 inhibitors, have transformed outcomes by targeting both glycemic control and cardiovascular-renal protection. These insights have also informed prevention strategies, emphasizing weight reduction, microbiome modulation, and precision interventions based on genetic risk. Yet major gaps remain, including functional annotation of risk loci, understanding of β-cell dedifferentiation and recovery, and equitable implementation across diverse populations. This review synthesizes molecular, genetic, and pharmacological progress from 2015 to 2025, highlights clinical translation, and identifies priorities for the next decade of research.
Cardiovascular Risk Reduction With GLP-1 RA Drugs.
Circulation
Marie Pigeyre, Hertzel C Gerstein
GLP-1 (glucagon-like peptide-1) receptor agonists (RAs) have emerged as a major therapeutic advance in cardiometabolic medicine. Initially developed as glucose-lowering therapies for type 2 diabetes, these agents have demonstrated broad benefits that extend well beyond glycemic control. GLP-1 RAs enhance glucose-dependent insulin secretion and reduce appetite, leading to improved glycemia and sustained weight loss. In addition, GLP-1 signaling exerts vascular and myocardial effects, including improved endothelial function, reduced inflammation and oxidative stress, and favorable changes in cardiac metabolism and remodeling. Large randomized cardiovascular outcomes trials have consistently shown that several GLP-1 RAs reduce major adverse cardiovascular events, including myocardial infarction, stroke, cardiovascular death, and heart failure. Benefits have been observed across diverse populations, including individuals with established cardiovascular disease and those with obesity but without diabetes. Emerging therapies targeting multiple incretin pathways, such as dual GIP (glucose-dependent insulinotropic polypeptide)-GLP-1 RAs, may further extend these benefits. Collectively, these findings suggest that GLP-1 RAs influence multiple cardiometabolic pathways and may shift the underlying metabolic milieu toward a more favorable physiological state. In this Clinical Primer, we review the physiology of GLP-1 signaling, the evidence supporting cardiovascular risk reduction, and practical considerations for the clinical use of incretin-based therapies.
Potential role of tirzepatide, a dual GLP-1 and GIP receptor agonist, for preventive treatment of migraine: A case series.
Headache
Tulsi Shah, Carrie Dougherty, Jessica Ailani +1 more
Obesity is a known comorbidity of migraine that can increase attack frequency and severity and lead to disease chronification. Glucagon-like peptide-1 (GLP-1) receptor agonists and related medications have demonstrated benefits beyond glycemic control and weight management, with emerging evidence suggesting a potential role in pain modulation. Clinical observations have also suggested the role of GLP-1 based therapies for the treatment of idiopathic intracranial hypertension, but their role in migraine has not been established.
Protocol for Novel Perioperative Optimization of Obese Osteoarthritic Patients pending Total Knee Replacement with glucagon-like peptide-1 receptor agonist (NPO-OOPS-TKR) : a pilot randomized controlled trial.
Bone Jt Open
Lawrence C M Lau, Tak W D Lui, Chunyi Wen +8 more
Obesity is associated with higher rates of perioperative complications and worse pain and functional outcomes after total knee arthroplasty (TKA). Preoperative optimization through weight management is therefore clinically appealing, but the current evidence base is mixed. No randomized controlled trial (RCT) has evaluated glucagon-like peptide-1 receptor agonists (GLP-1RAs) as a perioperative optimization strategy before TKA, and no such trial has focused on an Asian population. This pilot randomized trial therefore aims to determine the feasibility, tolerability, and acceptability of semaglutide-based optimization before and after TKA in older Asian adults with obesity.
The Brain Renin-Angiotensin System in Parkinson's Disease: Friend or Foe? Mechanistic Insights and Therapeutic Implications.
Ageing Res Rev
Gursimran Singh, Khadga Raj Aran
The renin-angiotensin system (RAS), classically known for its role in cardiovascular and fluid homeostasis, also regulates neuronal homeostasis in the central nervous system (CNS), where its dysregulation contributes to PD pathogenesis. The emerging evidence links excessive activation of the brain RAS in PD, where sustained activation of the angiotensin II (Ang II)/angiotensin type-1 receptor (AT1R) axis promotes oxidative stress, neuroinflammation, mitochondrial dysfunction, and blood-brain barrier (BBB) disruption that leads to progressive dopaminergic neurodegeneration. This AngII-AT1R signaling increases the production of reactive oxygen species (ROS) mediated by NADPH oxidase, primes microglia to a chronic pro-inflammatory state, disrupts the proteostatic regulation of nigrostriatal neuronal α-synuclein clearance, and intensifies the selective vulnerability of nigrostriatal neurons. The counter-regulatory ACE2/angiotensin (1-7)/Mas and AT2R pathway seems to have neuroprotective effects; however, it reverses the negative effects of Ang II. In preclinical, epidemiological, and emerging clinical evidence, pharmacological modulation of the RAS, particularly BBB-penetrant angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), has shown promise as neuroprotective agents. In the current area of research, RAS-targeted interventions represent a promising and mechanistically grounded strategy for disease modification rather than symptomatic management alone. This review explores molecular, cellular, and system-level insights into RAS dysregulation in PD, integrates translational evidence supporting RAS-modulating therapies, and highlights emerging biomarkers and precision medicine approaches that may guide therapeutic optimization. This review also highlights the brain RAS as a key mediator linking redox imbalance, neuroinflammation, and multisystem dysfunction in PD and makes it a promising therapeutic axis for slowing the disease progression.
Time to benefit of incretin-based therapies in adiposity-related heart failure with mildly reduced or preserved ejection fraction: a systematic review and meta-analysis.
J Card Fail
Bernardo F Spiazzi, Carolina P Zingano, Amanda R Vest
Obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF). Incretin-based therapies are associated with a reduction in worsening heart failure (HF) events for patients with HF with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), although the time to clinical benefit from these therapies is unknown.
GLP-1 receptor agonists in pediatric obesity.
Dig Liver Dis
Martina Abodi, Carlo V Agostoni, Alessandra Mazzocchi
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of obesity in adults and are now gaining attention in pediatric populations facing a dramatic rise of obesity prevalence and related comorbidities. In addition to weight loss, their role extends to cardiometabolic effects and improvements of kidney function. Liraglutide and semaglutide have demonstrated clinically meaningful efficacy in adolescents, leading to FDA and EMA approvals for patients ≥12 years. Ongoing trials are being conducted to combine GLP-1 analogues with other effective molecules or with bariatric surgery. Current evidence on safety most frequently highlights gastrointestinal adverse events, with no consistent impact on growth or pubertal development reported to date. Psychosocial dimensions, including stigma, mental health risks, and potential disordered eating, together with economic barriers and disparities in access, require careful consideration and efforts to be overcome. Implementing intensive lifestyle interventions is mandatory, including nutritional education, physical activity promotion, and family-based behavioral strategies, to support long-term weight management and address the broader determinants of health. Preliminary studies suggest complementary roles for GLP-1RAs alongside metabolic bariatric surgery in selected high-risk patients. Long-term data on safety and multidisciplinary approaches are required to define the optimal integration of pharmacotherapy into comprehensive, family-centered pediatric obesity care models.
GLP-1 Receptor Agonist Therapy in Children and Adolescents with Obesity: A Network Meta-Analysis of Differential Cardiometabolic Efficacy and Safety Profiles.
Pharmacol Res
Yao Li, Xiaoou Xu, Adili Tuersun +6 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used in adolescents with overweight or obesity, but their comparative effects on cardiometabolic outcomes across different agents remain uncertain. We aimed to compare the efficacy and safety of different GLP-1RAs on key cardiometabolic parameters in adolescents with overweight or obesity, with or without type 2 diabetes.
Effects of IGF1 and GnRH on gonadotropin subunits in the pituitary cells of the Indian freshwater catfish, Heteropneustes fossilis (Bloch).
Fish Physiol Biochem
Uma Bharati Sahu, Neeta Sehgal, Kumari Vandana Rani
Insulin-like growth factor 1 (IGF1) is a key somatotropic hormone that controls growth and metabolism, thereby conveying growth status to the reproductive endocrine system. The regulation of gonadotropin-releasing hormone (GnRH) to synthesize and release both the gonadotropin hormones (FSH and LH) is well documented. Numerous attempts have been made to understand the interaction of gonadotropic (reproductive) and somatotropic (growth) axis, but the dynamics of their interaction are still not clear at the pituitary level among teleost. The present study bioinformatically demonstrated protein-protein interaction of IGF1 with the proteins of both somatotropic and gonadotropic axes suggesting a cross-talk between them. In vitro, the effects of IGF1 alone or in combination with GnRH on pituitary transcripts for follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were examined. Experiments were conducted with dispersed pituitary cells of the catfish, Heteropneustes fossilis, to determine the time- and dose-dependent response of IGF1 and GnRH alone or in combination to assess fshβ and lhβ. The results showed a time-dependent effect with maximum transcripts level at 1 h of exposure. IGF1 and GnRH showed dose-dependent effects on differential expression of both transcripts when administered alone, with maximum fshβ and minimal lhβ levels at the higher dose. A synergistic impact on both the transcripts was observed in the presence of IGF1 and GnRH. Collectively, the study suggests that IGF1 plays a crucial role in regulating the synthesis of hormones in the catfish by interacting between the gonadotrophs and somatotrophs at the pituitary level.
Neuroendocrine mechanisms of stress-induced KNDy-GnRH pulse generator suppression: Linking HPA-axis activation to female reproductive dysfunction.
Front Neuroendocrinol
Wenjie Bo, Yujing Li, Ruiying Wang +6 more
Chronic stress disrupts female reproductive function, but the central mechanisms linking stress exposure to altered gonadotropin-releasing hormone (GnRH) pulsatility remain incompletely defined. The arcuate kisspeptin/neurokinin B/dynorphin (KNDy) network is a core component of the GnRH pulse generator, yet it functions within an expanded regulatory system involving fast amino-acid neurotransmission, steroid feedback, nitric oxide signaling, glial communication, metabolic cues, and stress-responsive neuropeptides. This review synthesizes evidence showing how hypothalamic-pituitary-adrenal (HPA)-axis activation may suppress KNDy-GnRH output. Corticotropin-releasing hormone, glucocorticoids, gonadotropin-inhibitory hormone/RFamide-related peptide-3, glial inflammatory mediators, serotonergic input, and energy-sensitive neuropeptides may converge to impair GnRH pulse-generator function. We further discuss the relevance of these mechanisms to functional hypothalamic amenorrhea, stress-sensitive polycystic ovary syndrome (PCOS) phenotypes, and developmental versus adult stress exposure. Overall, stress-induced reproductive dysfunction is best understood as disrupted network-level neuroendocrine rhythm regulation.
EGF and GHRP6 Co-Administration Attenuates Cognitive Decline in Preclinical Models: Behavioral and Molecular Evidences.
Neurotox Res
Daniela Risco-Acevedo, Nelvys Subirós-Martínez, Hanlet Camacho-Rodríguez +14 more
Cognitive decline is a hallmark of neurodegenerative diseases. The complex pathophysiology of these diseases has limited the efficacy of current therapies. The co-administration of epidermal growth factor (EGF) and growth hormone-releasing peptide 6 (GHRP6) emerges as a promising neuroprotective candidate. The present study evaluated the therapeutic potential of this combination in two preclinical models of cognitive impairment: (i) age-related decline and (ii) impairment induced by intracerebroventricular administration of streptozotocin (STZ). In both experiments, C57BL/6 mice were used and distributed into three experimental groups, each comprising 14-15 animals per group. Cognitive and motor function was assessed through gait pattern, Y-maze and novel object recognition tests. Differential gene expression was analyzed using qPCR. Both models reproduced hallmark features of cognitive decline, including deficits in working and spatial memory and changes in the expression of genes associated with oxidative stress, neuroinflammation and synaptic plasticity. In aged animals, EGF + GHRP6 treatment increased step length (p = 0.04). In the forced alternation Y-maze test, aged-EGF + GHRP6 animals made more visits to the novel arm than to the familiar arm 1 (p = 0.001) or to the familiar arm 2 (p = 0.04). Cognitive benefits were also observed in the STZ-induced model. STZ-EGF + GHRP6 group exhibited an alternation percentage higher than the STZ-vehicle group (p = 0.03). Moreover, EGF + GHRP6 treatment significantly increased the expression of genes associated with antioxidant defense (Hmox1), synaptic plasticity (Creb1), and oligodendrocyte differentiation (Olig1) while concurrently reducing the expression of Nfkb1. These findings highlight the therapeutic potential of EGF + GHRP6 co-administration as a neuroprotective strategy to mitigate neurodegeneration and preserve cognitive function.
Wernicke's Encephalopathy Following Semaglutide Treatment for Obesity: A Systematic PRISMA Review of Case-Based Evidence.
Obesity (Silver Spring)
Janice Bidesie, Erik Oudman
Glucagon-like peptide-1 receptor agonists are increasingly prescribed for obesity. Although generally considered safe, marked appetite suppression and persistent gastrointestinal adverse effects may increase the risk of nutritional deficiencies. Wernicke's encephalopathy (WE), caused by thiamine deficiency, is a rare but potentially fatal neurological disorder that may result in irreversible cognitive impairment if not promptly recognized and treated. Recently, cases of WE associated with semaglutide use have been reported. This study aimed to systematically review published case reports of WE occurring after semaglutide treatment for obesity from an endocrinological drug safety perspective.
Assessment of nutritional status among older people seeking health care in tertiary care hospitals in Mangalore.
BMC Geriatr
Pracheth Raghuveer, Mithun Rao, Dayasagar Reddy +5 more
As the proportion of the geriatric population has increased worldwide, increases in mortality and morbidity are inevitable. To ensure healthy aging, preventive measures must be taken at the earliest stage. SDG 2.2 aims to overcome malnutrition, including malnutrition, among the older population. Thus, this study was designed to assess the prevalence of malnutrition among older people who visit hospitals for various ailments so that suggestive measures can be advised.
The chemokine receptor-like fourth extracellular loop of the apelin receptor differentially regulates apelin and elabela binding and signalling.
Br J Pharmacol
Chloé Bonef, Hela Bouhsine, Carine Huynh +9 more
Apelin and Elabela are endogenous ligands of the apelin receptor (apelin receptor/APJ), a GPCR involved in cardiovascular regulation and body fluid homeostasis. The human receptor contains a conserved disulfide bridge linking the N-terminal domain to extracellular loop 3 (ECL3) via Cys19 and Cys281, forming a structural constraint analogous to a fourth extracellular loop ('ECL4'). In the chemokine receptor family, this motif plays a critical role in ligand engagement and receptor activation.
Rationale, design, and statistical analysis plan for a randomized, double-blind, placebo-controlled trial of Limosilactobacillus reuteri to support mother-infant bonding and maternal socioemotional functioning in postpartum women at increased risk for postpartum depression.
Contemp Clin Trials
Imen Becetti, Hannah Lamont, Luke Dysart +13 more
Postpartum depression (PPD) is common and can impair early mother-infant bonding. Oxytocin (OXT) supports socioemotional adaptation, yet intranasal OXT yields supraphysiological exposure and mixed results. The probiotic Limosilactobacillus reuteri (L. reuteri) increases endogenous oxytocin levels in rodents, suggesting that it may enhance OXT signaling via gut-brain pathways in humans. We designed a proof-of-concept trial to test whether postpartum L. reuteri improves early mother-infant bonding and maternal mental health, impulse control, and emotion recognition.
Sex-specific mechanisms of childhood trauma-related HPA axis dysregulation: Insights across four regulatory probes.
Psychoneuroendocrinology
Liza M Hinchey, James L Abelson
Blunted cortisol reactivity (BCR) to stress has been linked to trauma symptoms and early life adversity (ELA). Despite evidence for sex differences in ELA's impact on cortisol reactivity, few stress reactivity studies adequately assess sex-specificity. Further, most have measured salivary cortisol response to a single regulatory probe, limiting conclusions regarding mechanisms contributing to trauma-related HPA axis dysregulation. Using measures of cortisol binding globulin (CBG), serum adrenocorticotropic hormone (ACTH), and serum and salivary cortisol across four regulatory probes, this study assessed sex-specific mechanisms of ELA-related HPA axis dysregulation. 116 adults (55 female; 61 male) completed the Trier Social Stress Test (TSST), ACTH stimulation test, and low and high dose dexamethasone suppression tests (DST), and provided serum ACTH and cortisol, salivary cortisol, and CBG samples. For women, probes were scheduled to avoid ovulatory estrogen surges. Regressions in sex-disaggregated data examined the impact of ELA on cortisol reactivity and three candidate mechanisms of BCR. We found a negative association between salivary cortisol reactivity and ELA in females (p = .037), with no relation in males. In females, neither CBG nor adrenal sensitivity explained blunting; ELA was, however, associated with enhanced feedback inhibition (p = .033). Findings imply that the relation between ELA and adult BCR may primarily be present in females. The observed patterns were more consistent with enhanced feedback inhibition as a candidate pathway to trauma-related blunting in women than altered adrenal sensitivity or blunting explained by CBG. Future sex-disaggregated approaches may clarify persistently elusive pathways between trauma, HPA axis dysregulation, and adverse health outcomes.
PEGylated thymosin β4 is a thiol-site-specific prodrug treating myocardial infarction in vivo.
Bioeng Transl Med
Haisheng Peng, Yanqun Chai, Chen Gong +7 more
Thymosin beta 4 (Tβ4) has been clinically trialed for over 10 years to treat ulcers, dry eye syndrome, and acute myocardial infarction (MI). However, as of now, no Tβ4 drug has been approved. Tβ4, as a small protein drug, has to face druggability challenges such as abundant supply, high purity, verified efficacy and safety, long half-life, and shelf-life. Here, a modified prokaryotic expression system was developed to express recombination Tβ4 (rTβ4), followed by single thiol-site-specific PEGylation of rTβ4, namely PEG-rTβ4 as a prodrug. The identification and thermodynamic properties of PEG-rTβ4 were tested with a matrix-assisted laser desorption-ionization time of flight mass spectrometer, a differential scanning calorimeter, and a thermal gravimetric analyzer. The data showed the superiority of PEG-rTβ4 for treating MI. Long-circulating PEG-rTβ4 significantly relieves myocardial remodeling, restores cardiac function, promotes neoangiogenesis, and inhibits apoptosis via the Akt/Bcl-2/caspase-3 pathway. In summary, PEG-rTβ4 is a better choice for the drug development of this active protein.
The emerging landscape of performance-enhancing peptides modulating GH-IGF1 axis: bridging the gap between clinical evidence and patient self-administration.
Front Endocrinol (Lausanne)
Aleksander Dominikowski, Zofia Rękoś, Michał Olejarz +3 more
Performance-enhancing drugs (PEDs) marketed as "research compounds" include unregulated peptides intended to modulate the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis. The agents most commonly encountered in clinical practice and online self-administration protocols include growth hormone-releasing hormone (GHRH) analogues (e.g., sermorelin, tesamorelin, CJC-1295 with Drug Affinity Complex [DAC], CJC-1295 without DAC), growth hormone secretagogues (GHS; e.g., growth hormone-releasing peptide-2 (GHRP-2), growth hormone-releasing peptide-6 (GHRP-6), hexarelin, ipamorelin), the growth hormone (GH) fragment - AOD9604 (hGH 176-191), and insulin-like growth factor-1 (IGF-1) analogues (e.g., pegylated mechano growth factor (PEG-MGF), IGF-1 Long R3 (IGF-1 LR3)). Reported adverse effects span endocrine and metabolic disturbances (including prolactin and cortisol elevations, appetite changes, and dysglycaemia), fluid retention syndromes, musculoskeletal symptoms (myalgia/arthralgia), and injection-site reactions. Given the absence of regulatory approval for physique- or performance-related indications and the uncertainty surrounding product composition, dose, and stacking practices in unregulated supply chains, clinicians increasingly require a pragmatic framework to interpret symptoms and laboratory abnormalities in patients using these compounds. This narrative review contrasts peer-reviewed pharmacokinetic/pharmacodynamic and clinical evidence with commonly encountered online self-administration protocols, stratifying peptides into evidence tiers from regulatory-grade randomized trial data to a complete absence of human studies, and highlights the resulting uncertainty around putative performance and recomposition benefits. We summarise structural characteristics, pharmacologic effects, and commonly reported dosing patterns, and we synthesise clinically relevant adverse effects with particular attention to hormonal imbalance, endocrine-metabolic risk, and biologically plausible but unproven mitogenic concerns. Finally, we propose a clinically oriented assessment algorithm to support exposure history taking, triage of symptom domains, and risk communication without legitimising off-label peptide regimens.
Cost-Effectiveness of Semaglutide 2.4 mg for Obesity Disease Management in Japan: A Lifetime Economic Modeling Study Incorporating Retreatment Scenarios.
J Health Econ Outcomes Res
Yuta Kamada, Shogo Wada, Hiroyuki Matsuda +1 more
Obesity is a chronic disease associated with substantial morbidity and healthcare costs. In Japan, the Optimal Use Promotion Guidelines (OUG) impose restrictions on patient eligibility for semaglutide 2.4 mg and limit treatment duration. This study evaluated the cost-effectiveness of semaglutide 2.4 mg in Japan under retreatment assumptions informed by OUG requirements.
Concurrent diabetic ketoacidosis, acute pancreatitis, and subsequent ruptured acalculous cholecystitis in a patient receiving semaglutide: A case report.
SAGE Open Med Case Rep
Chuan-Tai Chiu, Ya-Hui Hu, Chia-Hui Chang
A 70-year-old male with type 2 diabetes presented to the emergency department with severe abdominal pain and dyspnea after 24 weeks of treatment with weekly subcutaneous semaglutide (1 mg). He was diagnosed with acute pancreatitis and diabetic ketoacidosis (DKA) and admitted to the intensive care unit. Following 5 days of stabilization and symptom relief, he was transferred to a general ward. However, the patient subsequently developed a high-grade fever persisting for 3 days, accompanied by severe leukocytosis, despite normalized serum lipase levels. A repeat abdominal computed tomography scan revealed acute acalculous cholecystitis complicated by gallbladder rupture. The patient underwent emergency percutaneous transhepatic gallbladder drainage and antibiotic therapy, leading to gradual recovery. This clinical course illustrates a rare cascade of severe complications in a patient receiving a glucagon-like peptide-1 (GLP-1) receptor agonist. Specifically, when new-onset systemic symptoms emerge following the initial stabilization of a critical illness, clinicians should maintain vigilance for repeating imaging studies. This rare case highlights the need for further investigation into whether the pharmacological effects of GLP-1 receptor agonists, such as biliary stasis, might act as a predisposing factor for complex biliary complications in the setting of severe physiological stress.