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peptide science.

Pharmacokinetics, Pharmacodynamics and Immunogenicity of AC02, a Novel Synthetic Derivate Peptide of Human Adrenocorticotropic Hormone for Infantile Spasms.

Pharmaceutics

Shunbo Zhao, Bingda Wu, Hui Shen +4 more

Objectives: AC02, a novel synthetic peptide derived from ACTH, is being developed as a potential therapeutic alternative to porcine ACTH1-39 for use in infantile spasms. Methods: The study comprised single-ascending dose cohorts (0.02, 0.04, 0.08, 0.16 mg/kg AC02) and multiple-ascending dose cohorts (0.04, 0.08 mg/kg AC02 daily for 5 days). A separate positive-control arm received porcine ACTH1-39 (25 U/day for 5 days). PD effects (free and total cortisol) were compared head-to-head with the positive control. Plasma concentrations of AC02, porcine ACTH1-39, free and total cortisol were quantified by validated LC-MS/MS methods, and anti-drug antibody responses were measured using a validated electrochemiluminescence bridging immunoassay. Population PK/PD modeling characterized the concentration-response relationships for free cortisol. Results: Across the 0.02-0.16 mg/kg dose range, AC02 exhibited approximately dose-proportional pharmacokinetics and no accumulation after multiple doses. At 0.04 and 0.08 mg/kg, the baseline-corrected effects on free cortisol were generally consistent with those of porcine ACTH1-39. Dynamic monitoring of the free cortisol fraction revealed a biphasic pattern across all groups: an early peak followed by a later rise. Total cortisol, by contrast, showed only a monophasic decline, indicating the limitations of total cortisol as a sole PD biomarker. No unexpected safety signals were observed. At 0.04 mg/kg, AC02 demonstrated pharmacodynamic responses comparable to those of marketed ACTH product based on the biologically active component of free cortisol, with favorable safety and pharmacokinetic profiles. Conclusions: This first-in-human study demonstrates that AC02 has favorable pharmacokinetic properties, and an acceptable safety profile.

Carcinoid syndrome revealed by chronic diarrhea and isolated severe tricuspid regurgitation.

JCEM Case Rep

Darpan Kothia, Otto Valdes, Tushar Patel +3 more

Carcinoid syndrome is an uncommon manifestation of metastatic neuroendocrine tumor (NET) and may present without classic flushing or bronchospasm. We describe a woman in her 50s with hypertension treated with hydrochlorothiazide who presented with confusion, severe hyponatremia with a serum sodium concentration of 114 mmol/L (reference range, 135-145 mmol/L), chronic watery diarrhea, bilateral leg edema, and 40-lb weight loss. Computed tomography (CT) revealed a calcified mesenteric mass and multiple hepatic lesions. Serum chromogranin A was 1434 ng/mL (SI: 1434 µg/L) (reference range, <100 ng/mL [SI: <100 µg/L]), and 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) was 108 mg/24 hours (SI: 565 µmol/24 hours) (reference range, <6 mg/24 hours [SI: <31 µmol/24 hours])-well above the threshold associated with carcinoid heart disease (CHD). Transthoracic echocardiography demonstrated severe tricuspid regurgitation with retracted leaflets, consistent with CHD. Liver biopsy confirmed a well-differentiated grade 2 NET. Urine sodium <20 mmol/L and urine osmolality 188 mOsm/kg indicated volume depletion from gastrointestinal losses, aggravated by hydrochlorothiazide. Hydrochlorothiazide was discontinued; isotonic saline, octreotide, and furosemide improved hyponatremia, diarrhea, and edema. Chronic diarrhea with isolated right-sided valvulopathy should prompt evaluation for carcinoid syndrome even when electrolyte derangement dominates.

Peptide Hormones in Appetite Regulation: A Complex Network.

Pharmaceuticals (Basel)

Sara Abdollahi, Hussan Adam, Othman Al Musaimi

Background: Appetite regulation is governed by a complex neuroendocrine network that integrates peripheral peptide signals with hypothalamic and brainstem circuits to coordinate energy intake and maintain energy homeostasis. Disruption of these pathways contributes to obesity and other disorders characterised by dysregulated feeding behaviour. Objective: To map and synthesise the current evidence on the role of appetite-regulating peptide hormones and central neural pathways in appetite control, obesity pathophysiology, and emerging therapeutic approaches. Methods: A scoping review of the literature was conducted to identify and synthesise evidence relating to the physiological and pathological mechanisms of appetite regulation. The review examined the actions of key peptide hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), leptin, and insulin, their interactions within the gut-brain axis, and their effects on central appetite-regulating circuits. Results: The evidence highlights the central role of the arcuate nucleus in integrating peripheral hormonal signals with neural pathways controlling feeding behaviour. Appetite regulation is mediated by the balance between orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons and anorexigenic pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) neurons, with further modulation by the paraventricular, lateral, and ventromedial hypothalamic nuclei. The literature identifies hormone resistance, impaired satiety signalling, and altered neuroendocrine feedback as major contributors to obesity. Evidence on therapeutic interventions demonstrates the potential of GLP-1 receptor agonists, including liraglutide and semaglutide, and the dual incretin agonist tirzepatide, while also highlighting challenges related to treatment durability, adverse effects, and weight regain following discontinuation. Conclusions: Current evidence demonstrates that appetite regulation involves highly interconnected peripheral and central signalling pathways. The reviewed literature supports the development of multi-target and precision-based therapeutic strategies for obesity and identifies important areas for future research, including mechanisms of treatment resistance, long-term efficacy, and inter-individual variability in neuroendocrine responses.

Integrated management of atrial fibrillation and comorbidities in the community: a generalist-specialist collaborative RCT and subgroup analysis.

Front Cardiovasc Med

Dai Huimin, Bo Jun, Jiang Meng +3 more

To develop, implement, and evaluate a community-based, patient-centered integrated care model for atrial fibrillation (AF) characterized by generalist-specialist collaboration and cardio-cerebrovascular co-management, and to examine whether its effectiveness varies across key patient subgroups.

The cost-effectiveness of second line diabetes medication added to standard therapy in preventing type 2 diabetes related nephropathy in Germany.

Cost Eff Resour Alloc

Hanni Hille, Wendelin Schramm, Ahmed Bounekkar

Type 2 diabetes and its associated complications like nephropathy impose a serious burden on health systems. Several blood glucose-lowering medications have shown to be likely to provide nephroprotective properties, delaying or preventing the onset of kidney damage. Kidney-specific health-economic evaluations, comparing different agents, remain rare for Germany.

Retinal Manifestations of Alzheimer's Disease: Insights from Animal Models, Clinical Detection, and Future Translation.

Prog Retin Eye Res

Xiayin Zhang, Dongli Zhuang, Chunran Lai +18 more

The retina, as an extension of the central nervous system, shares a common embryological origin with the brain. In Alzheimer's disease (AD), studies of human tissue and animal models have revealed that hallmark AD pathologies, including amyloid-β (Aβ) deposits and pathological tau protein tangles, also appear in the retina. These findings, coupled with advances in high-resolution retinal imaging techniques, suggest the potential to detect and characterize AD-related molecular and structural changes in the retina. However, retinal findings across different AD mouse models have significant discrepancies and show limited concordance with human phenotypes, complicating the identification of AD-specific alterations and the selection of optimal models for translational research. Moreover, the temporal sequence and functional significance of retinal abnormalities across the AD continuum, from preclinical stages to mild cognitive impairment and overt dementia, remain poorly defined. Addressing these knowledge gaps is essential to establish the retina as a reliable, non-invasive screening and monitoring approach. This review synthesizes current evidence on the spectrum of retinal alterations in AD, including vascular dysfunction, neuroinflammation, impaired Aβ clearance, and neurodegeneration, as observed in diverse mouse models. We compare these manifestations across species and between different models, highlighting findings along the disease continuum to delineate convergent and divergent pathways. We further discuss how emerging technologies enable the identification of AD-specific retinal alterations, and advocate for a paradigm shift from non-specific morphological assessment ("seeing shapes") toward molecular-level interrogation ("seeing components"). Interdisciplinary efforts and technological integration are crucial to establish retina as a dynamic mirror of pathology in AD.

GLP-1 receptor agonists in adolescent obesity: Incretin-based therapies during a sensitive developmental period.

Appetite

Austin M Mills, Emily E Noble

Adolescent obesity is a chronic disease associated with early cardiometabolic dysfunction and long-term health risk. Behavioral interventions alone produce modest and unsustained weight loss, leading to increasing use of pharmacotherapy. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as highly effective treatments for obesity, producing clinically significant reductions in body weight and improvements in glycemic control. Short-term safety profiles are characterized primarily by transient gastrointestinal symptoms and low rates of serious adverse events or psychiatric symptoms. However, the developmental implications and long-term effects have yet to be evaluated. The purpose of this review is to summarize existing literature concerning the use of GLP-1RAs for adolescents with obesity and to discuss the implications of GLP-1RA use in the adolescent population. This review serves to both identify areas of potential concern and to highlight the need for continued research. Although GLP-1RAs demonstrate robust efficacy for the treatment of adolescent obesity, adolescence is a sensitive period of development and critical knowledge gaps remain regarding long-term effects of GLP-1RAs on growth, pubertal development, cognition, neural reward processing, and lifelong energy balance regulation. Longitudinal and mechanistic studies are needed to determine the long-term effects on development and to guide safe, developmentally informed clinical use.

Lonigutamab Inhibits Hyaluronan Production by Reducing IGF-1R Levels in Thyroid Eye Disease Orbital Fibroblasts.

J Clin Endocrinol Metab

Elisa Roztocil, Farha Husain, Charkira C Patrick +6 more

In thyroid eye disease (TED), the connective tissue behind the eye becomes inflamed and expands, partly due to excessive deposition of hyaluronan (HA), which absorbs water, leading to osmotic swelling. Orbital fibroblasts (OFs) from patients with TED overexpress insulin-like growth factor 1 receptor (IGF-1R), a receptor that promotes cell survival, proliferation, and HA production. These processes contribute to orbital tissue remodeling and expansion, as well as to the inflammation and fibrosis characteristic of TED. Therapeutic options remain limited, highlighting the need for additional targeted therapies. Lonigutamab is a next-generation anti-IGF-1R monoclonal antibody that binds to a distinct epitope on IGF-1R with high affinity, eliciting a novel mechanism of action.

Linking pediatric obesity to youth-onset type 2 diabetes: integrated longitudinal and cross-sectional evidence from population-based studies worldwide.

Clin Exp Pediatr

Ashraf T Soliman, Fawzia Alyafei, Nada Alaaraj +3 more

Youth-onset type 2 diabetes mellitus (T2DM) is a rapidly growing pediatric metabolic disorder that parallels the global childhood obesity epidemic. Despite multiple population-based registries and a global meta-analysis documenting near-universal obesity at the time of a T2DM diagnosis, no integrated synthesis spanning 25 years and including diverse populations has been performed. Here we conducted a systematic review of PubMed and Scopus (January 2000 to March 2025) using longitudinal data from population-based registries in the USA (SEARCH), Canada (Manitoba), England and Wales (National Paediatric Diabetes Audit), Israel, Australia, and New Zealand as well as cross-sectional burden from a global meta-analysis (53 studies, n=8,942) and national audits. Study quality was appraised using the Newcastle-Ottawa Scale and A Measurement Tool to Assess Systematic Reviews v2. All registries showed a temporally parallel increase in the incidence of pediatric obesity and youth-onset T2DM. In the USA, the T2DM incidence rose 79% (3.8 → 6.8 per 100,000/yr, 2002-2018); in Manitoba, it nearly doubled (16.0 → 31.1 per 100,000/yr, 2009-2018); and Israel showed a 441% rise (0.63 → 3.41 per 100,000/yr, 2008-2019). The global pooled obesity prevalence at the T2DM diagnosis was 75.3% (95% confidence interval, 72.1%-78.5%), with approximately 41,600 new youth cases annually worldwide. Once-weekly semaglutide 2.4 mg (STEP TEENS trial) reduced the average body mass index by 16.1% at 68 weeks with concurrent glycemic improvement, while bariatric surgery achieved 95% T2DM remission at 3 years in adolescents (Teen-LABS cohort). Multicontinental evidence confirmed a robust temporally consistent obesity-T2DM link; obesity precedes T2DM at the population level and is present in approximately 75% of affected youths at diagnosis worldwide. Weight-reduction interventions, particularly glucagon-like peptide-1 receptor agonists and bariatric surgery, offer meaningful glycemic benefits; however, primary prevention of childhood obesity remains the most powerful strategy to arrest this epidemic.

Efficacy and Safety of Once-Weekly Semaglutide 2.0 mg as an Add-On to Dose-Reduced Insulin Glargine versus Dose-Titrated Insulin Glargine in People With Type 2 Diabetes and Overweight (SUSTAIN OPTIMIZE).

Diabetes Obes Metab

Helena W Rodbard, Concetta Irace, Jevitha Lobo +5 more

Type 2 diabetes (T2D) management with basal insulin can lead to hypoglycaemia and weight gain. SUSTAIN OPTIMIZE compared once-weekly semaglutide 2.0 mg as add-on to dose-reduced insulin glargine (Sema+IGlarreduced) versus dose-titrated IGlar (IGlartitrated) on glycated haemoglobin (HbA1c), body weight (BW), daily insulin dose, and participant satisfaction.

Incretin-Based Therapies, Obesity-Associated Inflammation, and Atherosclerotic Cardiovascular Risk.

Cells

Jan Kafol, Borut Jug, Zlatko Fras

Cardiovascular disease remains a leading cause of mortality despite major advances in lipid lowering and risk-factor control, highlighting the importance of residual cardiovascular risk. Inflammation is a central driver of atherosclerosis, while obesity promotes chronic low-grade inflammation, adipose tissue dysfunction, ectopic fat accumulation, and vascular injury. This narrative review focuses on obesity-associated inflammation as an upstream contributor to residual atherosclerotic risk and evaluates whether incretin-based therapies modify this pathway through weight loss, metabolic improvement, and additional inflammatory or vascular mechanisms. Data from mechanistic studies, biomarker analyses, vascular imaging studies, and cardiovascular outcome trials are reviewed. Anti-inflammatory trials support inflammation as a modifiable therapeutic pathway, although clinical benefit depends on the therapeutic target, timing, and patient selection. Glucagon-like peptide-1 receptor agonists reduce inflammatory and oxidative stress biomarkers and show anti-atherosclerotic effects in experimental models, but human vascular imaging data remain inconclusive. Cardiovascular outcome trials establish benefit with several GLP-1 receptor agonists, including semaglutide in selected patients with overweight or obesity without diabetes. However, direct human evidence for receptor-mediated anti-inflammatory or anti-atherosclerotic effects remains limited, and the relative contributions of weight loss, metabolic improvement, and additional mechanisms remain uncertain.

Body Composition Changes During GLP-1 Receptor Agonist Therapy in Pediatric Obesity: A Pilot Study.

Metabolites

Bogdan Mihai Pascu, Irina Bojoga, Anca Bălănescu +2 more

GLP-1 receptor agonists (GLP-1 RAs) are effective weight-loss therapies, but data on body composition changes in pediatric obesity remain scarce. The primary objective was to evaluate the effects of GLP-1 RAs on body composition in children with obesity.

Understanding Biased Signaling and Small-Molecule Binding for Treatment of Type 2 Diabetes Mellitus and Obesity at the Glucagon-Like Peptide-1 Receptor (GLP-1R) Based on Molecular Dynamics Simulations.

Med Chem Res

Jack Brubaker, Soo-Kyung Kim, Bo Li +2 more

Glucagon-like peptide-1 receptor (GLP-1R) is a class B1 G protein-coupled receptor expressed in multiple tissues and is a major therapeutic target for type 2 diabetes mellitus and obesity. Here, we investigate the mechanisms of GLP-1R binding and activation using molecular dynamics (MD) simulations of semaglutide, tirzepatide, danuglipron, and CHU-128bound GLP-1R-Gs complexes. We analyze these simulations as a function of temperature, ligand class (peptide vs. small molecule), and signaling profile (biased vs. non-biased) to assess how these factors affect GLP-1R interactions and conformational dynamics. Our results reveal distinct interaction patterns and structural features associated with each factor which persist over the MD trajectories. Together, these findings deepen our mechanistic understanding of GLP-1R agonism and further aid in the design of effective, orally available GLP-1R agonists with reduced side effects.

Impact of semaglutide withdrawal on cardiometabolic profile and physiology of energy balance: Recovery effects after semaglutide termination - The REST trial study protocol.

PLoS One

Taras Yevusiak, Alanna Weisman, Ravi Retnakaran +3 more

Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide have been shown to induce substantial weight loss and improve cardiometabolic risk factors in patients living with obesity. However, most individuals regain weight after abrupt withdrawal of semaglutide, with reversal of its beneficial cardiometabolic effects.

A Case of Severe Hypercalcemia in a Patient Taking Tirzepatide: Potential Risk Factors.

Cureus

Safiah Iqbal, Faiza Javed, Samson O Oyibo

Hypercalcemia is commonly caused by hyperparathyroidism and malignancy. Medication-induced hypercalcemia is less common. Tirzepatide is a dual glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonist (GLP-1/GIP RA) used to aid weight loss and glycemic control. It is associated with gastrointestinal side effects, but its effect on calcium homeostasis has not been well reported. We report the case of a 75-year-old woman with a history of type 2 diabetes, hypertension, obesity, chronic kidney disease, and post-surgical hypothyroidism and hypoparathyroidism, who presented with severe symptomatic hypercalcemia one month after starting tirzepatide while taking bendroflumethiazide, calcium carbonate, and alfacalcidol. Her serum calcium levels had been in the normal treatment range before the initiation of tirzepatide. All other possible causes of hypercalcemia were ruled out. Her calcium levels returned to normal after intravenous fluid therapy and withholding tirzepatide, bendroflumethiazide, and calcium carbonate. This case highlights the potential occurrence of severe hypercalcemia during the concurrent use of tirzepatide with bendroflumethiazide, a calcium supplement, and vitamin D in the context of chronic kidney disease. With the increasing use of tirzepatide, healthcare workers need to be mindful of the interaction between tirzepatide and these potential risk factors. While further research is required, we suggest serum calcium monitoring during similar clinical scenarios.

Accidental intradermal injection of tirzepatide associated with increased adverse events.

Postgrad Med J

Antonio Di Guardo

Nutritional intake changes during GLP-1 receptor agonist therapy: A systematic review and meta-analysis.

Diabetes Metab Syndr

Anh Tuan Quan, Hoang Linh Nguyen, Tran My Thanh Nguyen

Glucagon-like peptide-1 (GLP-1) receptor agonists, including the dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist tirzepatide, produce substantial weight loss, yet their effect on objectively measured dietary intake has not been quantitatively synthesized. We assessed their impact on ad libitum lunch energy intake.

Changes in the Adrenal Cortex Induced by Liraglutide Treatment and Exercise in a Rat Model of Menopausal Transition.

Cells

Ivona Gizdović, Branka Šošić-Jurjević, Dragana Vlahović +4 more

The menopausal transition is a key period marked by changes in cardiometabolic health and adrenal function, representing an important window for targeted interventions to improve women's health. Glucagon-like peptide-1 receptor agonists improve metabolic parameters, while physical exercise provides well-established benefits; however, their effects during the menopausal transition remain insufficiently explored. This study examined the effects of liraglutide (0.186 mg/kg; corresponding to the human equivalent dose of 1.8 mg/day used for type 2 diabetes treatment) and exercise on the adrenal gland in a rat model of menopausal transition. Three-month-old females served as young controls (CY), while 16-month-old acyclic females were assigned to control (C), liraglutide (L), exercise (E), or combined treatment (L+E). Compared with CY, the C group showed increased body mass and adrenal alterations, including reduced adrenal weight and volume, cortical atrophy, increased collagen content, decreased STAR, and increased pAMPKα optical density (p ≤ 0.05). Sf1 and Star were upregulated in L, E, and L+E compared with C, most prominently in L (p ≤ 0.05), while Cyp11b2 was increased in L and L+E (p ≤ 0.05). Hormone analysis showed reduced 17β-estradiol, corticosterone, and aldosterone in C compared with CY. Corticosterone was further reduced in L compared with C, while aldosterone increased in L and L+E compared with C (p ≤ 0.05). In conclusion, the menopausal transition induced adrenal morpho-functional remodeling. Liraglutide intervention had the greatest impact on steroidogenic output, both alone and in combination with exercise, while exercise alone showed no significant effect.

GLP-1 Receptor Agonists in Cardiac Surgery: From Metabolic Drug to Potential Perioperative Cardioprotective Agent.

J Cardiovasc Dev Dis

Vasiliki Androutsopoulou, Vanesa Brecher, Andrew Xanthopoulos +3 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have rapidly evolved from glucose-lowering agents to central players in cardiovascular risk reduction. Evidence from landmark randomized controlled trials has established their capacity to reduce major adverse cardiovascular events, promote anti-inflammatory signaling, attenuate ischemia-reperfusion injury, and improve myocardial metabolic efficiency. As the prevalence of obesity, type 2 diabetes mellitus, and heart failure in the cardiac surgical population grows, GLP-1 RAs are increasingly encountered in the perioperative setting. Yet the cardiac surgery literature has yet to synthesize their emergent role coherently. This is a narrative review; no systematic review or meta-analysis was performed. This narrative review integrates mechanistic, clinical, and translational evidence to reframe GLP-1 RAs as potential perioperative cardioprotective agents in patients undergoing cardiac surgery. We examine receptor-level biology, evidence from the GLOBE randomized trial, observational data linking GLP-1 RA use to reduced postoperative atrial fibrillation after coronary artery bypass grafting, the rationale for the forthcoming REVERSE-TAVR trial, and evolving perioperative management guidelines. Key evidence gaps are identified, including the absence of prospective data in open cardiac surgery, aortic surgery, and high-acuity populations. We propose a research agenda and conceptual framework to guide future investigation into GLP-1 RAs as a new dimension of perioperative cardioprotection. The current evidence is hypothesis-generating; a definitive perioperative cardioprotective benefit has not yet been demonstrated in cardiac surgery populations, and these agents are presented here as potential rather than proven cardioprotective tools.

Neurodegeneration in Parkinson's Disease: The Role of Environmental Toxins.

J Cent Nerv Syst Dis

Jamir Pitton Rissardo, Megan Katz, Vishnu Vardhan Byroju +2 more

Parkinson's disease (PD) is a rapidly growing global health challenge, with prevalence projected to reach 13-14 million cases by 2040. While aging and improved diagnostic awareness partly explain this trend, mounting evidence implicates environmental factors as critical contributors. This review synthesizes current literature on exposures such as pesticides, solvents, heavy metals, air pollutants, and infectious agents, emphasizing their mechanistic links to neurodegeneration. These factors interact with genetic susceptibility and aging, supporting the "multiple-hit" hypothesis, which posits that PD arises from cumulative insults rather than a single cause. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired protein clearance emerge as convergent pathways underlying dopaminergic vulnerability. Recent findings highlight viral infections-particularly SARS-CoV-2-as potential triggers or amplifiers of PD pathogenesis, raising concerns about long-term neurological sequelae following pandemics. Beyond individual toxins, the exposome concept underscores the lifelong interplay of physical, chemical, and social exposures in shaping disease risk. Climate-related changes, including increased air pollution and wildfire frequency, further compound these risks, suggesting a systemic dimension to PD etiology. Understanding these complex interactions is essential for developing preventive strategies, refining experimental models, and informing public health policies aimed at mitigating environmental contributions to neurodegeneration. This multifactorial perspective offers a foundation for future research targeting modifiable risk factors and resilience mechanisms in PD.