Peptide Research Database

Dual acellular subnormothermic machine perfusion for enhanced uterus preservation in a swine model.

In an animal study, in addition, subnormothermic machine perfusion may enable other applications, including graft assessment, treatment and tolerance induction. The aim of this study was to assess whether subnormothermic machine perfusion improves graft preservation compared with SCS in a porcine uterus model.

Cabanel L, Oubari H, Ellis BW, Dion L, Lavoué V, Sousa C, Van Dieren L, Morel O, Randolph MA, Cetrulo CL, Uygun K, Lellouch AG, Berkane Y, Uygun BE

Machine perfusion has rapidly developed in the last decade and demonstrated improved preservation of conventional and marginal organs by reducing ischemia and hypoxia injuries. The aim of this study was to assess whether subnormothermic machine perfusion improves graft preservation compared with SCS in a porcine uterus model. Swine uteri were procured from circulatory-dead donors and allocated into two groups. In the experimental group, the organs were preserved with 4 h-dual subnormothermic machine perfusion (n = 4) while the control group (n = 4) underwent 4 h-static cold storage. After preservation, all uteri received ex vivo whole blood normothermic reperfusion (NMP) to simulate transplantation. Perfusate samples were analyzed from uterine arteries and veins every 30 min for gas and metabolic analysis, and weight variations were recorded continuously during perfusion. Following simulated transplantation, uterine contraction was assessed after oxytocin injection, and macrovascular perfusion was evaluated using contrast angiography. Several biopsies were procured from different parts of the uterus for histological and immunohistochemistry analysis. In the experimental group, the weight of the uteri and lactate difference between vein and artery decreased during subnormothermic machine perfusion. Weight gain was significantly higher in the control group (p = 0.03), which was consistent with interstitial edema observed on histological sections in this group. Uterine contraction evaluated through semi-quantitative scoring was higher in the experimental group (p = 0.02). In this porcine model, subnormothermic machine perfusion reduces edema and preserves contractility more effectively than static cold storage. We demonstrate its particular interest in recovering organs procured from deceased donors. In addition, subnormothermic machine perfusion may enable other applications, including graft assessment, treatment and tolerance induction.

Histopathological and immunohistochemical characterization of MPTP-associated pancreatic injury and its attenuation by Hexarelin in mice.

In a mouse study, these findings suggest that MPTP exposure is associated with pancreatic inflammation, cell death-associated changes, and alterations in endocrine-marker immunoreactivity. Investigated MPTP-associated pancreatic histopathological and immunohistochemical alterations and evaluated the potential attenuating effects of Hexarelin.

Şahin M, Topsakal Ş, Elmas O, Özmen Ö

Parkinson's disease (PD) is associated with systemic inflammatory and metabolic alterations that may extend beyond the central nervous system. Although 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces several pathological features of Parkinsonian neurodegeneration, its effects on pancreatic tissue remain poorly characterized. This study investigated MPTP-associated pancreatic histopathological and immunohistochemical alterations and evaluated the potential attenuating effects of Hexarelin. Fifty male BALB/c mice were randomly assigned to five groups (n = 10/group): Sham, MPTP, Hexarelin, PreHexarelin, and PostHexarelin. Pancreatic tissues were examined using hematoxylin and eosin staining and immunohistochemistry for amylin, β-amyloid, caspase-3, glucagon, insulin, CD11b, CD68, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). MPTP administration was associated with marked pancreatic injury characterized by acinar degeneration, cytoplasmic vacuolization, vascular congestion, interstitial edema, inflammatory cell infiltration, and degeneration of the islets of Langerhans. Immunohistochemical analysis demonstrated increased inflammatory (CD11b, CD68, IL-1β, and TNF-α) and apoptosis-associated (caspase-3) marker immunoreactivity, together with increased β-amyloid immunoreactivity and decreased insulin and amylin immunoreactivities. Hexarelin treatment attenuated these histopathological and immunohistochemical alterations in both treatment groups, although the magnitude of improvement varied among individual markers. These findings suggest that MPTP exposure is associated with pancreatic inflammation, apoptosis-associated changes, and alterations in endocrine-marker immunoreactivity. Hexarelin treatment was associated with attenuation of these pathological changes and partial preservation of islet morphology and endocrine-marker immunoreactivity; however, the PostHexarelin findings should be interpreted cautiously because the absence of a sequence- and time-matched post-MPTP vehicle control prevents complete separation of Hexarelin-associated effects from temporal changes after MPTP administration.

Comparative effects of semaglutide tirzepatide and retatrutide on renal fibrosis in UUO and aged mice.

In a mouse study, this comparative study offers a framework for understanding the renoprotective actions of these drugs and generates hypotheses for future investigation.

Ding M, Li X, Wei Y, Wang J, Jiao B, Li C, Ma W, Peng Y, Shen J, Yu G, Gao C

Chronic kidney disease is a major health burden. Given the therapeutic potential of GLP-1 receptor agonists (semaglutide, tirzepatide, and retatrutide) in diabetic nephropathy, we evaluated their anti-fibrotic and anti-inflammatory effects in non-diabetic renal fibrosis using HK-2 cells and murine UUO and aging models. Integrating in vivo and in vitro data showed model- and drug-specific patterns of action among the three agents. In the UUO model, semaglutide effects were associated with PI3K-AKT inhibition, tirzepatide effects with PI3K-AKT inhibition and PPAR pathway activation, and retatrutide effects with concurrent inhibition of both PI3K-AKT and NF-κB pathways. In the aging model, all three drugs were linked to G2/M arrest mitigation. Retatrutide showed the greatest efficacy at the doses tested in the models studied. This comparative study offers a framework for understanding the renoprotective actions of these drugs and generates hypotheses for future investigation.

Oxytocin receptor signaling contributes to the mitochondrial integrity and maintain gastric mucosal homeostasis in male mice.

In a mouse study, our findings support the hypothesis that OXTR signaling in parietal cells is essential for maintaining gastric tissue lining metabolic balance and protects against diet-induced gastric disease. Investigates the physiological and pathophysiological role of OXTR signaling in parietal cells.

Maejima Y, Yokota S, Yamachi M, Yabe T, Vecchi E, Aoki M, Shimoyama S, Ono T, Nakajima D, Teruuchi Y, Fukushima M, Hidema S, Nishimori K, Kubo H, Waguri S, Zhao S, de Wet H, Shimomura K

The role of oxytocin receptor (OXTR) signaling in the stomach remains poorly understood. This study investigates the physiological and pathophysiological role of OXTR signaling in parietal cells. Using wild type (wt), OXT null and OXTR null mice fed either a standard diet (SD) or a high fat diet (HFD), we examined the effects of OXT and OXTR signaling on gastric mucosa histology and function. SD-fed mice lacking active OXTR/OXT showed mucosal hyperplasia, which was reversed by subcutaneous OXT administration in OXT null mice. HFD-fed wt mice developed typical gastric mucosal hyperplasia, parietal cell atrophy with mitochondrial damage, and impaired 18F-fluorodeoxyglucose uptake. Subcutaneous OXT administration ameliorated these effects in HFD-fed wt mice, but not in OXTR null mice, suggesting that OXTR activation likely preserves mitochondrial integrity. Our findings support the hypothesis that OXTR signaling in parietal cells is essential for maintaining gastric mucosal metabolic homeostasis and protects against diet-induced gastric pathology.

GLP-1R and GIPR crosstalk modulates insulinotropic signaling pathways.

This study found these findings highlight heterodimerization and receptor expression as key modulators of GLP-1R/GIPR signaling, offering mechanistic insights, and guiding drug design strategies that incorporate receptor crosstalk.

Lindquist P, Hoegen Dijkhof LR, Drzazga AK, Sabatier P, Stepniewski TM, Granlund L, Lechner MY, Zhong Y, Gasbjerg LS, Hartmann B, Lauschke VM, Holst JJ, Olsen JV, Korsgren O, Selent J, Wright SC, Hauser AS, Rosenkilde MM

Drugs targeting glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors (GLP-1R and GIPR) show strong clinical effects in type 2 diabetes and obesity. Both GIPR agonism and antagonism enhance GLP-1R agonist efficacy, indicating important incretin receptor crosstalk. We show that GLP-1 and semaglutide, but not exendin-4, promote heterodimerization between GLP-1R and GIPR through interactions between TM4 of GLP-1R and TM1/2 of GIPR. Phosphoproteomics and molecular dynamics reveal that dimerizing and non-dimerizing agonists differentially influence GLP-1R, activating divergent signaling pathways in human pancreatic islets. Moreover, semaglutide and exenatide display distinct patterns in their FDA-reported safety profiles. When co-expressed, GLP-1R enhances GIPR signaling in a β-arrestin-dependent manner, while increasing GIPR levels decreases GLP-1R signaling. Additionally, we show that changes in GIPR expression are clinically associated with adiposity and diabetic phenotypes. These findings highlight heterodimerization and receptor expression as key modulators of GLP-1R/GIPR signaling, offering mechanistic insights, and guiding drug design strategies that incorporate receptor crosstalk.

Nutritional Deficiencies, Complications, and Nutrition Therapy/Counseling in Pediatric Patients Using GLP-1 Receptor Agonists.

In a clinical study, integration of NT/C care into pediatric GLP-1RA treatment may support healthy growth and long-term outcomes. Examined nutritional deficiency incidence and nutrition therapy/counseling (NT/C) utilization among pediatric GLP-1RA users.

Kerr KW, Chang AT, Sulo S, Stutts JT, Panchalingam T, Ryder JR

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used to treat childhood obesity, prediabetes, and type 2 diabetes. We examined nutritional deficiency incidence and nutrition therapy/counseling (NT/C) utilization among pediatric GLP-1RA users. We analyzed Inovalon administrative claims data from 2017 to 2022 covering over 100 million patients to identify 2,031 GLP-1RA users aged 10-17 years who met continuous enrollment criteria and had no prior diagnosis of nutritional deficiency. Nutritional deficiencies were identified using the International Classification of Diseases, 10th edition codes for up to 1 year following GLP-1RA initiation. NT/C visits, time to first NT/C visit, and differences in nutritional deficiency diagnoses by NT/C consultation were assessed. Results are reported as proportions and means, with group comparisons using chi-square tests. The mean age was 15 (±1.8) years, 61.5% were female, and 62.6% had obesity. Liraglutide (78.6%), dulaglutide (10.4%), and semaglutide (9.1%) were the most prescribed GLP-1RA drugs. Within 1 year, 16.88% of patients were diagnosed with at least one nutritional deficiency or deficiency-related complication, most frequently vitamin D deficiency (12.4%), followed by nutritional anemia (1.55%), and iron-deficiency anemia (1.44%). Only 23.3% had NT/C visit within 180 days (mean time to first visit: 149 days). Patients with NT/C consultations had higher rates of nutritional deficiencies and deficiency-related complications than those without (23.2% vs. 14.8%, p < 0.01). Nutritional deficiencies are a meaningful and under-recognized risk among pediatric patients receiving GLP-1RA therapy. Current care patterns suggest missed opportunities for proactive and preventative nutrition support. Integration of NT/C care into pediatric GLP-1RA treatment may support healthy growth and long-term outcomes.

Weight Loss With Microdose Tirzepatide: Real-World Outcomes in Patients Initiating Treatment Below 2.5 mg Weekly

In a clinical study, these uncontrolled findings are hypothesis-generating; the 36-59- and 60-89-day estimates are particularly limited by sparse follow-up.

Hastings J, Lee J.

Background: Tirzepatide is conventionally initiated at 2.5 mg weekly and titrated to approved maintenance doses. Evidence describing weight change at injectable starting doses below 2.5 mg/week is limited. Methods: We conducted a retrospective, single-organization observational study of adults documented as new GLP-1 starts, with baseline body mass index (BMI) ≥27 kg/m2, who initiated compounded injectable tirzepatide at a microdose of 1 or 2 mg/week (below the standard 2.5 mg/week starting dose). Source records were reviewed for baseline validity, prior treatment, weight consistency, and treatment exposure. The main descriptive analysis selected the latest eligible measurement per patient within observation windows of 14-35, 36-59, and 60-89 days of adjudicated treatment exposure, excluding observations after escalation above 2 mg/week. All 93 eligible measurements were included in a supporting random-intercept model. Analyses were retrospective and hypothesis-generating; no formal sample-size calculation was performed. Results: Sixty patients contributed 93 eligible follow-up measurements, of which 84 were selected for patient-window summaries. Mean age was 47.3 years, 81.7% were female, and mean baseline BMI was 33.3 kg/m2. Mean body-weight loss was 2.18% (95% CI 1.61-2.76; n=57) in the 14-35-day window at a median 21 days, 3.58% (95% CI 2.43-4.72; n=19) in the 36-59-day window at a median 48 days, and 6.10% (95% CI 4.60-7.60; n=8) in the 60-89-day window at a median 65.5 days. The adjusted model estimated 2.16 percentage points greater loss per 30 days of treatment exposure (95% CI 1.69-2.63). Conclusions: Weight loss was observed within the 14-35-, 36-59-, and 60-89-day observation windows among evaluable adults initiating compounded injectable tirzepatide at 1-2 mg/week. These uncontrolled findings are hypothesis-generating; the 36-59- and 60-89-day estimates are particularly limited by sparse follow-up.

Preferences for Obesity Medications Among People With Overweight or Obesity in the United States: A Discrete-Choice Experiment (OPTIC).

This study found individuals with overweight or obesity prioritise weight-loss efficacy, CV risk reduction, and taken by mouth in OM treatment decisions; dosing instruction requirements were of low importance.

Almandoz JP, Tchang BG, Myers K, Traina A, Bhavsar J, Divino V, Kent C, Bell ST

To evaluate the relative importance of attributes driving obesity medication (OM) choice and preferences among individuals with overweight or obesity. US adults with obesity or overweight and ≥ 1 obesity-related complication completed an online survey including a discrete-choice experiment (DCE) in October-November 2025. In the DCE, participants chose between 2 hypothetical, experimentally designed OM profiles with attributes/levels related to efficacy, cardiovascular (CV) risk reduction, side effects, administration (route/frequency), and dosing instruction requirements. In a fixed-choice comparison, participants chose between 2 predefined oral OM profiles. Relative preference weights for the DCE attribute levels were estimated using a random-parameters logit model to estimate attribute importance, tradeoffs, and predicted treatment choice. Among 800 participants (400 OM-naïve/400 OM-experienced, 400 injection-naïve/400 injection-experienced), the most important attributes were route of administration, average weight-loss percentage, CV risk reduction, and the proportion of people achieving ≥ 20% weight loss. Dosing instructions had the lowest relative importance. There was a preference for 1 OM profile (Treatment A-a hypothetical oral semaglutide-like profile) over the alternative OM profile (Treatment B-a hypothetical orforglipron-like profile), according to the responses from the DCE (84.2% vs. 15.8%) and the fixed-choice question (90.0% vs. 10.0%). Only 23.4% indicated that taking an OM treatment on an empty stomach and waiting 30 min to eat would be disruptive to their lives. Most (73.3%) OM-naïve participants were open to taking an oral OM. Individuals with overweight or obesity prioritise weight-loss efficacy, CV risk reduction, and oral administration in OM treatment decisions; dosing instruction requirements were of low importance.

Effects of semaglutide on subclinical cardiovascular health in people with HIV.

In a randomized trial, semaglutide did not improve subclinical vascular markers over 32 weeks but notably improved overall cardiometabolic health and cardiovascular disease risk.

Daher J, Koberssy Z, Moussallem N, Wu Q, Sattar A, Fletcher AA, McComsey CM, Funderburg NT, Ailstock K, Eckard AR

Lipohypertrophy, characterized by central adipose tissue accumulation, is common in people with HIV (PWH) and contributes to cardiometabolic risk. In a recent randomized, double-blind, placebo-controlled phase 2b trial, semaglutide significantly improved weight, total fat, visceral adiposity, blood pressure, glucose metabolism, and lipids over 32 weeks in PWH with lipohypertrophy. This prespecified secondary analysis evaluated semaglutide's effects on subclinical cardiovascular health. Virologically suppressed adults with HIV without known diabetes, receiving stable antiretroviral therapy, with body mass index >25 kg/m2 and increased waist circumference/waist-to-hip ratio were enrolled. Participants were randomized 1 : 1 to semaglutide or placebo for 32 weeks. Pulse wave velocity (PWV) and endothelial peripheral arterial tonometry (endoPAT) assessed arterial stiffness and endothelial function, and coronary artery calcium (CAC) score assessed calcified coronary atherosclerosis. Indirect calorimetry measured resting energy expenditure (REE) and oxygen consumption (VO2). 10-year atherosclerotic cardiovascular disease (ASCVD) risk scores were calculated. Analyses followed intention-to-treat principles using sex-adjusted multiplicative regression. One hundred eight participants (n = 54 semaglutide) were enrolled (median age 53 years; 60% male; 65% non-White; 35% smokers). Semaglutide had no significant effect on PWV, CAC score, reactive hyperemia index, augmentation index, or REE. VO2 showed a downward trend (β -43 ml/min; P = 0.087). At week 32, significant reductions were observed in 10-year ASCVD risk (-32.6%; P = 0.026) and hsCRP (-23.4%; P = 0.02) in the semaglutide group relative to placebo. Semaglutide did not improve subclinical vascular markers over 32 weeks but significantly improved overall cardiometabolic health and cardiovascular disease risk. Longer and larger studies of GLP-1 RAs are indicated in HIV to further assess their effects on long-term cardiovascular disease outcomes. NCT04019197.

Semaglutide in Bipolar Disorder: A Differential Finding Needs a Differential Mechanism.

Demas A