Peptide Research Database

Anaphylaxis to Tirzepatide Confirmed by Positive Skin Prick Testing.

Steele C, Crisp H

GLP-1 receptor agonist use and mental health outcomes in adolescents with obesity: a retrospective review.

In a research review, these findings support the short-term psychosocial safety of GLP-1RA therapy in adolescents with obesity. Evaluated changes in depressive symptoms and suicidality screening scores among adolescents with obesity treated with GLP-1RAs in a pediatric endocrinology setting.

Said J, Liegl M, Pan AY, Dabrowski E

Adolescent obesity is associated with increased rates of depression and suicidality. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used to treat pediatric obesity, yet concerns remain regarding potential psychiatric effects. This study evaluated changes in depressive symptoms and suicidality screening scores among adolescents with obesity treated with GLP-1RAs in a pediatric endocrinology setting. We evaluated changes in depressive symptoms and suicidality following initiation of GLP-1RA therapy in adolescents with obesity. We performed a retrospective chart review of adolescents aged 12-21 years with obesity treated with liraglutide or semaglutide at a single academic center between June 2022 and December 2024. Demographic, clinical, and psychosocial data were extracted from the electronic health record at baseline and follow-up. Depressive symptoms or suicidality were screened at clinic visits per protocol using either the Patient Health Questionnaire-9 (PHQ-9) or the Ask Suicide-Screening Questions (ASQ), respectively. Analyses were restricted to patients with paired baseline and follow-up assessments using the same instrument. Paired nonparametric tests were used for longitudinal comparisons. Forty-four adolescents met inclusion criteria. Among patients with paired PHQ-9 data (n=15), the median PHQ-9 score decreased significantly from 6 (IQR 2-14) at baseline to 1 (IQR 0-5) at follow-up (p=0.003), independent of changes in BMI. Among patients with paired ASQ data (n=23), no increase in suicidality or new suicidal ideation was observed. In this small, exploratory retrospective review, no evidence of short-term psychological harm or increased suicidality was observed among adolescents receiving GLP-1RA therapy. These findings support the short-term psychosocial safety of GLP-1RA therapy in adolescents with obesity. Larger prospective case-control studies are needed to better characterize psychiatric safety and psychosocial outcomes.

Calcium-binding protein expression cannot serve as a general classifier for GABAergic neurons in macaque cortex.

In an animal study, go on to consider alternative approaches, discussing under what circumstances each might be useful.

Brigande AM, Krueger J, Park C, Disney AA

Understanding neuron subclasses and their functional consequences can contribute to understanding brain circuits. A scheme long used to classify GABAergic neurons in the neocortex is based on expression of three calcium-binding proteins (CBPs): parvalbumin (PV), calbindin D-28K (CB), and calretinin (CR). Because CB and CR are frequently co-expressed by individual neurons in rodents, this scheme has been replaced by one based on PV and two signaling peptides: somatostatin (SST) and vasoactive intestinal peptide (VIP). In macaques, however, CBPs are generally not co-expressed, and so their use has persisted despite suggestions that the underlying populations are not, in fact, entirely GABAergic. We set out to quantitatively evaluate CBPs as a classification scheme for GABAergic neurons in early and mid-level visual regions in macaque cortex. Combining immunohistochemistry and in situ hybridization, we find that up to half of neurons expressing CBPs are likely not GABAergic. Furthermore, contrary to what has been previously suggested, the GABAergic subpopulations cannot be distinguished based on staining intensity. Thus, the CBP-based classification scheme is not valid, at least as it has traditionally been used. Instead, we find support for co-labeling CB and CR neurons with SST and VIP, an approach that can identify GABAergic subpopulations within the CBP classes; or simply adopting the PV/SST/VIP scheme. We discuss the functional implications of expressing these various cell type markers, and how consideration of marker functions can support proper selection of a classification scheme for a given experimental purpose.Significance Statement The findings of this study challenge the currently dominant classification scheme for GABAergic neurons in macaque cortex, a scheme based on expression of the calcium-binding proteins parvalbumin, calbindin D-28K, and calretinin. Specifically, we show that a large proportion of neurons that express protein or mRNA for these calcium-binding proteins are likely not GABAergic. We go on to consider alternative approaches, discussing under what circumstances each might be useful.

Psychiatric Safety of GLP-1 and Dual GIP/GLP-1 Receptor Agonists in Adolescents With Obesity.

This study found although a lower risk was observed compared with lifestyle intervention, this finding should be interpreted cautiously given potential selection bias and the lack of a significant difference in the active-comparator analysis with metformin.

Liu TH, Shen YL, Kuo TH, Wu JY, Lin CH, Lai CC

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists are increasingly used for adolescent obesity, but concerns persist regarding psychiatric adverse events, particularly suicidality. This retrospective cohort study used deidentified electronic health records from the TriNetX Global Collaborative Network. Adolescents with overweight or obesity were included. New users of semaglutide, liraglutide, or tirzepatide were compared with those receiving lifestyle interventions. Cohorts were balanced using propensity score matching. The primary outcome was suicide-related events (suicidal ideation or suicide attempt). Secondary outcomes included suicidal ideation, suicide attempt, anxiety, insomnia, depression, and eating disorders, assessed from 30 days to 1095 days after the index date. After propensity score matching, 9222 adolescents were included in each group. Incretin-based therapy was associated with lower risks of suicide-related events (HR, 0.74; 95% CI, 0.57-0.95), suicidal ideation (HR, 0.73; 95% CI, 0.56-0.96), and anxiety (HR, 0.92; 95% CI, 0.84-0.99) compared with lifestyle intervention. No significant differences were observed for suicide attempt, insomnia, depression, or eating disorders. Risk reductions were significant among female adolescents (HR, 0.61; 95% CI, 0.46-0.82) and those without Type 2 diabetes (HR, 0.63; 95% CI, 0.47-0.85), but not among males or those with Type 2 diabetes. Sensitivity analyses supported the primary findings. Among adolescents with obesity, incretin-based therapy was not associated with increased psychiatric risk and was associated with lower risks of suicide-related events, suicidal ideation, and anxiety compared with lifestyle intervention. Although a lower risk was observed compared with lifestyle intervention, this finding should be interpreted cautiously given potential selection bias and the lack of a significant difference in the active-comparator analysis with metformin.

Prior GLP-1RA or Tirzepatide Use and Early Cardiorenal Outcomes After Metabolic and Bariatric Surgery.

In a case report, these findings support further investigation of preoperative metabolic optimization strategies and their potential role in improving postoperative cardiorenal outcomes.

Tseng TC, Chang R

To compare early postoperative cardiovascular and kidney outcomes after metabolic and bariatric surgery (MBS) according to prior glucagon-like peptide-1 receptor agonist (GLP-1RA) or tirzepatide use. This retrospective cohort study used the US Medical Records Database. Adults undergoing MBS from 2016 through 2025 were included. Prior use was defined by at least 1 GLP-1RA or tirzepatide prescription from 365 to 7 days before MBS; patients with prescriptions closer to surgery were excluded. Prior users and nonusers were propensity score matched 1:1. The primary outcome was 4-point major adverse cardiovascular events (MACE), and a key secondary outcome was early postoperative kidney events, assessed from postoperative day 1 through day 90. After matching, each group included 11,052 patients, with well-balanced baseline characteristics. Prior use was associated with lower risks of 4-point MACE (36 patients [0.3%] vs 67 patients [0.6%]; hazard ratio [HR], 0.535; 95% CI, 0.357-0.803) and early postoperative kidney events (158 patients [1.4%] vs 256 patients [2.3%]; HR, 0.613; 95% CI, 0.502-0.747). Prior GLP-1RA or tirzepatide use was also associated with lower risks of coronary events and heart failure. Among adults undergoing MBS, prior GLP-1RA or tirzepatide use was associated with lower 90-day risks of 4-point MACE and early postoperative kidney events. These findings support further investigation of preoperative metabolic optimization strategies and their potential role in improving postoperative cardiorenal outcomes.

Obstructive sleep apnea, GLP-1 receptor agonist pharmacotherapy, and the oral microbiome: competing biological influences and implications for oral health monitoring.

In a research review, prospective studies are warranted, oral health monitoring beginning at treatment initiation is scientifically justified, and seven priority research questions are identified at the convergence of sleep medicine, endocrinology, and oral biology.

Comisi JC

Obstructive sleep apnea (OSA) is associated with reproducible oral microbiome dysbiosis mediated by five simultaneous biological pathways: chronic intermittent hypoxia-driven immune dysregulation, obligate mouth breathing causing salivary desiccation, elevated salivary glucose promoting cariogenic biofilm proliferation, gastroesophageal reflux acid challenge, and hypothalamic-pituitary-adrenal axis activation suppressing mucosal immunity. The December 2024 FDA approval of tirzepatide for moderate-to-severe OSA and the emergence of retatrutide and orforglipron have placed GLP-1 receptor agonists (GLP-1RAs) at the center of OSA pharmacotherapy. This review examines the oral microbiome consequences of GLP-1RA therapy in OSA patients, characterizes the competing biological influences these agents introduce, and identifies the monitoring and research implications of the resulting uncertainty. A narrative review of published literature examining OSA-related oral microbiome dysbiosis, GLP-1RA pharmacological mechanisms relevant to oral biology, salivary gland pharmacovigilance data, and gut microbiome restoration evidence. Sources included PubMed, Web of Science, and Scopus databases searched through June 2026. GLP-1RA therapy engages five restoration pathways that mechanistically counter each OSA-driven dysbiosis mechanism: direct AHI reduction, attenuating hypoxia-driven immune dysregulation; pharyngeal airway improvement, reducing obligate mouth breathing; glycemic normalization, reducing salivary fermentable substrate; gastric emptying delay and weight loss, attenuating GERD acid challenge; and sleep architecture restoration, reducing cortisol-mediated mucosal immune suppression. Pharmacovigilance data, however, indicate that semaglutide may impair salivary gland responsiveness through β-arrestin-mediated receptor desensitization-a competing oral risk that partially or fully counteracts the restoration benefits. Tirzepatide's biased agonism profile (preferential activation of cAMP signaling over β-arrestin internalization) may confer differential salivary gland safety, and orforglipron's daily oral dosing introduces direct oropharyngeal drug exposure with uncharacterized microbiological consequences. The net oral microbiome outcome in any treated patient is the product of these competing influences and has not been characterized prospectively. GLP-1RA pharmacotherapy in OSA creates a biologically complex oral microbiome environment whose clinical trajectory cannot be predicted from current evidence. Prospective studies are warranted, oral health monitoring beginning at treatment initiation is scientifically justified, and seven priority research questions are identified at the convergence of sleep medicine, endocrinology, and oral biology.

NUPR1-dependent metallothionein-2 transcription attenuates ferroptosis-associated myocardial injury in diabetic cardiomyopathy

In a mouse study, the NUPR1-MT2 axis therefore represents a candidate cardioprotective pathway and a potential therapeutic entry point that warrants in living animals MT2 epistasis and human validation. Investigated whether nuclear protein 1 (NUPR1) protects the diabetic heart through transcriptional regulation of metallothionein-2 (MT2).

Zhang X, Wang R, Yang X, Yan M, Zhang Y, Lu X, Ye H, Liu H, Wen Y, Wang J, Li S, Mu G, Zhao Y, Wu L, Shan L, Lu Y, Wang Z, Wang L.

Abstract Background Diabetic cardiomyopathy (DbCM) develops in a setting of sustained glucolipotoxic stress, mitochondrial dysfunction, and maladaptive myocardial remodeling. Ferroptosis-associated lipid peroxidation and iron dysregulation have been implicated in diabetic myocardial injury, but the stress-responsive transcriptional programs that restrain this process remain incompletely defined. We investigated whether nuclear protein 1 (NUPR1) protects the diabetic heart through transcriptional regulation of metallothionein-2 (MT2). Methods DbCM was induced in male C57BL/6J mice by high-fat feeding followed by streptozotocin. Cardiac NUPR1 was increased or reduced using adeno-associated virus serotype 9 vectors, and primary neonatal mouse cardiomyocytes were exposed to high glucose plus palmitate for complementary gain- and loss-of-function studies. Cardiac function, remodeling, mitochondrial ultrastructure, iron accumulation, lipid peroxidation, and ferroptosis-associated proteins were assessed. RNA sequencing, promoter-reporter assays, and chromatin immunoprecipitation were used to identify and validate NUPR1-regulated targets. LNP-formulated NUPR1 mRNA and zinc supplementation were evaluated as proof-of-concept interventions. Data were analyzed using two-tailed t tests, one-way ANOVA, or two-way ANOVA for factorial designs, with multiplicity-adjusted post hoc comparisons as appropriate. Results NUPR1 expression increased in diabetic hearts and glucolipotoxic cardiomyocytes. NUPR1 knockdown worsened cardiac dysfunction, hypertrophy, fibrosis, mitochondrial injury, iron accumulation, and lipid peroxidation, whereas NUPR1 overexpression produced the opposite effects. Ferrostatin-1 attenuated the vulnerability associated with NUPR1 loss, supporting a contribution of ferroptosis-associated injury. Transcriptomic analysis identified Mt2 as a metal-homeostasis candidate downstream of NUPR1. NUPR1 increased Mt2 promoter activity and occupied the Mt2 promoter in cardiomyocytes, while MT2 silencing weakened NUPR1-mediated cytoprotection in vitro. Systemic NUPR1 mRNA-LNP administration increased myocardial NUPR1 and MT2 expression and improved cardiac function and remodeling in DbCM mice. Zinc supplementation produced limited functional benefit in unselected DbCM mice but improved the aggravated phenotype associated with NUPR1 deficiency. Conclusions NUPR1 functions as an adaptive myocardial stress-response factor that limits iron-associated oxidative injury in DbCM, in part through transcriptional activation of MT2. The NUPR1-MT2 axis therefore represents a candidate cardioprotective pathway and a potential therapeutic entry point that warrants in vivo MT2 epistasis and human validation.

Improvement of post-COVID-19 vaccination dysautonomia with GLP-1 receptor agonist.

In a randomized trial, this case report suggests that GLP-1 receptor agonists might be beneficial for treatment of recurrent VVS, other forms of dysautonomia and post-vaccination syndromes with neuropathic pain, and may be considered as candidates for randomized placebo-compared trials in this patient population.

Blitshteyn S, Schofield JR, Haire N, Afrin LB

Vasovagal syncope (VVS) is the most common form of cardiovascular dysautonomia that has multiple etiologies. Post-vaccination dysautonomia, in the form of VVS and postural orthostatic tachycardia syndrome, has been reported in the literature after various vaccines, including COVID-19 mRNA vaccination. Treatment of post-vaccination syndromes has not been explored leaving patients with post-vaccination dysautonomia with limited therapeutic options. We report a 42-year-old woman who developed post-vaccination VVS after COVID-19 mRNA vaccination and improved significantly with semaglutide treatment. The patient's COMPASS-31 score decreased by 44% post-treatment, Orthostatic Hypotension Questionnaire score decreased by 59%, and an average 24-hour heart rate decreased from 97 beats per minute (bpm) to 80 bpm, indicating significant reduction in the autonomic symptom burden. In addition, her post-vaccination neuropathic pain in the legs completely resolved after treatment with semaglutide. This case report suggests that GLP-1 receptor agonists might be beneficial for treatment of recurrent VVS, other forms of dysautonomia and post-vaccination syndromes with neuropathic pain, and may be considered as candidates for randomized placebo-controlled trials in this patient population.

Pavlovian conditioned approach with different reward magnitudes reveals opposing effects of acute and chronic semaglutide treatment

In a rat study, these findings suggest that nonspecific behavioral suppression or malaise may have contributed to reduced responding after sudden treatment.

Desrochers SS, Li R, Flagel SB.

Rationale Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have attracted interest for their effects on motivational processes beyond satiation and weight loss, including motivation for drug rewards. Reward-predictive cues can acquire motivational value and promote food- and drug-seeking, raising the possibility that GLP-1RAs affect intake by altering cue-motivated behavior. Preclinical studies report reduced food intake and responding for drug rewards following GLP-1RA treatment. However, many preclinical studies have used acute treatment; whereas, clinically, GLP1-RAs are administered as chronic treatments with dose escalation to mitigate adverse effects. Objectives Using a modified Pavlovian conditioned approach (PavCA) paradigm, we directly compared the effects of acute and chronic semaglutide treatment on conditioned approach behavior elicited by cues predicting different magnitudes of palatable food reward in male and female rats. Results Although both treatment regimens reduced body weight relative to vehicle treatment, chronic semaglutide increased, whereas acute semaglutide decreased, sign-tracking toward reward-associated cues. Rats exhibited greater sign-tracking toward cues predicting large versus small rewards, but semaglutide did not differentially alter this reward-magnitude effect. Acutely treated rats consumed fewer reward pellets and exhibited less food-cup activity during non-cue periods. These findings suggest that nonspecific behavioral suppression or malaise may have contributed to reduced responding after acute treatment. Conclusions The effects of semaglutide on cue-motivated behavior depend on the treatment regimen. Acute-treatment studies should be interpreted cautiously because adverse or nonspecific effects may contribute to apparent reductions in motivation.

ACTH-independent hypercortisolism across the cardiometabolic spectrum

In a clinical study, these findings reveal new insights into cortisol pathophysiology as a function of ACTH and cardiometabolic risk profiles. Aimed to evaluate the prevalence of ACTH-independent hypercortisolism across the spectrum of cardiometabolic risk.

Newman AJ, Mahrokhian S, Hanna I, Tsai C, Parisien-La Salle S, Auchus RJ, Brown JM, Vaidya A.

Background: Accumulating evidence suggests that the prevalence of hypercortisolism in patients with cardiometabolic risk factors is much higher than previously thought. This study aimed to evaluate the prevalence of ACTH-independent hypercortisolism across the spectrum of cardiometabolic risk. Methods: Participants were prospectively recruited into three cohorts to undergo protocolized assessment of adrenal physiology:1) normotensive participants; 2) participants with hypertension and obesity, but without diabetes; 3) participants with diabetes and overweight/obesity. All participants (n=216) underwent overnight 1 mg dexamethasone suppression testing followed by cosyntropin stimulation test, and 24-hour urine free cortisol (UFC) testing. ACTH-independent hypercortisolism was defined as post-dexamethasone serum cortisol >1.8 μg/dL (50 nmol/L) with a concomitant post-dexamethasone ACTH ≤10 pg/mL (2.2 pmol/L). Result: 16 of 216 (7.4%) participants were found to have ACTH-independent hypercortisolism, including 5.6% (4/71) in the normotensive cohort, 6.2% (5/81) in the hypertension-obesity cohort and 10.9% (7/64) in the diabetes-obesity cohort. Age, body mass index, hemoglobin A1c, blood pressure, renal function, morning ACTH, and 24-hour UFC were similar among those with and without ACTH-independent hypercortisolism. Following cosyntropin stimulation, those with ACTH-independent hypercortisolism had higher stimulated cortisol levels (greater ACTH-dependent responses) when compared to those without ACTH-independent hypercortisolism: 25.8 +/- 4.5 versus 20.6 +/- 4.1 μg/dL (711 +/- 124 v. 568 +/- 113 nmol/L) (PConclusions: In this prospective study, the prevalence of ACTH-independent hypercortisolism paralleled the burden of cardiometabolic risk features. ACTH-independent hypercortisolism was associated with greater ACTH-stimulable cortisol production, identifying a unique biochemical phenotype. These findings reveal new insights into cortisol pathophysiology as a function of ACTH and cardiometabolic risk profiles.