Explore the vast range of titles available.

Introduction The suprachiasmatic nucleus (SCN) is responsible for generating the circadian rhythmicity in mammals. The ventral region or core of the SCN contains neurons that express the neuropeptide vasoactive intestinal polypeptide (VIP). VIP signaling is central for coherency and synchrony of SCN activity. VIP-expressing neurons in the SCN densely project to the ventral subregions of the subparaventricular zone (vSPZ). We studied the effects of VIP on vSPZ neurons in brain slices of mice with a combined calcium imaging and whole-cell patch-clamp recording techniques. We used calcium imaging to assess the effects of VIP on vSPZ neurons as a population and we acquired patch-clamp recordings to explore the effects of VIP on the electrical properties and the synaptic inputs to vSPZ neurons. Methods We expressed GCamp6 in vSPZ neurons by stereotaxically injecting AAV10-DIO-Ef1a-GCamp6 into the vSPZ of vGAT-IRES-Cre mice. Brain slices were prepared two weeks later and images were captured using a standard GFP filter set. We performed whole-cell recordings of the vSPZ neurons of wild-type mice. We assessed the effects of VIP on the membrane potential and the on excitatory synaptic input in vSPZ neurons. Results Using GCamp6-based in vitro calcium imaging we found that VIP excites 17% of vSPZ neurons and this effect was maintained in the presence of tetrodotoxin (TTX) and synaptic blockers for AMPA/NMDA and GABAA transmissions suggesting a direct effect of VIP on vSPZ neurons. We confirmed this result with patch-clamp recordings. We found that 29% of vSPZ neurons were excited by VIP. VIP produced a membrane depolarization of vSPZ neurons in the presence of antagonists for AMPA/NMDA and GABAA receptors. In addition, we found that in a small percentage of vSPZ neurons VIP increased the frequency of the glutamatergic excitatory postsynaptic currents, suggesting an additional excitatory mechanism. Conclusion Our results demonstrate that exogenous VIP directly excites the vSPZ neurons producing an increase in intracellular calcium and membrane depolarization. In addition, VIP increases glutamatergic afferent inputs to vSPZ neurons indicating an additional synergistic excitation. We conclude that when VIP is released from the SCN VIP fibers it can activate vSPZ neurons. Support (if any) NS091126 and HL149630.

Cagrilintide, a long-acting amylin analogue, and semaglutide 2·4 mg, a glucagon-like peptide-1 analogue, are both being investigated as options for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of this drug combination. In this randomised, placebo-controlled, multiple-ascending dose, phase 1b trial, individuals aged 18–55 years with a body-mass index 27·0−39·9 kg/m2 and who were otherwise healthy were recruited from a single centre in the USA. The trial included six sequential overlapping cohorts, and in each cohort eligible participants were randomly assigned (3:1) to once-weekly subcutaneous cagrilintide (0·16, 0·30, 0·60, 1·2, 2·4, or 4·5 mg) or matched placebo, in combination with once-weekly subcutaneous semaglutide 2·4 mg, without lifestyle interventions. In each cohort, the doses of cagrilintide and semaglutide were co-escalated in 4-week intervals to the desired dose over 16 weeks, participants were treated at the target dose for 4 weeks, and then followed up for 5 weeks. Participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was number of treatment-emergent adverse events from baseline to end of follow-up. Secondary pharmacokinetic endpoints assessed from day of last dose (week 19) to end of treatment (week 20) were area under the plasma concentration-time curve from 0 to 168 h (AUC0–168 h) and maximum concentration [Cmax] of cagrilintide and semaglutide; exploratory pharmacokinetic endpoints were half-life, time to Cmax [tmax], plasma clearance, and volume of distribution of cagrilintide and semaglutide; and exploratory pharmacodynamic endpoints were changes in bodyweight, glycaemic parameters, and hormones. Safety, pharmacokinetic, and pharmacodynamic endpoints were assessed in all participants who were exposed to at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03600480, and is now complete. Between July 25, 2018, and Dec 17, 2019, 285 individuals were screened and 96 were randomly assigned to cagrilintide (0·16–2·4 mg group n=12; 4·5 mg group n=11) or placebo (n=24), in combination with semaglutide 2·4 mg, of whom 95 were exposed to treatment (one patient in 0·60 mg cagrilintide group was not exposed) and included in the safety and full analysis datasets. The mean age was 40·6 years (SD 9·2), 56 (59%) of 95 participants were men and 51 (54%) were Black or African American. Of 566 adverse events reported in 92 participants (69 [97%] of 71 participants assigned to 0·16–4·5 mg cagrilintide and 23 [96%] of 24 assigned to placebo), 207 (37%) were gastrointestinal disorders. Most adverse events were mild to moderate in severity and the proportion of participants with one or more adverse event was similar across treatment groups. Exposure was proportional to cagrilintide dose and did not affect semaglutide exposure or elimination. AUC0–168 h ranged from 926 nmol × h/L to 24 271 nmol × h/L, and Cmax ranged from 6·14 nmol/L to 170 nmol/L with cagrilintide 0·16–4·5 mg. AUC0–168 h ranged from 12 757 nmol × h/L to 15 305 nmol × h/L, and Cmax ranged from 96·4 nmol/L to 120 nmol/L with semaglutide 2·4 mg. Cagrilintide 0·16−4·5 mg had a half-life of 159–195 h, with a median tmax of 24–72 h. Semaglutide 2·4 mg had a half-life of 145–165 h, with a median tmax of 12–24 h. Plasma clearance and volume of distribution for both cagrilintide and semaglutide were similar across treatment groups. At week 20, mean percentage bodyweight reductions were greater with cagrilintide 1·2 and 2·4 mg than with placebo (15·7% [SE 1·6] for cagrilintide 1·2 mg and 17·1% [1·5] for cagrilintide 2·4 mg vs 9·8% [1·2] for pooled placebo cohorts 1–5; estimated treatment difference of −6·0% [95% CI −9·9 to −2·0] for cagrilintide 1·2 mg and −7·4% [−11·2 to −3·5] for cagrilintide 2·4 mg vs pooled placebo), and with cagrilintide 4·5 mg than with matched placebo (15·4% [1·3] vs 8·0% [2·2]; estimated treatment difference −7·4% [−12·8 to −2·1]), all in combination with semaglutide 2·4 mg. Glycaemic parameters improved in all treatment groups, independently of cagrilintide dose. Changes in hormones were similar across treatment groups. Concomitant treatment with cagrilintide and semaglutide 2·4 mg was well tolerated with an acceptable safety profile. Future larger and longer trials are needed to fully assess the efficacy and safety of this treatment combination. Novo Nordisk A/S.

This open-label, 40-week, phase 3 trial assessed the efficacy and safety of tirzepatide, a weekly dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist under development for type 2 diabetes. Tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks.

The cellular identity of pancreatic polypeptide (Ppy)-expressing γ-cells, one of the rarest pancreatic islet cell-type, remains elusive. Within islets, glucagon and somatostatin, released respectively from α- and δ-cells, modulate the secretion of insulin by β-cells. Dysregulation of insulin production raises blood glucose levels, leading to diabetes onset. Here, we present the genetic signature of human and mouse γ-cells. Using different approaches, we identified a set of genes and pathways defining their functional identity. We found that the γ-cell population is heterogeneous, with subsets of cells producing another hormone in addition to Ppy. These bihormonal cells share identity markers typical of the other islet cell-types. In mice, Ppy gene inactivation or conditional γ-cell ablation did not alter glycemia nor body weight. Interestingly, upon β-cell injury induction, γ-cells exhibited gene expression changes and some of them engaged insulin production, like α- and δ-cells. In conclusion, we provide a comprehensive characterization of γ-cells and highlight their plasticity and therapeutic potential. The cellular identity and function of the pancreatic polypeptide (Ppy)-producing γ-cells are incompletely understood. Here the authors show that these cells are heterogeneous and display adaptive plasticity to engage in insulin production following β-cell injury, but loss of the Ppy gene or γ-cells in mice does not affect weight or glycemia under basal conditions.

Current treatment options for youth-onset type 2 diabetes are limited and have demonstrated lower glycaemic efficacy than those for adult-onset type 2 diabetes. We aimed to assess the safety and efficacy of tirzepatide, a glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, compared with placebo in youth-onset type 2 diabetes. We conducted a phase 3, double-blind, placebo-controlled, multicentre (39 sites), multinational (eight countries) trial over 30 weeks, followed by an open-label extension for 22 weeks in which all participants received tirzepatide. Participants aged 10 to <18 years with youth-onset type 2 diabetes inadequately controlled with metformin and/or basal insulin were randomly assigned (1:1:1) to receive tirzepatide 5 mg, 10 mg, or placebo administered by subcutaneous injection with a single-dose pen. Randomisation was stratified by age group (≤14 years or >14 years) and antihyperglycaemic medication use (metformin, basal insulin, or both). All participants, investigators, and the sponsor were masked to treatment assignment during the 30-week double-blind period. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to week 30. Data from all participants who received at least one dose of study drug were used to analyse efficacy and safety. This completed trial is registered with ClinicalTrials.gov (NCT05260021). Between April 12, 2022, and Dec 27, 2023, 146 participants were screened, of whom 99 (60 [61%] female, 39 [39%] male; mean age 14·7 years [SD 1·8]; mean baseline HbA1c 8·04% [1·23]) were randomly assigned to tirzepatide 5 mg (n=32), tirzepatide 10 mg (n=33), or placebo (n=34). At week 30, tirzepatide was superior to placebo in reducing HbA1c, with a mean reduction of 2·23% in the pooled tirzepatide group versus an increase of 0·05% in the placebo group (estimated treatment difference −2·28%; 95% CI −2·87 to −1·69; p<0·0001). Glycaemic efficacy was sustained up to 52 weeks with tirzepatide treatment. Tirzepatide also resulted in significant reductions in BMI of 7·4% and 11·2% for the 5 mg and 10 mg groups, respectively, compared with 0·4% in the placebo group at 30 weeks. The most common adverse events with tirzepatide treatment were gastrointestinal, all mild to moderate in severity, and decreased over time. Two (6%) patients in the tirzepatide 5 mg group discontinued study drug due to an adverse event. The safety profile of tirzepatide was consistent with that reported in adults. No deaths were reported during the study period. Tirzepatide demonstrated significant improvements in glycaemic control and BMI compared with placebo. These effects were sustained over 1 year. Eli Lilly and Company.

In this randomized trial, adults with obesity treated with weekly tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, had major weight loss over 72 weeks.

We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist tirzepatide versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications. This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on five continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA1c) of 7·5–10·5% (58–91 mmol/mol), body-mass index of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week tirzepatide (5 mg, 10 mg, or 15 mg) or glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL. The primary endpoint was non-inferiority (0·3% non-inferiority boundary) of tirzepatide 10 mg or 15 mg, or both, versus glargine in HbA1c change from baseline to 52 weeks. All participants were treated for at least 52 weeks, with treatment continued for a maximum of 104 weeks or until study completion to collect and adjudicate major adverse cardiovascular events (MACE). Safety measures were assessed over the full study period. This study was registered with ClinicalTrials.gov, NCT03730662. Patients were recruited between Nov 20, 2018, and Dec 30, 2019. 3045 participants were screened, with 2002 participants randomly assigned to tirzepatide or glargine. 1995 received at least one dose of tirzepatide 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%), and were included in the modified intention-to-treat population. At 52 weeks, mean HbA1c changes with tirzepatide were −2·43% (SD 0·05) with 10 mg and −2·58% (0·05) with 15 mg, versus −1·44% (0·03) with glargine. The estimated treatment difference versus glargine was −0·99% (multiplicity adjusted 97·5% CI −1·13 to −0·86) for tirzepatide 10 mg and −1·14% (−1·28 to −1·00) for 15 mg, and the non-inferiority margin of 0·3% was met for both doses. Nausea (12–23%), diarrhoea (13–22%), decreased appetite (9–11%), and vomiting (5–9%) were more frequent with tirzepatide than glargine (nausea 2%, diarrhoea 4%, decreased appetite <1%, and vomiting 2%, respectively); most cases were mild to moderate and occurred during the dose-escalation phase. The percentage of participants with hypoglycaemia (glucose <54 mg/dL or severe) was lower with tirzepatide (6–9%) versus glargine (19%), particularly in participants not on sulfonylureas (tirzepatide 1–3% vs glargine 16%). Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) occurred in 109 participants and were not increased on tirzepatide compared with glargine (hazard ratio 0·74, 95% CI 0·51–1·08). 60 deaths (n=25 [3%] tirzepatide; n=35 [4%] glargine) occurred during the study. In people with type 2 diabetes and elevated cardiovascular risk, tirzepatide, compared with glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycaemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk. Eli Lilly and Company.

Excess adiposity is a reversible etiologic risk factor for obstructive sleep apnea. In this trial, tirzepatide reduced the apnea–hypopnea index of participants with obstructive sleep apnea and obesity.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide hormone. The PACAP receptor PAC1R, which belongs to the class B G-protein-coupled receptors (GPCRs), is a drug target for mental disorders and dry eye syndrome. Here, we present a cryo-EM structure of human PAC1R bound to PACAP and an engineered Gs heterotrimer. The structure revealed that transmembrane helix TM1 plays an essential role in PACAP recognition. The extracellular domain (ECD) of PAC1R tilts by ~40° compared with that of the glucagon-like peptide-1 receptor (GLP-1R) and thus does not cover the peptide ligand. A functional analysis demonstrated that the PAC1R ECD functions as an affinity trap and is not required for receptor activation, whereas the GLP-1R ECD plays an indispensable role in receptor activation, illuminating the functional diversity of the ECDs in class B GPCRs. Our structural information will facilitate the design and improvement of better PAC1R agonists for clinical applications.Cryo-EM structure of the human PAC1R receptor bound to its neuropeptide ligand PACAP and to an engineered Gs complex reveals the mode of PACAP recognition and suggests functional diversity of the extracellular domains in class B GPCRs.

Among numerous challenges encountered at the beginning of extrauterine life, the most celebrated is the first breath that initiates a life-sustaining motor activity 1 . The neural systems that regulate breathing are fragile early in development, and it is not clear how they adjust to support breathing at birth. Here we identify a neuropeptide system that becomes activated immediately after birth and supports breathing. Mice that lack PACAP selectively in neurons of the retrotrapezoid nucleus (RTN) displayed increased apnoeas and blunted CO 2 -stimulated breathing; re-expression of PACAP in RTN neurons corrected these breathing deficits. Deletion of the PACAP receptor PAC1 from the pre-Bötzinger complex—an RTN target region responsible for generating the respiratory rhythm—phenocopied the breathing deficits observed after RTN deletion of PACAP, and suppressed PACAP-evoked respiratory stimulation in the pre-Bötzinger complex. Notably, a postnatal burst of PACAP expression occurred in RTN neurons precisely at the time of birth, coinciding with exposure to the external environment. Neonatal mice with deletion of PACAP in RTN neurons displayed increased apnoeas that were further exacerbated by changes in ambient temperature. Our findings demonstrate that well-timed PACAP expression by RTN neurons provides an important supplementary respiratory drive immediately after birth and reveal key molecular components of a peptidergic neural circuit that supports breathing at a particularly vulnerable period in life. A peptidergic brainstem circuit is identified that supports the initiation and establishment of breathing by providing a supplementary respiratory drive immediately after birth.