The effect of Lu AG09222 on PACAP38- and VIP-induced vasodilation, heart rate increase, and headache in healthy subjects: an interventional, randomized, double-blind, parallel-group, placebo-controlled study.

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP), structurally related to vasoactive intestinal peptide (VIP), is one of the important mediators in the pathogenesis of migraine and is known to dilate cranial arteries and induce headache and migraine. Our objective was to determine whether Lu AG09222-an investigational humanized monoclonal antibody directed against PACAP ligand-would inhibit the PACAP-signaling cascade by abolishing its vasodilatory and headache-inducing abilities.

Methods: In a randomized, double-blind, parallel-group, single-dose, placebo-controlled study of Lu AG09222, healthy volunteers aged 18-45 years without history of headache disorders were randomly allocated to three treatment sequences (1:2:2) on two experimental infusion visits with 9 ± 3 days' interval: placebo + saline + saline (n = 5), placebo + PACAP38 + VIP (n = 10), and Lu AG09222 + PACAP38 + VIP (n = 10).

Effect of upper gastrointestinal disease on the pharmacokinetics of oral semaglutide in subjects with type 2 diabetes.

Aim: To investigate whether upper gastrointestinal (GI) disease has any effect on the exposure of oral semaglutide, an important consideration given that its absorption occurs primarily in the stomach.

Materials And Methods: In an open-label, parallel-group trial (NCT02877355), subjects aged 18-80 years with type 2 diabetes with mild-to-moderate upper GI disease (N = 36; chronic gastritis [n = 5], gastroesophageal reflux disease [n = 8], and both [n = 23]) or without upper GI disease (N = 19) received oral semaglutide 3 mg once daily for 5 days, followed by 7 mg for 5 days. The primary and key supportive endpoints were the area under the semaglutide plasma concentration-time curve (AUC) from 0 to 24 hours after last trial product administration on day 10 (AUC ) and the maximum semaglutide plasma concentration (C ), respectively.

Absence of QTc Prolongation with Sodium N-(8-[2-Hydroxybenzoyl] Amino) Caprylate (SNAC), an Absorption Enhancer Co-Formulated with the GLP-1 Analogue Semaglutide for Oral Administration.

Introduction: Oral delivery of proteins, including glucagon-like peptide 1 (GLP-1) receptor agonists, is impeded by low gastrointestinal permeation. Oral semaglutide has been developed for once-daily oral administration by co-formulation of the GLP-1 analogue semaglutide with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC, 300 mg). A randomised, partially double-blind, placebo-controlled thorough QT/corrected QT (QTc) trial was conducted to confirm the absence of unacceptable QTc interval prolongation with SNAC.

Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes.

Background: Oral semaglutide is a novel tablet containing the human glucagon-like peptide-1 (GLP‑1) analogue semaglutide, co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The safety and pharmacokinetics of oral semaglutide were investigated in two randomised, double-blind, placebo-controlled trials.

Methods: In a single-dose, first-in-human trial, 135 healthy males received oral semaglutide (2-20 mg semaglutide co-formulated with 150-600 mg SNAC) or placebo with SNAC.

Pharmacokinetics, Safety and Tolerability of Oral Semaglutide in Subjects with Renal Impairment.

Background: Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) as a tablet for oral administration. This trial (NCT02014259) investigated the pharmacokinetics, safety and tolerability of oral semaglutide in subjects with and without renal impairment.

Methods: Subjects were categorised as having normal renal function (n = 24), mild (n = 12), moderate (n = 12) or severe (n = 12) renal impairment, or end-stage renal disease (ESRD) requiring haemodialysis (n = 11) and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days) in the fasting state, followed by 30 min fasting after dosing.

Insulin degludec's ultra-long pharmacokinetic properties observed in adults are retained in children and adolescents with type 1 diabetes.

Insulin degludec (IDeg) is a basal insulin with an ultra-long pharmacokinetic profile in adults that at steady-state produces remarkably flat and stable insulin levels; however, no studies have yet reported on the pharmacokinetic properties of IDeg in subjects younger than 18 years of age. This was a single-centre, randomised, single-dose, double-blind, two-period crossover trial conducted in children (6-11 years), adolescents (12-17 years), and adults (18-65 years) with type 1 diabetes. Subjects received a single subcutaneous dose of 0.

Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes.

Several common genetic variations have been associated with type 2 diabetes, but the exact disease mechanisms are still poorly elucidated. Using congenic strains from the diabetic Goto-Kakizaki rat, we identified a 1.4-megabase genomic locus that was linked to impaired insulin granule docking at the plasma membrane and reduced beta cell exocytosis.

Separately inherited defects in insulin exocytosis and beta-cell glucose metabolism contribute to type 2 diabetes.

The effects of genetic variation on molecular functions predisposing to type 2 diabetes are still largely unknown. Here, in a specifically designed diabetes model, we couple separate gene loci to mechanisms of beta-cell pathology. Niddm1i is a major glucose-controlling 16-Mb region in the diabetic GK rat that causes defective insulin secretion and corresponds to loci in humans and mice associated with type 2 diabetes.

High-resolution quantitative trait locus analysis reveals multiple diabetes susceptibility loci mapped to intervals<800 kb in the species-conserved Niddm1i of the GK rat.

Niddm1i, a 16-Mb locus within the major diabetes QTL in the diabetic GK rat, causes impaired glucose tolerance in the congenic NIDDM1I strain. Niddm1i is homologous to both human and mouse regions linked with type 2 diabetes susceptibility. We employed multiple QTL analyses of congenic F2 progeny selected for one recombination event within Niddm1i combined with characterization of subcongenic strains.