title: Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without type 2 diabetes.
abstract: Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine cells. In animals, Xen regulates gastrointestinal function and glucose homeostasis, typically by initiating neural relays. However, little is known about Xen action in humans. This study determines whether exogenously administered Xen modulates gastric emptying and/or insulin secretion rates (ISRs) following meal ingestion. Fasted subjects with normal (NGT) or impaired (IGT) glucose tolerance and Type 2 diabetes mellitus (T2DM; n = 10-14 per group) ingested a liquid mixed meal plus acetaminophen (ACM; to assess gastric emptying) at time zero. On separate occasions, a primed-constant intravenous infusion of vehicle or Xen at 4 (Lo-Xen) or 12 (Hi-Xen) pmol · kg(-1) · min(-1) was administered from zero until 300 min. Some subjects with NGT received 30- and 90-min Hi-Xen infusions. Plasma ACM, glucose, insulin, C-peptide, glucagon, Xen, GIP, and glucagon-like peptide-1 (GLP-1) levels were measured and ISRs calculated. Areas under the curves were compared for treatment effects. Infusion with Hi-Xen, but not Lo-Xen, similarly delayed gastric emptying and reduced postprandial glucose levels in all groups. Infusions for 90 or 300 min, but not 30 min, were equally effective. Hi-Xen reduced plasma GLP-1, but not GIP, levels without altering the insulin secretory response to glucose. Intense staining for Xen receptors was detected on PGP9.5-positive nerve fibers in the longitudinal muscle of the human stomach. Thus Xen reduces gastric emptying in humans with and without T2DM, probably via a neural relay. Moreover, endogenous GLP-1 may not be a major enhancer of insulin secretion in healthy humans under physiological conditions.
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Sara
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Dominic N
authors.initials: DN
authors.lastname: Reeds
authors.forename: Dan L
authors.initials: DL
authors.lastname: Crimmins
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Patterson
authors.forename: Erin
authors.initials: E
authors.lastname: Laciny
authors.forename: Songyan
authors.initials: S
authors.lastname: Wang
authors.forename: Hung D
authors.initials: HD
authors.lastname: Tran
authors.forename: Terry A
authors.initials: TA
authors.lastname: Griest
authors.forename: David A
authors.initials: DA
authors.lastname: Rometo
authors.forename: Judit
authors.initials: J
authors.lastname: Dunai
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wallendorf
authors.forename: Jack H
authors.initials: JH
authors.lastname: Ladenson
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Polonsky
authors.forename: Burton M
authors.initials: BM
authors.lastname: Wice
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D004334:Drug Administration Schedule; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects*; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D008923:Missouri; D009496:Neurotensin / Q000008:administration & dosage / Q000627:therapeutic use*; D019518:Postprandial Period; D018028:Receptors, Neurotensin / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D018028:Receptors, Neurotensin; C077659:xenin 25; D009496:Neurotensin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon
keywords: GIP; GLP-1; gastric emptying; glucagon; incretin; insulin secretion; xenin