title: A potent and highly selective VPAC2 agonist enhances glucose-induced insulin release and glucose disposal: a potential therapy for type 2 diabetes.
abstract: Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) activate two shared receptors, VPAC1 and VPAC2. Activation of VPAC1 has been implicated in elevating glucose output, whereas activation of VPAC2 may be involved in insulin secretion. A hypothesis that a VPAC2-selective agonist would enhance glucose disposal by stimulating insulin secretion without causing increased hepatic glucose production was tested using a novel selective agonist of VPAC2. This agonist, BAY 55-9837, was generated through site-directed mutagenesis based on sequence alignments of PACAP, VIP, and related analogs. The peptide bound to VPAC2 with a dissociation constant (K(d)) of 0.65 nmol/l and displayed >100-fold selectivity over VPAC1. BAY 55-9837 stimulated glucose-dependent insulin secretion in isolated rat and human pancreatic islets, increased insulin synthesis in purified rat islets, and caused a dose-dependent increase in plasma insulin levels in fasted rats, with a half-maximal stimulatory concentration of 3 pmol/kg. Continuous intravenous or subcutaneous infusion of the peptide reduced the glucose area under the curve following an intraperitoneal glucose tolerance test. The peptide had effects on intestinal water retention and mean arterial blood pressure in rats, but only at much higher doses. BAY 55-9837 may be a useful therapy for the treatment of type 2 diabetes.
authors.affiliation: Department of Metabolic Disorders Research, Pharmaceutical Division, Bayer Corporation, West Haven, Connecticut, USA.
authors.forename: Manami
authors.initials: M
authors.lastname: Tsutsumi
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Claus
authors.forename: Yin
authors.initials: Y
authors.lastname: Liang
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.forename: Fernando
authors.initials: F
authors.lastname: Dela Cruz
authors.forename: Xianbu
authors.initials: X
authors.lastname: Peng
authors.forename: Hongxing
authors.initials: H
authors.lastname: Chen
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Yung
authors.forename: Sarah
authors.initials: S
authors.lastname: Hamren
authors.forename: James N
authors.initials: JN
authors.lastname: Livingston
authors.forename: Clark Q
authors.initials: CQ
authors.lastname: Pan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D003967:Diarrhea / Q000188:drug therapy / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006728:Hormones / Q000097:blood; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D011979:Receptors, Pituitary Hormone / Q000378:metabolism; D018005:Receptors, Vasoactive Intestinal Peptide / Q000819:agonists* / Q000378:metabolism; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D006728:Hormones; D007328:Insulin; D010446:Peptide Fragments; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D011979:Receptors, Pituitary Hormone; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495506:VIPR1 protein, human; C495509:VIPR2 protein, human; C495508:Vipr1 protein, rat; C495511:Vipr2 protein, rat; C409214:vasoactive intestinal peptide (1-7)-GRF (8-27), Lys(15)-Arg(16)-Leu(27)-; D014660:Vasoactive Intestinal Peptide; D005947:Glucose