title: Overexpression of pituitary adenylate cyclase-activating polypeptide in islets inhibits hyperinsulinemia and islet hyperplasia in agouti yellow mice.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) is an intraislet neuropeptide and shares insulinotropic and insulin-sensitizing properties with glucagon-like peptide-1 (GLP-1); however, the pathophysiological significance of PACAP in diabetes remains largely unknown. To assess this, we crossed our recently developed transgenic mice overexpressing PACAP in pancreatic beta-cells (Tg/+), with lethal yellow agouti (KKA(y)) mice (A(y)/+), a genetic model for obesity-diabetes, and examined the metabolic and morphological phenotypes of F(1) animals. Tg/+ mice with the A(y) allele (Tg/+:A(y)/+) developed maturity-onset obesity and diabetes associated with hyperglycemia, hyperlipidemia, and hyperphagia, similar to those of A(y)/+ mice, but hyperinsulinemia was significantly ameliorated in Tg/+:A(y)/+ mice. Although A(y)/+ mice exhibited a marked increase in islet mass resulting from hyperplasia and hypertrophy, this increase was significantly attenuated in Tg/+:A(y)/+ mice. Size frequency distribution analysis revealed that the very large islets comprising one-fourth of islets of A(y)/+ mice were selectively reduced in Tg/+:A(y)/+ mice. Because functional defects have been demonstrated in the large islets of obese animal models, together these findings suggest that PACAP regulates hyperinsulinemia and the abnormal increase in islet mass that occurs during the diabetic process.
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tomimoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Norihito
authors.initials: N
authors.lastname: Shintani
authors.forename: Kyohei
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kawabata
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hamagami
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yamagata
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Miyagawa
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D004435:Eating; D005260:Female; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000517:prevention & control*; D006965:Hyperplasia / Q000517:prevention & control; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000378:metabolism* / Q000502:physiology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014280:Triglycerides / Q000097:blood
chemical_list: C495402:Adcyap1 protein, mouse; D001786:Blood Glucose; D007328:Insulin; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014280:Triglycerides