PT  - JOURNAL ARTICLE
AU  - Shuhei Tomimoto
AU  - Hitoshi Hashimoto
AU  - Norihito Shintani
AU  - Kyohei Yamamoto
AU  - Yuki Kawabata
AU  - Ken-Ichi Hamagami
AU  - Kazuya Yamagata
AU  - Jun-Ichiro Miyagawa
AU  - Akemichi Baba
TI  - Overexpression of Pituitary Adenylate Cyclase-Activating Polypeptide in Islets Inhibits Hyperinsulinemia and Islet Hyperplasia in Agouti Yellow Mice
AID  - 10.1124/jpet.103.062919
DP  - 2004 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 796--803
VI  - 309
IP  - 2
4099  - http://jpet.aspetjournals.org/content/309/2/796.short
4100  - http://jpet.aspetjournals.org/content/309/2/796.full
SO  - J Pharmacol Exp Ther2004 May 01; 309
AB  - 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 β-cells (Tg/+), with lethal yellow agouti (KKAy) mice (Ay/+), a genetic model for obesity-diabetes, and examined the metabolic and morphological phenotypes of F1 animals. Tg/+ mice with the Ay allele (Tg/+:Ay/+) developed maturity-onset obesity and diabetes associated with hyperglycemia, hyperlipidemia, and hyperphagia, similar to those of Ay/+ mice, but hyperinsulinemia was significantly ameliorated in Tg/+:Ay/+ mice. Although Ay/+ mice exhibited a marked increase in islet mass resulting from hyperplasia and hypertrophy, this increase was significantly attenuated in Tg/+:Ay/+ mice. Size frequency distribution analysis revealed that the very large islets comprising one-fourth of islets of Ay/+ mice were selectively reduced in Tg/+:Ay/+ 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. The American Society for Pharmacology and Experimental Therapeutics