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First published on January 23, 2004; DOI: 10.1124/jpet.103.062919

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Received for publication November 13, 2003.
Revised December 24, 2003.
Accepted for publication January 21, 2004.

Overexpression of PACAP in Islets Inhibits Hyperinsulinemia and Islet Hyperplasia in Agouti Yellow Mice

Shuhei Tomimoto 1, Hitoshi Hashimoto 1, Norihito Shintani 1, Kyohei Yamamoto 1, Yuki Kawabata 1, Ken-ichi Hamagami 1, Kazuya Yamagata 2, Jun-ichiro Miyagawa 2, Akemichi Baba 1*

1 Graduate School of Pharmaceutical Sciences, Osaka University 2 Graduate School of Medicine, Osaka University

* Address correspondence to: E-mail: baba{at}phs.osaka-u.ac.jp

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an intraislet neuropeptide and shares insulinotropic and insulin-sensitizing properties with 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 (KKAy) mice (Ay/+), a genetic model for obesity-diabetes, and examined the metabolic and morphologic 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. Since functional defects have been demonstrated in the large islets of obese animal models, taken together, these findings suggest that PACAP regulates hyperinsulinemia and the abnormal increase in islet mass that occurs during the diabetic process.


Key words: diabetes, histomorphometric analysis, insulin, lethal yellow KKAy mice, pituitary adenylate cyclase-activating polypeptide (PACAP), transgenic mice


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