Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes
- Kyohei Yamamoto1,
- Hitoshi Hashimoto1,
- Shuhei Tomimoto1,
- Norihito Shintani1,
- Jun-ichi Miyazaki2,
- Fumi Tashiro2,
- Hiroyuki Aihara2,
- Takao Nammo3,
- Ming Li3,
- Kazuya Yamagata3,
- Jun-ichiro Miyagawa3,
- Yuji Matsuzawa3,
- Yuki Kawabata1,
- Yuji Fukuyama1,
- Kazumi Koga1,
- Wakaba Mori1,
- Kazuhiro Tanaka1,
- Toshio Matsuda4 and
- Akemichi Baba15
- 1Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
- 2Division of Stem Cell Regulation Research, Osaka University Medical School, Osaka, Japan
- 3Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan
- 4Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
- 5Laboratory of Molecular Pharmacology, Osaka University Medical School, Suita, Osaka, Japan
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal peptide/secretin/glucagon family, stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. To assess PACAP’s pancreatic function in vivo, we generated transgenic mice overexpressing PACAP in the pancreas under the control of human insulin promoter. Northern blot and immunohistochemical analyses showed that PACAP is overexpressed in pancreatic islets, specifically in transgenic mice. Plasma glucose and glucagon levels during a glucose tolerance test were not different between PACAP transgenic mice and nontransgenic littermates. However, plasma insulin levels in transgenic mice were higher after glucose loading. Also, increases of streptozotocin-induced plasma glucose were attenuated in transgenic compared with nontransgenic mice. Notably, an increase in 5-bromo-2-deoxyuridine-positive β-cells in the streptozotocin-treated transgenic mice was observed but without differences in the staining patterns by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Morphometric analysis revealed that total islet mass tends to increase in 12-month-old transgenic mice but showed no difference between 12-week-old transgenic and nontransgenic littermates. This is the first time that PACAP has been observed to play an important role in the proliferation of β-cells.
Footnotes
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Address correspondence and reprint requests to Akemichi Baba, Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: baba{at}phs.osaka-u.ac.jp.
Received for publication 12 December 2001 and accepted in revised form 24 January 2003.
BrdU, 5-bromo-2-deoxyuridine; GLP-1, glucagon-like peptide 1; MAP, mitogen-activated protein; PACAP, pituitary adenylate cyclase-activating polypeptide; PAC1 receptor, PACAP receptor; STZ, streptozotocin; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; VIP, vasoactive intestinal peptide; VPAC receptor, VIP/PACAP receptor.
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