Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes

Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes Kyohei Yamamoto 1 , Hitoshi Hashimoto 1 , Shuhei Tomimoto 1 , Norihito Shintani 1 , Jun-ichi Miyazaki 2 , Fumi Tashiro 2 , Hiroyuki Aihara 2 , Takao Nammo 3 , Ming Li 3 , Kazuya Yamagata 3 , Jun-ichiro Miyagawa 3 , Yuji Matsuzawa 3 , Yuki Kawabata 1 , Yuji Fukuyama 1 , Kazumi Koga 1 , Wakaba Mori 1 , Kazuhiro Tanaka 1 , Toshio Matsuda 4 and Akemichi Baba 1 5 1 Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan 2 Division of Stem Cell Regulation Research, Osaka University Medical School, Osaka, Japan 3 Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan 4 Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan 5 Laboratory 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 Address correspond