Overexpression of PACAP in transgenic mouse pancreatic beta-cells enhances insulin secretion and ameliorates streptozotocin-induced diabetes.
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 beta-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 beta-cells.
Yamamoto
Kyohei
K
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Hashimoto
Hitoshi
H
Tomimoto
Shuhei
S
Shintani
Norihito
N
Miyazaki
Jun-ichi
J
Tashiro
Fumi
F
Aihara
Hiroyuki
H
Nammo
Takao
T
Li
Ming
M
Yamagata
Kazuya
K
Miyagawa
Jun-ichiro
J
Matsuzawa
Yuji
Y
Kawabata
Yuki
Y
Fukuyama
Yuji
Y
Koga
Kazumi
K
Mori
Wakaba
W
Tanaka
Kazuhiro
K
Matsuda
Toshio
T
Baba
Akemichi
A
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000235:genetics*; D009928:Organ Specificity; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors
C495401:ADCYAP1 protein, human; C495402:Adcyap1 protein, mouse; D007328:Insulin; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger