| Project/Area Number |
06454147
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
General physiology
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| Research Institution | Kagoshima University |
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Principal Investigator |
YADA Toshihiko Kagoshima University, Faculty of Medicine Physiology, Associate Professor, 医学部, 助教授 (60166527)
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| Co-Investigator(Kenkyū-buntansha) |
MARUYAMA Ikuro Kagoshima University, Faculty of Medicine Laboratory Medicine, Professor, 医学部, 教授 (20082282)
KAKEI Masafumi Kagoshima University, Faculty of Medicine Internal Medicine, Lecturer, 医学部, 講師 (90214270)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 1995: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1994: ¥4,100,000 (Direct Cost: ¥4,100,000)
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| Keywords | PACAP / insulin secretion / islet / autocrine / beta-cells / PACAP receptor / Ca^<2+> / 受容体 / サイクリックAMP |
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| Research Abstract |
Insulin secretion from pancreatic islets is controlled by peptides as well as by nutrients. Two forms of pituitary adenylate cyclase activating polypeptide (PACAP27 and PACAP38) as low as 10^<-13> M stimulated insulin release from rat islets in a glucosedependent manner. PACAP also increased cytosolic Ca^<2+> concentration ( [Ca^<2+>] _i) in islet beta-cells. A blocker of the L-type Ca^<2+> channel abolished both [Ca^<2+>] _i and insulin responses. PACAP stimulated production of cAMP in islets, and a rise in cAMP mimicked PACAP in increasing [Ca^<2+>] _i in beta-cells. Vasoactive intestinal peptide, a peptide exhibiting high amino acid homology with PACAP,also increased [Ca^<2+>] _i in beta-cells but only at concentrations in the nanomolar range, indicating that PACAP27 is 4 logs more potent. High-affinity type-I PACAP receptor was immunohistochemically localized in islets.
We next examined the source and physiological role of PACAP in islets. PACAP-immunoreactivity was demonstrated in pancreatic nerve fibers and islets. PACAP mRNA was detected in islets and in the beta-cell line MIN6. Stimulation of insulin release by high glucose from isolated islets was attenuated by a specific PACAP antiserum. The islet incubation medium with high glucose possessed a capacity, which was neutralized by PACAP antiserum, to increase [Ca^<2+>] _i in beta-cells.
The results indicate that PACAP reacts with high affinity PACAP-selective receptor and raises cAMP in beta-cells, which in turn enhances the L-type Ca^<2+> channel activity, increases [Ca^<2+>] _i and consequently potentiates glucose-induced insulin release. PACAP is by far the most potent insulinotropic peptide known. Moreover, PACAP is released from islets and acts on islet beta-cells, thus acting as an autocrine hormone. PACAP,via the autocrine action, amplifies glucose-induced insulin secretion in islets, which is characteristically impaired in non-insulin-dependent diabetes mellitus.
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