1995 Fiscal Year Final Research Report Summary
Extraordinarily Potent Insulinotropin PACAP : Its Characterization as a Pancreatic Peptide and Action Mechanisms in Islet beta-Cells
| 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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| Keywords | PACAP / insulin secretion / islet / autocrine / beta-cells / PACAP receptor / Ca^<2+> |
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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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[Publications] Yada, T., Sakurada, M., Ihida, K., Nakata, M., Murata, F., Arimura, A.and Kikuchi, M.: "Pituitary adenylate cyclase activating polypeptide is an extraordinarily potent intra-pancreatic regulator of insulin secretion from islet beta-cells." J.Biol.Chem.269. 1290-1293 (1994)
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[Publications] Aizawa, T., Yada, T., Asanuma, N., Sato, Y., Ishihara, F., Hamakawa, N., Yaekura, K.and Hashizume, K.: "Effect of thapsigargin, an intracellular Ca^<2+> pump inhibitor, on inulin release by rat pancreatic B-cells." Life Sciences. 57. 1375-1381 (1995)
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[Publications] Fujitani, S., Ikenoue, T., Akiyoshi, M., Maki, T.and Yada, T.: "Somatostatin and insulin secretion due to common mechanisms by a new hypoglycemic agent, A-4166, in Perfused Rat Pancreas." Metabolism. 45 (in press). (1996)
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