1998 Fiscal Year Final Research Report Summary
Control of glucose metabolism by PACAP : stimulation of insulin secretion and potentiation of insulin action
| Project/Area Number |
09670052
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General physiology
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| Research Institution | Kagoshima University |
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Principal Investigator |
YADA Toshihiko Faculty of Medicine, Kagoshima University, Associate Professor, 医学部, 助教授 (60166527)
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| Co-Investigator(Kenkyū-buntansha) |
KAKEI Masafumi University Hospital, Kagoshima University, Assistant Professor, 医学部・附属病院, 講師 (90214270)
SHIODA Seiji Showa University Faculty of Medicine, Associate Professor, 医学部, 助教授 (80102375)
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| Project Period (FY) |
1997 – 1998
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| Keywords | PACAP / islet / autocrine / insulin secretion / adipocyte / insulin action / glucose uptake / PACAP receptor |
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| Research Abstract |
We examined whether pituitary adenylate cyclase-activating polypeptide (PACAP) serves as an intra-islet regulator of glucose-induced insulin secretion. High glucose-stimulated insulin release from isolated rat islets was attenuated by an antiserum specific for PACAP, but not by nonimmune sera. The islet incubation medium with high glucose possessed a capacity, which was neutralized by the PACAP antiserum, to increase cytosotic Ca^<2+> concentration ([Ca^<2+>]_i) in beta-cells. PACAP antiserum also neutralized the [Ca^<2+>]_i-increasing action of synthetic PACAP, but not VIP and glucagon. In islets and a beta-cell line, MIN6, expression of PACAP mRNA was detected by reverse-transcription polymerase chain reaction (RT-PCR) and biosynthesis of PACAP was detected by metabolic labeling and immunoblotting. Immunoreactivity for PACAP-selective receptor (PAC1-R) was observed in islets. [Ca^<2+>]_i measurements combined with immunocytochemistry with insulin antiserum demonstrated that glucose-u
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nresponsive beta-cells are recruited by PACAP into [Ca^<2+>]_i responses. These results reveal that PACAP is a novel islet substance, which is synthesized and released by islet cells and then) in an autocrine/paracrine manner, potentiates and arouses beta-cell responses to glucose, thereby amplifying glucose-induced insulin secretion in islets.
Next, we explored a possible extra-pancreatic action of PACAP.PAC1-R was expressed in the rat fat tissue and an adipocyte cell line, 3T3-Li. PACAP significantly enhanced the insulin-induced 2-deoxyglucose uptake by 333-Li adipocytes. Both insulin receptor beta-subunit and insulin receptor substrate-1 (IRS-1) were tyrosine-phosphorylated by insulin, on which PACAP had no additional effect. In contrast, the insulin-stimulated phosphatidylinositol (PI) 3-kinase activity was further increased by PACAP.The basal 2-deoxyglucose uptake and PI 3-kinase activity were not altered by PACAP.These results indicate that PACAP promotes insulin-induced glucose uptake by increasing PI 3-kinase activity, and reveal that PACAP not only potentiates glucose-induced insulin secretion in islets but also potentiates insulin action in adipocytes. Less
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