2007 Fiscal Year Final Research Report Summary
Formation of the integrated insulin secretion system and its failure
| Project/Area Number |
15002002
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| Research Category |
Grant-in-Aid for Specially Promoted Research
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kobe University |
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Principal Investigator |
SEINO Susumu Kobe University, Graduate School of Medicine, Professor (80236067)
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| Co-Investigator(Kenkyū-buntansha) |
YOKOI Norihide Kobe University, Graduate School of Medicine, Associate Professor (70311610)
SHIBASAKI Tadao Kobe University, Graduate School of Medicine, Assistant Professor (00323436)
IWANAGA Toshihiko Hokkaido University, Graduate School of Medicine, Professor (10160128)
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| Project Period (FY) |
2003 – 2007
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| Keywords | Diabetes / Cell signaling / Development&Differentiation / Bioimaging / Insulin secretion / Gene |
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| Research Abstract |
1) How is insulin secretory function acquired during β-cell differentiation? (1) We have demonstrated directly by cell lineage tracing that pancreatic acinar cells can transdifferentiate into insulin-secreting cells in vitro. Destruction and remodeling of cadherin-mediated cell-cell adhesion was found to be important for the transdifferentiation, and activation of PI3-kinase was required for these processes. (2) We have shown that pancreatic β-cells of Kir6.2G132S transgenic mice were spontaneously regenerated, and that intraislet DBA-labeled cells may represent progenitors for the β-cells. (3) We have identified a novel transcriptional factor, Mgx-1 (Isx), which is expressed specifically in gut. Isx inactivation is required for the gut-derived cell to express Pdx1 and Insulin2.
2) How are the signaling components in insulin secretion spatially and temporally integrated in β-cells? (1) Both 1st and 2nd phases of glucose-induced fusion event involved mostly granules that are newly recrui
… More
ted and immediately fused to the plasma membrane without docking (restless newcomer). (2) Activation of cAMP signaling clearly potentiated both phases of glucose-induced fusion events. All granules responsible for this potentiation were restless newcomer. We have found that Epac2/Rap1 signaling is essential in the potentiation of insulin granule exocytosis by cAMP, primarily in the first phase of cAMP-potentiated exocytosis, by increasing the number of restless newcomer. (3) We have proposed that Epac2-containing cAMP compartment is distinct from PKA-containing compartment.
3) How do B-cells interact functionally with other organs such as the brain and gastrointestine? (1) Although K_<ATP> channel-deficient mice lack glucose-induced insulin secretion, we found that gastrointestinal hormone incretin (such as GLP-1 and GIP) is released by food ingestion and endows Kir6.2^<-/-> β-cells with glucose responsiveness. (2) By studying the mice deficient in an exocytosis-related molecule Noc2, we found that Noc2 elicits an inhibitory effect on G_<i/o> mediated suppression of insulin secretion.
4) Pathophysiology due to defects in the system (1) We have generated mice deficient in transcription factor Otx3 (Dmbxl), which we previously identified in insulinoma cell lines. By cross-breeding with agouti yellow (Ay) mice, a hereditary mouse model of obesity and diabetes, we found that Dmbx1 is essential for developing obesity and diabetes of Ay mice. (2) Type 1 diabetes was reconstituted on a non-KDP genetic background with the two major susceptibility genes, MHC-RT1u and Cblb mutation, in the rat. By association study of variants involved in pancreatic β-cell function in Japanese type 2 diabetes, a significant association of a variant in SUR1(ABCC8) was found. Less
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Research Products
(237 results)
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[Journal Article] Identification and functional analysis of CBLB mutations in type 1 diabetes.2008
Author(s)
Yokoi N, Fujiwara Y, Wang HY, Kitao M, Hayashi C, Someya T, Kanamori M, Oiso Y, Tajima N, Yamada Y, Seino Y, Ikegami H, Seino S
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Journal Title
Biochem Biophys Res Commun 368
Pages: 37-42
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Isx participates in the maintenance of vitamin A metabolism by regulation of β-carotene 15, 15'-monooxygenase (Bcmo1) expression.2008
Author(s)
Seino Y, Miki T, Kiyonari H, Abe T, Fujimoto W, Kimura K, Takeuchi A, Takahashi Y, Oiso Y, Iwanaga T, Seino S
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Journal Title
J Biol Chem 283
Pages: 4905-4911
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP.2007
Author(s)
Shibasaki T, Takahashi H, Miki T, Sunaga Y, Matsumura K, Yamanaka M, Zhang C, Tamamoto A, Satoh T, Miyazaki J, Seino S
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Journal Title
Proc Natl Acad Sci USA 104
Pages: 19333-19338
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Association studies of variants in the genes involved in pancreatic β-cell function in type 2 diabetes in Japanese subjects.2006
Author(s)
Yokoi N, Kanamori M, Horikawa Y, Takeda J, Sanke T, Furuta H, Nanjo K, Mori H, Kasuga M, Hara K, Kadowaki T, Tanizawa Y, Oka Y, Iwami Y, Ohgawara H, Yamada Y, Seino Y, Yano H, Cox NJ, Seino S
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Journal Title
Diabetes 55
Pages: 2379-2386
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] PDX-1 protein is internalized by lipid raft-dependent macropinocytosis.2005
Author(s)
Noguchi H, Matsumoto S, Okitsu T, Iwanaga Y, Yonekawa Y, Nagata H, Matsushita M, Wei FY, Matsui H, Minami K, Seino S, Masui Y, Futaki S, Tanaka K
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Journal Title
Cell Transplant 14
Pages: 637-645
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Noc2 is essential in normal regulation of exocytosis in endocrine and exocrine cells.2004
Author(s)
Matsumoto M, Miki T, Shibasaki T, Kawaguchi M, Shinozaki H, Nio J, Saraya A, Koseki H, Miyazaki M, Iwanaga T, Seino S
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Journal Title
Proc Natl Acad Sci USA 101
Pages: 8313-8318
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Prediction of the coding sequences of mouse homologues of KIAA gene : IV. The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries.2004
Author(s)
Okazaki N, R FK, Ohara R, Inamoto S, Koseki H, Hiraoka S, Saga Y, Seino S, Nishimura M, Kaisho T, Hoshino K, Kitamura H, Nagase T, Ohara O, Koga H
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Journal Title
DNA Res 11
Pages: 205-218
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Genetic disruption of Kir6.2, the pore-forming subunit of ATP-sensitive K^+ channel, predisposes to catecholamine-induced ventricular dysrhythmia.2004
Author(s)
Liu XK, Yamada S, Kane GC, Alekseev AE, Hodgson DM, O'Cochlain F, Jahangir A, Miki T, Seino S, Terzic A
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Journal Title
Diabetes 53
Pages: S165-168
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] ATP-sensitive K^+ channel knockout compromises the metabolic benefit of exercise training, resulting in cardiac deficits.2004
Author(s)
Kane GC, Behfar A, Yamada S, Perez-Terzic C, O'Cochlain F, Reyes S, Dzeja PP, Miki T, Seino S, Terzic A
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Journal Title
Diabetes 53
Pages: S169-175
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] International Union of Pharmacology. XLI. Compendium of voltage-gated ion channels : potassium channels.2003
Author(s)
Gutman GA, Chandy KG, Adelman JP, Aiyar J, Bayliss DA, Clapham DE, Covarriubias M, Desir GV, Furuichi K, Ganetzky B, Garcia ML, Grissmer S, Jan LY, Karschin A, Kim D, Kuperschmidt S, Kurachi Y, Lazdunski M, Lesage F, Lester HA, McKinnon D, Nichols CG, O'Kelly I, Robbins J, Robertson GA, Rudy B, Sanguinetti M, Seino S, Stuehmer W, Tamkun MM, Vandenberg CA, Wei A, Wulff H, Wymore RS
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Journal Title
Pharmacol Rev 55
Pages: 583-586
Description
「研究成果報告書概要(欧文)」より
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[Presentation] 膵β細胞の機能と再生2006
Author(s)
清野 進
Organizer
第79回日本内分泌学会学術総会
Place of Presentation
神戸
Year and Date
2006-05-20
Description
「研究成果報告書概要(和文)」より
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[Presentation] 膵β細胞の生物学2005
Author(s)
清野 進
Organizer
第17回高遠・分子細胞生物学シンポジウム
Place of Presentation
長野
Year and Date
20050818-20050819
Description
「研究成果報告書概要(和文)」より
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[Presentation] 膵β細胞研究の新展開2005
Author(s)
清野 進
Organizer
第71回日本糖尿病学会中部地方会
Place of Presentation
岐阜
Year and Date
2005-03-26
Description
「研究成果報告書概要(和文)」より
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