2006 Fiscal Year Final Research Report Summary
Molecular mechanism of insulin secretion by a novel target of HNF1 colectrin
| Project/Area Number |
17590928
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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 |
Metabolomics
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| Research Institution | Osaka University |
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Principal Investigator |
YAMAGATA Kazuya Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (70324770)
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| Co-Investigator(Kenkyū-buntansha) |
IWAHASHI Hiromi Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (60397627)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Diabetes mellitus / Insulin / HNF / Collectrin / Exocytosis / SNARE complex / MODY |
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| Research Abstract |
Mutations in the HNF-1a gene cause a monogenic form of type 2 diabetes, maturity-onset diabetes of the young (MODY),characterized by impaired insulin secretion. The molecular mechanism of MODY3 is not fully understood. To identify novel molecular mechanisms of insulin secretion by HNF-1,we screened the downstream target genes of HNF-1a transcription factor by PCR-based suppression subtraction hybridization technique.
We found that collectrin, a recently cloned kidney-specific gene of unknown function, is a target of HNF-1a in pancreatic b-cells. Expression of collectrin was decreased in the islets of HNF-1a KO mice, but was increased in obese hyperglycemic mice. Overexpression of collectrin in INS-1 b-cells or in the b-cells of transgenic mice enhanced glucose-stimulated insulin edxocytosis, without affecting Ca2+ influx. Coversely, suppression of collectrin attenuated insulin secretion. Collectrin bound to SNARE complexes by interacting with snapin, a SNAP25 binding protein, and facilitated SNARE complex formation. Therefore, collectrin is a regulator of SNARE complex function, which thereby controls insulin exocytosis.
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