| Project/Area Number |
18590978
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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 | The University of Tokyo |
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Principal Investigator |
MITSURU Ohsugi The University of Tokyo, Graduate School of Medicine, Assistant Professor (00420216)
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| Co-Investigator(Kenkyū-buntansha) |
KADOWAKI Takashi The University of Tokyo, Graduate School of Medicine, Assistant Professor (30185889)
TOBE Kazuyuki Toyama University, Graduate School of Medicine and Pharmaceutical Sciencse for Research, Professor (30251242)
KUBOTA Naoto The University of Tokyo, Graduate School of Medicine, Associate (50396719)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Diabetes Melitus / Signal Transduction / Pancreatic β cells |
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| Research Abstract |
1. Molecuar mechanisms of IRS-2 mRNA and protein level determination. Utilizing mouse pancreatic islets in vivo as well as isolated islets, we discovered following experimental facts. (A) IRS-2 mRNA and protein levels were positively regulated chiefly by glucose stimulation. (B) This glucose-stimulated IRS-2 induction requires glucose metabolism and Ca2+ influx. (C) CREB phosphorylation/activation was required for Glucose-stimulated IRS-2 induction in the islets. (D) Calmodulin-dependent kinases, not PKA, play a major roles in CREB phoshorylation and subsequent IRS-2 induction by glucose
2. Importance of intact Glucose-IRS-2 pathway in adaptive β cell growth in response to insulin resistance. By examining the pancreas islets of obese diabetic mice, including ob/ob, db/db, KK-Ay, and KK/Ta mice, we discovered that CREB phosphorylation was enhanced and IRS-2 mRNA and protein levels were elevated when these pancreatic islets were capable of proliferating in response to insulin resistance. These observations confirmed the importance of glucose-IRS-2 pathway in adaptive β cell growth.
3. Importance of IRS-2 in adaptive β cell growth in response to insulin resistance. In addition to our previous publications (J Cline Invest. 2004; 114; 917-27 and Diabetes 2000; 49: 1880-9) we further confirmed the importance of IRS-2 in adaptive adaptive β cell growth in response to insulin resistance. Pancreatic specific glucokinase heterozygous knockout mice exhibited defective β cell growth and reduced IRS-2 protein in the islets when these mice were fed with a high fat diet. A transgenic expression of IRS-2 partially ameliorated the defective β cell growth in glucokinase heterozygous knockout mice.
4. Identifying new genes involved in adaptive β cell growth. Gene expression profiles of the pancreatic islets of insulin resistant mice were surveyed with DNA microarrays. We identified more than 300 genes of which their expression levels were significantly altered.
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