2011 Fiscal Year Final Research Report
The physiological and pathophysiological role of IRS-1 and IRS-2 in the liver
| Project/Area Number |
21591156
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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 | National Institute of Health and Nutrition |
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Principal Investigator |
KUBOTA Tetsuya 独立行政法人国立健康・栄養研究所, 臨床栄養研究部栄養療法研究室, 室長 (60385698)
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| Co-Investigator(Kenkyū-buntansha) |
KUBOTA Naoto 東京大学, 医学部, 准教授 (50396719)
KADOWAKI Takashi 東京大学, 医学部, 教授 (30185889)
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| Project Period (FY) |
2009 – 2011
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| Keywords | 糖尿病 / シグナル伝達 / 遺伝子 |
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| Research Abstract |
In the liver in type 2 diabetes, PEPCK pathway is resistant to insulin action, leading to hyperglycemia via upregulation of gluconeogenesis. On the other hand, insulin pathway is superactive to upregulate SREBP1c to cause steatosis and hypertriglyceridemia. Why impaired insulin action in glucose metabolism "hyperglycemia"and exaggerated insulin action in lipid metabolism"steatosis, coexist in the liver in type 2 diabetes? To investigate these mechanisms, we fed our LIRS1KO and LIRS2KO mice on a HF diet. IRS1 expression levels on a HF diet did not show any change in the control mice. In contrast, unlike IRS1, IRS2 underwent profound downregulation in the control mice on a HF diet. LIRS1KO mice on a HF diet showed severe glucose intolerance and suppression of hepatic steatosis. In contrast, LIRS2KO mice showed only mild glucose intolerance and hepatic steatosis. Under a HF diet, IRS2 is profoundly downregulated, which is causally involved in the dysregulation of glucose metabolism. On the other hand, hyperinsulinemia-mediated IRS1 signal is rather increased, because IRS1 is not downregulated. So, it is causally involved in the steatosis.
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[Journal Article] A liver-derived secretory protein, selenoprotein p, causes insulin resistance2010
Author(s)
Misu H, Takamura T, Takayama H, Hayashi H, Matsuzawa-Nagata N, Kurita S, Ishikura K, Ando H, Takeshita Y, Ota T, Sakurai M, Yamashita T, Mizukoshi E, Yamashita T, Honda M, Miyamoto K, Kubota T, Kubota N, Kadowai T, et al
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Journal Title
Cell Metab
Volume: 12
Pages: 483-495
URL
Peer Reviewed
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[Presentation] Impaired Insulin Signaling in the Endothelial Cells Reduces Insulininduced Glucose Uptake by the Skeletal Muscle2011
Author(s)
Tetsuya Kubota, Naoto Kubota, Tomokatsu Iwamura, Marika Inoue, Hiroyuki Sate, Takanori Hayashi, Iseki Takamoto, Toshimasa Yamauchi, Kohjiro Ueki, Takashi Kadowaki
Organizer
The 16th Japan-Korea Symposium on Diabetes Mellitus
Place of Presentation
Tokyo, Japan
Year and Date
20111000
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[Presentation] The Effects of SK-o4os, a highly selective DPP-4 inhibitor, on(s-cell mass and function in haploinsufficiency of) s-cellspecific glucokinase mice on a high-fat diet2011
Author(s)
Keizo Nakaya, Naoto Kubota, Iseki Takamoto, Tetsuya Kubota, Hisayuki Katsuyama, Hiroyuki Sate, Shinji Hashimoto, Moritaka Goto, Takahito Jomori, Kohjiro Ueki, and Takashi Kadowaki
Organizer
71th American Diabetes Association's Scientific Sessions
Place of Presentation
San diego, USA
Year and Date
20110600
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[Presentation] 肥満・インスリン分泌不全を呈する2型糖尿病モデル動物に対するDPP-4阻害薬の長期投与効果2011
Author(s)
中屋恵三,佐藤寛之,窪田直人,高本偉碩,窪田哲也,勝山修行,橋本信嗣,後藤守兄,城森孝仁,植木浩二郎,門脇孝
Organizer
第25回日本糖尿病・肥満動物学会年次学術集会
Place of Presentation
東京
Year and Date
2011-11-05
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[Presentation] DPP-4阻害薬の2型糖尿病モデル動物に対する抗糖尿病作用2011
Author(s)
中屋恵三,窪田直人,高本偉碩,窪田哲也,佐藤寛之,勝山修行,橋本信嗣,後藤守兄,城森孝仁,植木浩二郎,門脇孝
Organizer
第54回日本糖尿病学会年次学術集会
Place of Presentation
札幌
Year and Date
2011-05-21
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