| Project/Area Number |
05557050
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
内分泌・代謝学
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| Research Institution | University of Tokyo |
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Principal Investigator |
KADOWAKI Takashi University of Tokyo, Assistant, 医学部・附属病院, 助手 (30185889)
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| Co-Investigator(Kenkyū-buntansha) |
KODAMA Tatsuhiko University of Tokyo, Assistant, 医学部・附属病院, 助手 (90170266)
TERAUCHI Yasuo University of Tokyo, medical staff, 医学部・附属病院, 医員
TAMAMOTO Hiroyuki University of Tokyo, medical staff, 医学部・附属病院, 医員
TOBE Kazuyuki University of Tokyo, Assistant, 医学部・附属病院, 助手 (30251242)
佐倉 宏 東京大学, 医学部(病), 助手 (70240710)
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| Project Period (FY) |
1993 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥17,200,000 (Direct Cost: ¥17,200,000)
Fiscal Year 1995: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1994: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 1993: ¥7,200,000 (Direct Cost: ¥7,200,000)
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| Keywords | genetic engineering / NIDDM / insulin secretory defect / insulin resistance / IRS-1 / glucokinase / genetic reconstitution of NIDDM / insulin action / 多因子遺伝 / トランスジェニックマウス / グルユキナーゼ / シーンターゲティング / PI3キナーゼ / 糖尿病モデル動物 |
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| Research Abstract |
Non-insulin-dependent diabetes mellitus(NIDDM)is considered a polygenic disorder in which insulin resistance and insulin secretory defect are the major etiologic factors. Homozygous mice with insulin receptor substrate-1(IRS-1)gene knockout showed normal glucose tolerance associated with insulin resistance and compensatory hyperinsulinemia. Heterozygous mice with beta-cell glucokinase(GK)gene knockout showed impaired glucose tolerance due to decreased insulin secretion to glucose. To elucidate the interplay between insulin resistance and insulin secretory defect for the development of NIDDM,we generated a double knockout mouse with ***ption of IRS-1 and beta-cell GK genes by crossing the mice with each of the single gene knockout. The double knockout mice developed overt diabetes. Blood glucose levels 120min after intraperitoneal glucose load(1.5mg/ g body weight)were 108(]SY.+-。[)24(wide-type), 95(]SY.+-。[)26(IRS-1 knockout), 159(]SY.+-。[)68(GK knockout), and 210(]SY.+-。[)38(double knockout) mg/dl(mean(]SY.+-。[)SD)(double vs. wild-type, IRS-1, or GK ; P<0.01). The double knockout mice showed fasting hyperinsulinemia and selective hyperplasia of the beta-cells as the IRS-1 knockout mice(fasting insulin levels : 0.38(]SY.+-。[)0.30(double knockout), 0.35(]SY.+-。[)0.27(IRS-1 knockout)vs. 0.25(]SY.+-。[)0.12(wild-type)ng/ml)(proportion of areas of insulin-positive cells to the pancreas : 1.18(]SY.+-。[)0.68% ; P<0.01(double knockout), 1.20(]SY.+-。[)0.95% ; P<0.05(IRS-1 knockout)vs. 0.54(]SY.+-。[)0.26%(wild-type)), but impaired insulin secreation to glucose(the ratio of increment of insulin to that of glucose during the first 30min after load : 31(double knockout)vs. 163(wild-type)or 183(IRS-1 knockout)ng insulin/mg glucose x 103). In conclusions, the genetic abnormalities, each of which is non-diabetogenic by itself, cause overtdiabetes if they coexist. This report provides the first genetic reconstitution of NIDDM as a polygenic disorder in mice.
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