| Project/Area Number |
15390019
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
INOKUCHI Jun-ichi Hokkaido Univ., Grad.School of Pharm., Asso.Prof., 大学院・薬学研究科, 助教授 (70131810)
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| Co-Investigator(Kenkyū-buntansha) |
IGARASHI Yasuyuki Hokkaido Univ., Grad.School of Pharm., Prof., 大学院・薬学研究科, 教授 (70091965)
坂上 慎二 北海道大学, 大学院・医学研究科, 助手 (50333604)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥15,300,000 (Direct Cost: ¥15,300,000)
Fiscal Year 2004: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2003: ¥11,300,000 (Direct Cost: ¥11,300,000)
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| Keywords | lifestyle-related disease / type 2 diabetes / ganalioside / Insulin resistance / microdomain / adioocyte / TNFα / 癌 / 抗ガン剤抵抗性 |
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| Research Abstract |
Membrane microdomains (lipid rafts) are now recognized as critical for proper compartmentalization of insulin signaling, but their role in the pathogenesis of insulin resistance has not been investigated. Detergent-resistant membrane microdomains (DRMs), isolated in the low density fractions, are highly enriched in cholesterol, glycosphingolipids and various signaling molecules. TNFα induces insulin resistance in type 2 diabetes, but its mechanism of action is not fully understood. We have found a selective increase in the acidic glycosphingolipid ganglioside GM3 in 3T3-L1 adipocytes treated with TNFα, suggesting a specific function for GM3. In the DRMs from TNFα-treated 3T3-L1 adipocytes, GM3 levels were doubled compared with results in normal adipocytes. Additionally, insulin receptor (IR) accumulations in the DRMs were diminished, while caveolin and flotillin levels were unchanged. Furthermore, insulin-dependent IR internalization and intracellular movement of the IR substrate 1(IRS-1) were both greatly suppressed in the treated cells, leading to an uncoupling of IR-IRS-1 signaling. GM3 depletion was able to counteract the TNFα-induced inhibitions of IR internalization and accumulation into DRMs. Together, these findings provide compelling evidence that in insulin resistance the insulin metabolic signaling defect can be attributed to a loss of IRs in the microdomains due to an accumulation of GM3.
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