2006 Fiscal Year Final Research Report Summary
Insulin signaling in endothelial cells (insulin receptor substrate) and atherosclerosis
| Project/Area Number |
17590952
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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 National Institute of Health and Nutrition, Clinical Nutrition Program, Postdoctoral Researcher, 臨床栄養プログラム, 任期付研究員 (60385698)
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| Co-Investigator(Kenkyū-buntansha) |
KUBOTA Naoto National Institute of Health and Nutrition, Clinical Nutrition Program, Cooperation researcher, 臨床栄養プログラム, 協力研究員 (50396719)
KADOWAKI Takashi National Institute of Health and Nutrition, Clinical Nutrition Program, Director, 臨床栄養プログラム, リーダー (30185889)
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| Project Period (FY) |
2005 – 2006
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| Keywords | insulin resistance / atherosclerosis / insulin signaling / endothelial cell-specific IRS-2 knockout mice / bone marrow cells, macrophage |
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| Research Abstract |
We previously demonstrated that both insulin receptor substrate (Irs) 1 knockout (KO) and Irs2 KO mice showed insulin resistance, hypertension, and hypercholesterolemia to a similar degree. Irs2 KO mice, however, exhibited much greater neointimal formation in response to cuff-injury than Irs1 KO mice. Irs2 is mainly expressed in endothelial cells. To more precisely determine the roles of Irs2 in vascular endothelial cells, we generated endothelial cell-specific Irs2 knockdown (ETIrs2KO) mice. Endothelial-dependent vascular relaxation in response to insulin was significantly impaired in ETIrs2KO mice. ETIrs2KO mice also showed mild hypertension and impaired insulin-stimulated phosphorylation of eNOS. ETIrs2KO mice were fertile and normal metabolic parameter. Interestingly, insulin resistance and glucose intolerance were observed in ETIrs2KO mice. In hyperinsulinemic-euglycemic clamp, glucose infusion rate (GIR) and rate of glucose disappearance (Rd) were significantly lower in ETIrs2KO mice than wild-type mice, whereas endogenous glucose production (EGP) did not differ between ETIrs2KO and wild-type mice. These data indicate that ETIrs2KO mice showed insulin resistance in skeletal muscle. Consistent with this, ETIrs2KO mice showed impaired insulin-stimulated phosphorylation of Akt in skeletal muscle after hyperinsulinemic-euglycemic clamp. ETIrs2KO mice also showed decreased blood flow in skeletal muscle after hyperinsulinemic-euglycemic clamp. These data suggest that the skeletal muscle insulin resistance observed in the ETIrs2KO mice may, at least in part, be caused by the decrease in skeletal muscle blood flow. To clarify the role of Irs2 of endothelial cells in atherosclerosis, we would like to examine neointimal formation response to cuff-injury in ETIrs2KO mice in the future.
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