1996 Fiscal Year Final Research Report Summary
The role and function of insulin/insulin receptor like I receptor hybrid
| Project/Area Number |
07671119
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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 |
内分泌・代謝学
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| Research Institution | TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY |
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Principal Investigator |
TAKATA Yasumitsu Toyama Medical and Pharmaceutical University, assistant professor, 医学部, 助手 (50242491)
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| Project Period (FY) |
1995 – 1996
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| Keywords | Insulin Receptor / IGF-I Receptor / Hybrid Receptor / Insulin Resistance |
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| Research Abstract |
(1) A functional assessment of insulin /IGF-I receptor hybrid : To study interaction between insulin receptor and IGF-I receptor tyrosine kinases, we examined IGF-I action in Rat-1 cells expressing a naturally occurring tyrosine-kinase deficient mutant insulin receptor (Asp 1048 IR) (Diabetes 42 : 1837,1993). IGF-I normally stimulated receptor autophosphorylation, IRS-I phosphorylation and glycogen synthesis in the cells expressing Asp 1048 IR.However, the Asp 1048 IR inhibited IGF-I-stimulated thymidine and amino acid uptake (AIB) in the Asp 1048 IR cells. Furthermore, She phosphorylation and MAP kinase activity was inhibited. The inhibition on the mitogenesis and AIB uptake was restored with the amelioration of the impaired kinase activity and She phosphorylation by the introduction of abundant wild type IGF-I receptors in Asp 1048 IR cells. These results suggest that the Asp 1048 IR causes a dominant negative effect on IGF-I receptors in transmitting signals to She and MAP kinase activation, which leads to decreased IGF-I-stimulated DNA synthesis and that the kinase defective insulin receptor does not affect IGF-I-stimulated IRS-I phosphorylation, which leads to the normal IGF-I-stimulated glycogen synthesis.
(2) The effect of hyperinsulinism on hybrid receptor tyrosine kinase :
These results indicate that IGF-I stimulated tyrosine kinase activity of hybrid receptors requires insulin receptor counterparts with normal tyrosine kinase domain and suggest that the cross-talk for kinase activation between insulin receptor and IGF-I receptor may operate for insulin-induced IGF-I resistance in mitogenesis and hybrid receptor tyrosine kinase activity.
(3) The effect of hypoglycemic agents and free-fatty acids on receptor tyrosine kinase : The direct effect of new sulfonyl urea agent, insulin sensitizer and free fatty acids on tyrosine kinase activity on various cells were studied.
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[Publications] Takada Y., Takata Y., Iwanishi M., Imamura T., Sawa T., Morioka H., Ishihara H., Ishiki M., Usui I., Temaru R., Urakaze M., Satoh Y., Inami T., Tsuda S., and Kobayashi M.: "Effect of glimepiride (HOE 490) on insulin receptors of skeletal muscles from genetically diabetic KK-Ay mouse." Eur. J.Pharmacol.308. 205-210 (1996)
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