2005 Fiscal Year Final Research Report Summary
Elucidation of abnormality of plasma membrane microdomain in type 2 diabetes mellitus
| Project/Area Number |
16390259
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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 |
Metabolomics
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| Research Institution | Tohoku University |
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Principal Investigator |
SUZUKI Susumu Tohoku University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (70216399)
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| Co-Investigator(Kenkyū-buntansha) |
MIYAGI Taeko Miyagi Prefectural Cancer Center, Director, 生化学部門, 部長(研究職) (50006110)
HINOKIO Yoshinori Tohoku University Hospital, Lecturer, 大学病院, 講師 (10282071)
KATAGIRI Hideki Tohoku University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (00344664)
ISHIHARA Hisamitsu Tohoku University Hospital, Research Associate, 大学病院, 助手 (60361086)
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| Project Period (FY) |
2004 – 2005
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| Keywords | diabetes / ganglioside / sialidase / adenovirus vector / glucose tolerance / insulin resistance / insulin receptor / insulin receptor substrate 1 |
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| Research Abstract |
Membrane microdomains rich in gangliosides are recognized as being critical for proper compartmentalization of insulin signaling. Plasma membrane-associated sialidase, NEU3, is a key enzyme for ganglioside hydrolysis. We previously reported that the mice overexpressing NEU3 developed severe insulin-resistant diabetes. To examine possible the contributions of NEU3 to in vivo insulin sensitivity and glucose tolerance, NEU3 was expressed using adenoviral vectors in the livers of C57BL/6 mice on standard and high-fat diets, and insulin-resistant KKAy mice on standard diets. Hepatic NEU3 overexpression significantly improved glucose tolerance and insulin sensitivity in the C57BL/6 mice fed standard diets, and glucose tolerance in the C57BL/6 mice fed high-fat diets and in KKAy mice. Hepatic NEU3 overexpression increased hepatic glycogen deposition and triglyceride accumulation, and enhanced the hepatic PPARg and fetuin expression in the C57BL/6 mice on standard and high-fat diets, and in KKAy mice. TLC analysis demonstrated increased levels of GM1 and markedly reduced GM3 in the livers of mice with hepatic NEU3 overexpression (NEU3 mice). Basal and insulin-stimulated tyrosine phosphorylations of insulin receptor substrate 1 (IRS1) were significantly increased, but tyrosine phosphorylations of the insulin receptor and IRS2 in the NEU3 liver were unchanged. Insulin-stimulated tyrosine phosphorylations of the insulin receptor were increased in adipose tissues of NEU3 mice. These results suggest that hepatic NEU3 overexpression improves insulin sensitivity and glucose tolerance through modification of ganglioside composition and PPARγ signaling. Our findings also provide further evidence that NEU3 is an important regulator of insulin sensitivity and glucose tolerance.
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