The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism
Open accessAbstract
Hepatic insulin resistance is a critical component in the development of type 2 diabetes mellitus. In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. The alterations in the dual-knockdown mice were associated with defective Akt activation and Foxo1 phosphorylation. Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism.
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Metadata
- Authors
- Taniguchi, C. M., Ueki, K., & Kahn, C. R.
- Venue
- Journal of Clinical Investigation
- Published
- 2005-03-01
- Volume
- 115
- Issue
- 3
- Pages
- 718-727
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2050941179
- Cited by
- 272
- References
- 9
- FWCI
- 8.41
- Type
- journal article
- Language
- en
- Status
- Retracted
- Open access
- bronze
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