Abstract

Insulin and insulin-like growth factor-1 (IGF-1) regulate metabolism and body growth through homologous receptor tyrosine kinases that phosphorylate the insulin receptor substrate (IRS) proteins. IRS-2 is an important IRS protein, as it mediates peripheral insulin action and beta-cell survival. In this study, we show that insulin, IGF-1, or osmotic stress promoted ubiquitin/proteasome-mediated degradation of IRS-2 in 3T3-L1 cells, Fao hepatoma, cells and mouse embryo fibroblasts; however, insulin/IGF-1 did not promote degradation of IRS-1 in 3T3-L1 preadipocytes or mouse embryo fibroblasts. MG132 or lactacystin, specific inhibitors of 26S proteasome, blocked insulin/IGF-1-induced degradation of IRS-2 and enhanced the detection of ubiquitinated IRS-2. Insulin/IGF1-induced ubiquitination and degradation of IRS-2 was blocked by inhibitors of phosphatidylinositol 3-kinase (wortmannin or LY294002) or mTOR (rapamycin). Chronic insulin or IGF-1 treatment of IRS-1-deficient mouse embryo fibroblasts inhibited IRS-2-mediated activation of Akt and ERK1/2, which was reversed by lactacystin pretreatment. By contrast, IRS-1 activation of Akt and ERK1/2 was not inhibited by chronic insulin/IGF-1 stimulation in IRS-2-deficient mouse embryo fibroblasts. Thus, we identified a novel negative feedback mechanism by which the ubiquitin/proteasome-mediated degradation of IRS-2 limits the magnitude and duration of the response to insulin or IGF-1.

Highlights

  • Insulin and insulin-like growth factor 1 (IGF-1)1 regulate a variety of biological functions through homologous tyrosine kinases that phosphorylate the insulin receptor substrate (IRS) proteins

  • We show that insulin, insulin-like growth factor-1 (IGF-1), or osmotic stress promoted ubiquitin/proteasome-mediated degradation of IRS-2 in 3T3-L1 cells, Fao hepatoma, cells and mouse embryo fibroblasts; insulin/IGF-1 did not promote degradation of IRS-1 in 3T3-L1 preadipocytes or mouse embryo fibroblasts

  • Moderate hyperinsulinemia might be well tolerated in the short term, chronic hyperglycemia and hyperinsulinemia exacerbate insulin resistance; if uncontrolled, this process continues until ␤-cells fail to compensate, resulting in diabetes [3, 4, 26]

Read more

Summary

Introduction

Insulin and insulin-like growth factor 1 (IGF-1)1 regulate a variety of biological functions through homologous tyrosine kinases that phosphorylate the insulin receptor substrate (IRS) proteins. We show that insulin and IGF-1 stimulate ubiquitination and degradation of IRS-2 in multiple cell types via a PI 3-kinase/Akt/ mTOR-dependent pathway, which correlates closely with the inhibition of insulin signaling. Insulin/IGF-1 Stimulates 26 S Proteasome-mediated Degradation of IRS-2—IRS-2 protein levels decreased after 1 h of insulin treatment and reached the lowest level within 3 h (data not shown).

Results
Conclusion
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.