HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Sentinelli, F Articles by Baroni, M G Search for Related Content PubMed PubMed Citation Articles by Sentinelli, F Articles by Baroni, M G

¹ Department of Clinical Sciences, Division of Endocrinology, Policlinico Umberto I, University of Rome ‘La Sapienza’, Viale del Policlinico 155, 00161 Rome, Italy
² Department of Medical Sciences, University of Cagliari, Cagliari, Italy

(Requests for offprints should be addressed to M G Baroni; Email: marco.baroni{at}uniroma1.it)

The insulin receptor substrate-1 (IRS-1) plays a central role in insulin sensitivity, and association studies have shown that the IRS-1 G972R variant is a risk factor for insulin resistance. However, how this mutation may lead to impaired insulin sensitivity is still to be determined. Our study aimed to evaluate, after transfection of the IRS-1 G972R variant in 3T3L1 adipocytes, the effect of this mutation on insulin signaling and on cell differentiation. The 3T3L1 cells were transfected with pcDNA3 expression vector containing either the human wild-type IRS-1 or the G972R variant. After induction of differentiation, the 3T3L1 transfected with wild-type IRS-1 differentiated in 6–8 days, while the cells transfected with G972R variant did not differentiate. To determine whether the defect in IRS-1 was responsible for this, we analyzed the expression of several genes involved in the insulin signaling pathway. Results showed that PPAR expression was significantly reduced in cells transfected with the mutated IRS-1, together with a significant decrease in binding of phosphatidylinositol-3 kinase (PI 3-kinase) to IRS-1 G972R and in PI 3-kinase activity. In addition, we observed that the interaction between the insulin receptor (IR) and the IRS-1 G972R protein was increased and that the autophosphorylation of the IR was significantly inhibited in 3T3L1-G972R cells compared with 3T3L1-WT. Treatment of the 3T3L1-G972R cells with pioglitazone (PIO), a PPAR agonist, restored differentiation with higher level of PPAR expression and restoration of PI 3-kinase binding to IRS-1 G972R and PI 3-kinase activity. IR autophosphorylation was also increased. Withdrawal of PIO in fully differentiated 3T3L1-G972R cells determined the reappearance of the insulin signaling defect. Finally, we observed higher levels of IRS-2 expression, suggesting that IRS-2 may play a more important role in adipocyte insulin signaling. In conclusion, IRS-1 G972R variant impairs insulin signaling, and treatment with PPAR agonist restores the normal phenotype of 3T3L1 cells.

This article has been cited by other articles:

				J. Shi, D.-M. Wang, C.-M. Wang, Y. Hu, A.-H. Liu, Y.-L. Zhang, B. Sun, and J.-G. Song Insulin Receptor Substrate-1 Suppresses Transforming Growth Factor-{beta}1-Mediated Epithelial-Mesenchymal Transition Cancer Res., September 15, 2009; 69(18): 7180 - 7187. [Abstract] [Full Text] [PDF]

				T. Shimada, N. Hiramatsu, K. Hayakawa, S. Takahashi, A. Kasai, Y. Tagawa, M. Mukai, J. Yao, Y. Fujii-Kuriyama, and M. Kitamura Dual suppression of adipogenesis by cigarette smoke through activation of the aryl hydrocarbon receptor and induction of endoplasmic reticulum stress Am J Physiol Endocrinol Metab, April 1, 2009; 296(4): E721 - E730. [Abstract] [Full Text] [PDF]