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Published online July 15, 2008
Diabetes 57:2644-2651, 2008
DOI: 10.2337/db06-0454
© 2008 by the American Diabetes Association
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Muscle-Specific IRS-1 Ser->Ala Transgenic Mice Are Protected From Fat-Induced Insulin Resistance in Skeletal Muscle

Katsutaro Morino1,2, Susanne Neschen1,2, Stefan Bilz2, Saki Sono2, Dimitrios Tsirigotis2,3, Richard M. Reznick2,3, Irene Moore1, Yoshio Nagai1, Varman Samuel2, David Sebastian2, Morris White4, William Philbrick2, and Gerald I. Shulman1,2,3

1 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
2 Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
3 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
4 Howard Hughes Medical Institute, Children's Hospital Boston, Boston, Massachusetts

Corresponding author: Gerald I. Shulman, gerald.shulman{at}yale.edu

OBJECTIVE—Insulin resistance in skeletal muscle plays a critical role in the pathogenesis of type 2 diabetes, yet the cellular mechanisms responsible for insulin resistance are poorly understood. In this study, we examine the role of serine phosphorylation of insulin receptor substrate (IRS)-1 in mediating fat-induced insulin resistance in skeletal muscle in vivo.

RESEARCH DESIGN AND METHODS—To directly assess the role of serine phosphorylation in mediating fat-induced insulin resistance in skeletal muscle, we generated muscle-specific IRS-1 Ser302, Ser307, and Ser612 mutated to alanine (Tg IRS-1 Ser->Ala) and IRS-1 wild-type (Tg IRS-1 WT) transgenic mice and examined insulin signaling and insulin action in skeletal muscle in vivo.

RESULTS—Tg IRS-1 Ser->Ala mice were protected from fat-induced insulin resistance, as reflected by lower plasma glucose concentrations during a glucose tolerance test and increased insulin-stimulated muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. In contrast, Tg IRS-1 WT mice exhibited no improvement in glucose tolerance after high-fat feeding. Furthermore, Tg IRS-1 Ser->Ala mice displayed a significant increase in insulin-stimulated IRS-1–associated phosphatidylinositol 3-kinase activity and Akt phosphorylation in skeletal muscle in vivo compared with WT control littermates.

CONCLUSIONS—These data demonstrate that serine phosphorylation of IRS-1 plays an important role in mediating fat-induced insulin resistance in skeletal muscle in vivo.


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