Muscle-Specific IRS-1 Ser→Ala Transgenic Mice Are Protected From Fat-Induced Insulin Resistance in Skeletal Muscle
- Katsutaro Morino12,
- Susanne Neschen12,
- Stefan Bilz2,
- Saki Sono2,
- Dimitrios Tsirigotis23,
- Richard M. Reznick23,
- Irene Moore1,
- Yoshio Nagai1,
- Varman Samuel2,
- David Sebastian2,
- Morris White4,
- William Philbrick2 and
- Gerald I. Shulman123
- 1Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
- 2Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- 3Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
- 4Howard Hughes Medical Institute, Children's Hospital Boston, Boston, Massachusetts
- Corresponding author: Gerald I. Shulman, gerald.shulman{at}yale.edu
Abstract
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.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008.
K.M. and S.N. contributed equally to this article.
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- Accepted July 3, 2008.
- Received April 6, 2006.
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