Muscle specific IRS-1 Ser→Ala transgenic mice are protected from fat-induced insulin resistance in skeletal muscle

Abstract

Objective. Insulin resistance in skeletal muscle plays a critical role in the pathogenesis of type 2 diabetes mellitus, 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-1 (IRS-1) in mediating fat-induced insulin resistance in skeletal muscle in vivo.

Research Design and Methods. In order 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 PI3-kinase activity and Akt phosphorylation in skeletal muscle in vivo compared to wild type 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.