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

K Morino, S Neschen, S Bilz, S Sono, D Tsirigotis… - Diabetes, 2008 - Am Diabetes Assoc
K Morino, S Neschen, S Bilz, S Sono, D Tsirigotis, RM Reznick, I Moore, Y Nagai, V Samuel
Diabetes, 2008Am Diabetes Assoc
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 …
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.
Am Diabetes Assoc