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


METHODS
To directly assess the role of serine phosphorylation in mediating fat-induced insulin resistance in skeletal muscle, we generated muscle-specific IRS-1 Ser(302), Ser(307), and Ser(612) 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.
Morino
Katsutaro
K
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
Neschen
Susanne
S
Bilz
Stefan
S
Sono
Saki
S
Tsirigotis
Dimitrios
D
Reznick
Richard M
RM
Moore
Irene
I
Nagai
Yoshio
Y
Samuel
Varman
V
Sebastian
David
D
White
Morris
M
Philbrick
William
W
Shulman
Gerald I
GI
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D015153:Blotting, Western; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012694:Serine / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D004041:Dietary Fats; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D014280:Triglycerides; D012694:Serine; D000409:Alanine