Prevention of fat-induced insulin resistance by salicylate.
Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may involve fat-induced activation of a serine kinase cascade involving IKK-beta. To test this hypothesis, we first examined insulin action and signaling in awake rats during hyperinsulinemic-euglycemic clamps after a lipid infusion with or without pretreatment with salicylate, a known inhibitor of IKK-beta. Whole-body glucose uptake and metabolism were estimated using [3-(3)H]glucose infusion, and glucose uptake in individual tissues was estimated using [1-(14)C]2-deoxyglucose injection during the clamp. Here we show that lipid infusion decreased insulin-stimulated glucose uptake and activation of IRS-1-associated PI 3-kinase in skeletal muscle but that salicylate pretreatment prevented these lipid-induced effects. To examine the mechanism of salicylate action, we studied the effects of lipid infusion on insulin action and signaling during the clamp in awake mice lacking IKK-beta. Unlike the response in wild-type mice, IKK-beta knockout mice did not exhibit altered skeletal muscle insulin signaling and action following lipid infusion. In summary, high-dose salicylate and inactivation of IKK-beta prevent fat-induced insulin resistance in skeletal muscle by blocking fat-induced defects in insulin signaling and action and represent a potentially novel class of therapeutic agents for type 2 diabetes.
Kim
J K
JK
Howard Hughes Medical Institute, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA.
Kim
Y J
YJ
Fillmore
J J
JJ
Chen
Y
Y
Moore
I
I
Lee
J
J
Yuan
M
M
Li
Z W
ZW
Karin
M
M
Perret
P
P
Shoelson
S E
SE
Shulman
G I
GI
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000517:prevention & control; D004041:Dietary Fats / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D051550:I-kappa B Kinase; D007262:Infusions, Intravenous; D007333:Insulin Resistance; D008055:Lipids / Q000008:administration & dosage; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D020156:Salicylic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D004041:Dietary Fats; D004791:Enzyme Inhibitors; D008055:Lipids; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D005947:Glucose; D020156:Salicylic Acid