Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.
We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IkappaB kinase beta (IKKbeta) attenuated insulin signaling in cultured cells, whereas IKKbeta inhibition reversed insulin resistance. Thus, IKKbeta, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkbeta+/-) protected against the development of insulin resistance during high-fat feeding and in obese Lep(ob/ob) mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKbeta pathway as a target for insulin sensitization.
Yuan
M
M
Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Konstantopoulos
N
N
Lee
J
J
Hansen
L
L
Li
Z W
ZW
Karin
M
M
Shoelson
S E
SE
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D004041:Dietary Fats / Q000008:administration & dosage*; D017353:Gene Deletion; D018390:Gene Targeting; D005951:Glucose Tolerance Test; D051550:I-kappa B Kinase; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009132:Muscles / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D012980:Sodium Salicylate / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha; D011451:Prostaglandin-Endoperoxide Synthases; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D001241:Aspirin; D012980:Sodium Salicylate