Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 108, Issue 3, Pages 437-446Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200111559
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Funding
- NIDDK NIH HHS [R01 DK-59635, R01 DK-45493, R01 DK051729, DK-51729, P30 DK045735, R01 DK040936, P30 DK-45735, U24 DK059635, U24 DK-59635] Funding Source: Medline
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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-H-3]glucose infusion, and glucose uptake in individual tissues was estimated using [1-C-14]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.
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