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Recent studies have implicated fatty acid-dependent activation of the serine kinase IKK[beta], which plays a key role in tissue inflammation, in the pathogenesis of insulin resistance. High doses of salicylates have recently been shown to inhibit IKK[beta] activity and might therefore ameliorate insulin resistance and improve glucose tolerance in patients with type 2 diabetes. To test this hypothesis, we studied nine type 2 diabetic subjects before and after 2 weeks of treatment with aspirin (~7 g/d). Subjects underwent mixed-meal tolerance tests and hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose to assess glucose turnover before and after treatment. High-dose aspirin treatment resulted in a ~25% reduction in fasting plasma glucose, associated with a ~15% reduction in total cholesterol and C-reactive protein, a ~50% reduction in triglycerides, and a ~30% reduction in insulin clearance, despite no change in body weight. During a mixed-meal tolerance test, the areas under the curve for plasma glucose and fatty acid levels decreased by ~20% and ~50%, respectively. Aspirin treatment also resulted in a ~20% reduction in basal rates of hepatic glucose production and a ~20% improvement in insulin-stimulated peripheral glucose uptake under matched plasma insulin concentrations during the clamp. In conclusion, these data support the hypothesis that IKK[beta] represents a new target for treating type 2 diabetes mellitus.

Copyright (C) 2002 The American Society for Clinical Investigation, Inc.