Reversal of Diet-Induced Insulin Resistance: Another Use for Aspirin?

Michael Karin
University of California, San Diego
R37ES04151

Background: Type II diabetes is a chronic disease characterized by the body's inability to use its own insulin to regulate blood levels of the sugar, glucose. It is the seventh leading killer in this country with costs in excess of $98 billion each year. The insulin resistance that is characteristic of diabetes can be defined as a cluster of abnormalities, including obesity, hypertension, abnormal lipid levels and type 2 (adult onset) diabetes, that are associated with insulin resistance and compensatory excessive production of insulin. The syndrome is characterized by diminished cellular and metabolic responses to the actions of insulin. To compensate for resistance, the pancreas secretes more insulin causing high circulating plasma insulin levels. The causes of insulin resistance and likewise the mechanisms by which weight loss and exercise reverse its effects are largely unknown.

Aspirin is one of the salicylate class of chemicals that might provide a clue to treatment of insulin resistance. Salicylates are anti-inflammatory compounds that interrupt the cascade of molecular events that lead to inflammation. High doses of aspirin and other salicylate-containing drugs are used to treat rheumatic fever, rheumatoid arthritis and other inflammatory diseases. High doses of salicylates also decrease blood sugar but their potential for treatment of diabetes has largely been forgotten. Classically, aspirin has been believed to exhibit anti-inflammatory actions due to the inhibition of cyclooxygenases (COX), enzymes that are important in the inflammatory pathway. Results reported here suggest that another enzyme in the inflammatory cascade, IkB; kinase ß (IKKß), rather than COX is the molecular target of salicylates. IKKß activates NfkB which is a major regulator of immune responses stimulated by pro-inflammatory stimuli such as tumor necrosis factor (TNFalpha). NIH-supported scientists investigated the possible involvement of the IKKß complex in insulin resistance and aspirin as a possible treatment.

Advance: In severely insulin-resistant laboratory rats and mice, high doses of aspirin or sodium salicylate (equivalent to a 150 pound person taking 25 aspirin tablets per day) reversed the high blood sugar and insulin levels. Additional experiments using cells cultures showed that TNFalpha, which activates the IKKß complex, induced insulin resistance. However, the COX inhibitors ibuprofen and naproxen did not reverse TNFalpha insulin resistance. Additionally, animals deficient in IKKß expression exhibited improved insulin resistance over those with normal IKKß expression.

Implications: These experiments indicate that the IKKß complex is important in the development of insulin resistance. High doses of aspirin and other salicylate containing drugs inhibit the IKKß complex resulting in lowered blood glucose and insulin levels. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes. These studies provide important insights into the development of insulin resistance and may lead to improvements in treatment or possibly prevention of insulin resistance and the resulting development of type 2 diabetes.

Citation: Yuan M, Konstantopoulos N, Lee J, Hansen L, Li Z-W, Karin M, Shoelson SE. (2001) Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of IKKß . Science, 293 (5535), 1673-77.