pd-0325901 and Insulin-Resistance

Extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance associated with obesity and type 2 diabetes mellitus. We have now examined the potential of pharmacological targeting of the ERK pathway with MEK (ERK kinase) inhibitors (PD184352 and PD0325901) for the treatment of obesity-associated insulin resistance. The effects of PD184352 and PD0325901 on the expression of adipocytokines and lipolysis activity were thus examined in 3T3-L1 adipocytes maintained in long-term culture as a model of adipocyte hypertrophy. Leptin receptor-deficient (db/db) mice and high-fat diet-fed KKAy mice, both of which are models of type 2 diabetes, were also treated orally with PD184352 to examine its effects on the diabetic condition. ERK activity was increased in hypertrophic 3T3-L1 adipocytes as well as in adipose tissue of db/db mice and high-fat diet-fed KKAy mice, and this enhanced ERK signaling was associated with dysregulation of adipocytokine expression and increased lipolysis activity. Specific blockade of the ERK pathway in hypertrophic 3T3-L1 adipocytes by MEK inhibitors ameliorated the dysregulation of adipocytokine expression and suppressed the enhanced lipolysis activity. Furthermore, repeated oral administration of PD184352 normalized hyperglycemia and hyperlipidemia and improved insulin sensitivity and glucose tolerance in the diabetic mice. These results suggest that sustained activation of the ERK pathway in adipocytes is associated with the pathogenesis of type 2 diabetes and that selective blockade of this pathway with MEK inhibitors warrants further study as a promising approach to the treatment of insulin resistance and type 2 diabetes.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Adiponectin; Animals; Benzamides; Blood Glucose; Chemokine CCL2; Diabetes Mellitus, Type 2; Diet, High-Fat; Diphenylamine; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Fatty Acids, Nonesterified; Glucose Tolerance Test; Hyperlipidemias; Immunoblotting; In Vitro Techniques; Insulin; Insulin Resistance; Interleukin-6; Lipolysis; Male; MAP Kinase Signaling System; Mice; Protein Kinase Inhibitors; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Triglycerides; Tumor Necrosis Factor-alpha