Pharmacological inhibition of p38 MAP kinase results in improved glucose uptake in insulin-resistant 3T3-L1 adipocytes.
Inhibition of p38, a member of the mitogen-activated protein kinase family, has been shown to prevent the loss of GLUT4 protein expression in insulin-resistant adipocytes without improving insulin receptor substrate 1 (IRS-1) protein levels and presumably insulin signaling. Thus, it was unclear whether p38 inhibitors would have a beneficial effect upon insulin-stimulated glucose uptake. We evaluated the effects of p38 inhibition during the development of insulin resistance upon glucose uptake and components of the insulin signaling pathway to determine the therapeutic value of p38 inhibitors. Treatment with the specific p38 inhibitor, A304000, during the development of insulin resistance increased basal glucose uptake as well as glucose uptake in response to a subsequent insulin stimulation. p38 inhibition increased GLUT1 protein levels and prevented the loss of GLUT4. However, p38 inhibition did not prevent the loss of IRS-1 protein levels or insulin signaling to PKB in insulin-resistant cells. Rapamycin, an inhibitor or mTOR, could partially improve insulin-stimulated glucose uptake through maintaining IRS-1 protein levels. Combined treatment with both A304000 and rapamycin had an additive effect upon glucose uptake. These data indicate that p38 inhibition can enhance glucose uptake through regulating the expression of GLUT1 and 4, but did not prevent the development of insulin resistance.
Carlson
Christian J
CJ
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, IL 60064, USA.
Rondinone
Cristina M
CM
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D047468:Immunoprecipitation; D007333:Insulin Resistance; D051379:Mice; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose