mercaptopurine and Insulin-Resistance

The purine anti-metabolite 6-mercaptopurine (6-MP) is widely used for the treatment of leukemia and inflammatory diseases. The cellular effects of 6-MP on metabolism remain unknown; however, 6-MP was recently found to activate the orphan nuclear receptor NR4A3 in skeletal muscle cell lines. We have reported previously that NR4A3 (also known as NOR-1, MINOR) is a positive regulator of insulin sensitivity in adipocytes. To further explore the role of NR4A3 activation in insulin action, we explored whether 6-MP activation of NR4A3 could modulate glucose transport system activity in L6 skeletal muscle cells. We found that 6-MP increased both NR4A3 expression and NR4A3 transcriptional activity and enhanced glucose transport activity via increasing GLUT4 translocation in both basal and insulin-stimulated L6 cells in an NR4A3-dependent manner. Furthermore, 6-MP increased levels of phospho-AS160, although this effect was not modulated by NR4A3 overexpression or knockdown. These primary findings provide a novel proof of principle that 6-MP, a small molecule NR4A3 agonist, can augment glucose uptake in insulin target cells, although this occurs via both NR4A3-dependent and -independent actions; the latter is related to an increase in phospho-AS160. These results establish a novel target for development of new treatments for insulin resistance.

Topics: 3T3 Cells; Animals; Antimetabolites; Cells, Cultured; DNA-Binding Proteins; Glucose; Glucose Transport Proteins, Facilitative; Glucose Transporter Type 4; GTPase-Activating Proteins; Insulin Resistance; Mercaptopurine; Mice; Muscle Fibers, Skeletal; Nerve Tissue Proteins; Rats; Real-Time Polymerase Chain Reaction; Receptors, Steroid; Receptors, Thyroid Hormone; RNA; RNA, Small Interfering; Stimulation, Chemical; Translocation, Genetic

Topics: Diabetes Mellitus; Dimercaprol; Drug Hypersensitivity; Humans; Insulin; Insulin Resistance; Mechlorethamine; Mercaptopurine; Prednisone

Topics: Diabetes Mellitus; Humans; Insulin; Insulin Resistance; Mercaptopurine; Metabolism; Pharmacology; Prednisone; Research