1. Effects of rexinoids on glucose transport and insulin-mediated signaling in skeletal muscles of diabetic (db/db) mice
- Author
-
Gerald I. Shulman, Peter J.A. Davies, Mark D. Leibowitz, Gary W. Cline, and Qi Shen
- Subjects
medicine.medical_treatment ,Receptors, Cytoplasmic and Nuclear ,Ligands ,Biochemistry ,Ligases ,Mice ,Insulin ,Proto-Oncogene Proteins c-cbl ,Organic Chemicals ,Phosphorylation ,Reverse Transcriptase Polymerase Chain Reaction ,Anticholesteremic Agents ,Muscles ,medicine.anatomical_structure ,Rosiglitazone ,medicine.drug ,Signal Transduction ,medicine.medical_specialty ,Ubiquitin-Protein Ligases ,Blotting, Western ,Biology ,Deoxyglucose ,Protein Serine-Threonine Kinases ,Diabetes Mellitus, Experimental ,Insulin resistance ,Internal medicine ,Proto-Oncogene Proteins ,medicine ,Animals ,RNA, Messenger ,Muscle, Skeletal ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Triglycerides ,Body Weight ,Skeletal muscle ,Biological Transport ,Cell Biology ,medicine.disease ,Precipitin Tests ,Receptor, Insulin ,Insulin receptor ,Endocrinology ,Glucose ,biology.protein ,Tyrosine ,Cattle ,Thiazolidinediones ,Acyl Coenzyme A ,Insulin Resistance ,Proto-Oncogene Proteins c-akt ,Transcription Factors - Abstract
Rexinoids and thiazolidinediones (TZDs) are two classes of nuclear receptor ligands that induce insulin sensitization in diabetic rodents. TZDs are peroxisome proliferator-activated receptor gamma (PPARgamma) activators, whereas rexinoids are selective ligands for the retinoid X receptors (RXRs). Activation of both the insulin receptor substrates (IRSs)/Akt and the c-Cbl-associated protein (CAP)/c-Cbl pathways are important in regulating insulin-stimulated glucose transport. We have compared the effects of a rexinoid (LG268) and a TZD (rosiglitazone) on these two signal pathways in skeletal muscle of diabetic (db/db) mice. The results we have obtained show that treatment of db/db mice with either LG268 or rosiglitazone for 2 weeks results in a significant increase in insulin-stimulated glucose transport activity in skeletal muscle. Treatment with LG268 increases insulin-stimulated IRS-1 tyrosine phosphorylation and Akt phosphorylation in skeletal muscle without affecting the activity of the CAP/c-Cbl pathway. In contrast, rosiglitazone increases the levels of CAP expression and insulin-stimulated c-Cbl phosphorylation without affecting the IRS-1/Akt pathway. The effects of LG268 on the IRS-1/Akt pathway were associated with a decrease in the level of IRS-1 Ser(307) phosphorylation. Taken together, these data suggest that rexinoids improve insulin sensitivity via changes in skeletal muscle metabolism that are distinct from those induced by TZDs. Rexinoids represent a novel class of insulin sensitizers with potential applications in the treatment of insulin resistance.
- Published
- 2004