There are two classes of nuclear receptor ligands, Retinoid X Receptor ligands (rexinoids) and PPARg ligands (thiazolidinediones-TZDs) that are capable of inducing insulin sensitization in animal models of Type II Diabetes. In studies carried out in diabetic rodents, we have found that rexinoids and TZDs have very different effects on gene expression in both adipose tissue and skeletal muscle. While TZDs markedly induce gene expression in adipose tissue, rexinoids regulate the expression of genes in skeletal muscle. The goal of this project is to characterize the mechanisms involved in the insulin - sensitizing effect of rexinoids in skeletal muscle. In muscle, rexinoids regulate the expression of genes associated with the """"""""slow twitch"""""""" (Type I) myofiber phenotype (such as myoglobin and Troponin I slow) and the enzymes of oxidative fatty acid metabolism. Since Type I myofibers (slow twitch fibers) are more insulin - sensitive than Type II (fast twitch) fibers, it is our hypothesis that rexinoids induce insulin sensitization in diabetic animals by activating the slow twitch gene regulatory program in skeletal muscle. We will test this hypothesis by addressing the following three specific aims:
Aim #1 To investigate the interactions of rexinoids and calcineurin / NFAT signal transduction pathway in the regulation of slow twitch gene expression in skeletal muscle cells in vitro and in vivo.
Aim #2. To identify the nuclear receptors that mediate the effects of rexinoids on slow twitch gene expression in skeletal muscle.
Aim #3. To examine the fiber type - specific effects of rexinoids on the insulin sensitivity and the insulin signal transduction pathway in diabetic rodents. Rexinoids are an entirely novel class of insulin sensitizers that produce their effects by directly altering gene expression in the skeletal muscle. Understanding their mechanisms of action will provide new insights into novel pharmacologic approaches to the treatment of diabetes and the management of a number of myopathies that arise from the loss of the slow twitch myofiber expression.
|Shen, Qi; Cline, Gary W; Shulman, Gerald I et al. (2004) Effects of rexinoids on glucose transport and insulin-mediated signaling in skeletal muscles of diabetic (db/db) mice. J Biol Chem 279:19721-31|