v- and t-SNARE protein expression in models of insulin resistance - Normalization of glycemia by rosiglitazone treatment corrects overexpression of cellubrevin, vesicle-associated membrane protein-2, and syntaxin 4 in skeletal muscle of Zucker diabetic fatty rats

Insulin stimulation of adipose and muscle cells results in the translocatio n of GLUT4 from an intracellular location to the plasma membrane; this tran slocation is defective in insulin resistance. Studies have suggested an imp ortant role for synaptobrevin and syntaxin homologues in this event, partic ularly the v-soluble N-ethylmaleimide attachment protein receptors (SNAREs) cellubrevin and vesicle-associated membrane protein-2 (VAMP-2) and the t-S NARE syntaxin 4, but the expression of these proteins has not been studied in insulin-resistant tissues. Therefore, we examined SNARE protein content in skeletal muscle from Zucker diabetic fatty (ZDF) rats compared with lean controls and determined the effect of the thiazolidinedione insulin sensit izer rosiglitazone on these proteins. GLUT4 levels in skeletal muscle from ZDF rats were similar to those in lean control animals. In contrast, cellub revin, VAMP-2, and syntaxin 4 protein levels were elevated (2.8-fold, P = 0 .02; 3.7-fold, P = 0.01; and 2.2-fold, P < 0.05, respectively) in skeletal muscle from ZDF rats compared with lean controls. Restoration of normoglyce mia and normoinsulinemia in ZDF rats with rosiglitazone (30 mu mol/kg) norm alized cellubrevin, VAMP-2, and syntaxin 4 protein to levels approaching th ose observed in lean control animals. These data show that elevated v- and t-SNARE protein levels are associated with insulin resistance in skeletal m uscle and that these increases may be reversed by rosiglitazone treatment c oncomitant with a restoration of glycemic control. Such increases in SNARE protein levels were not observed in streptozotocin-induced diabetic rats, w hich suggests that hyperinsulinemia rather than hyperglycemia may be more i mportant in modulating SNARE protein expression in rodent models of insulin resistance. Consistent with this hypothesis, elevated levels of SNARE prot eins were also observed in 3T3-L1 adipocytes chronically treated with insul in (500 nmol/l for 24 h). These data argue that SNARE protein levels may be altered in insulin-resistant states and that the levels of these proteins are modulated by agents that increase insulin sensitivity. Moreover, these data demonstrate for the first time altered expression of proteins known to regulate GLUT4 translocation in a model of diabetes.