Insulin stimulation of adipose and muscle cells results in the translocation of GLUT4 from an intracellular location to the plasma membrane; this translocation is defective in
insulin resistance. Studies have suggested an important role for
synaptobrevin and
syntaxin homologues in this event, particularly the v-soluble
N-ethylmaleimide attachment
protein receptors (
SNAREs)
cellubrevin and vesicle-associated membrane protein-2 (VAMP-2) and the
t-SNARE 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 sensitizer
rosiglitazone on these
proteins. GLUT4 levels in skeletal muscle from ZDF rats were similar to those in lean control animals. In contrast,
cellubrevin,
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 normoglycemia and normoinsulinemia in ZDF rats with
rosiglitazone (30 micromol/kg) normalized
cellubrevin,
VAMP-2, and
syntaxin 4 protein to levels approaching those observed in lean control animals. These data show that elevated v- and
t-SNARE protein levels are associated with
insulin resistance in skeletal muscle and that these increases may be reversed by
rosiglitazone treatment concomitant with a restoration of
glycemic control. Such increases in
SNARE protein levels were not observed in
streptozotocin-induced diabetic rats, which suggests that
hyperinsulinemia rather than
hyperglycemia may be more important in modulating
SNARE protein expression in rodent models of
insulin resistance. Consistent with this hypothesis, elevated levels of
SNARE proteins were also observed in 3T3-L1 adipocytes chronically treated with
insulin (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.