Skeletal muscle of stroke-prone spontaneously hypertensive rats exhibits reduced insulin-stimulated glucose transport and elevated levels of caveolinand flotillin

Insulin resistance is of major pathogenic importance in several common huma n disorders, but the underlying mechanisms are unknown. The stroke-prone sp ontaneously hypertensive (SHRSP) rat is a model of human insulin resistance and is characterized by reduced insulin-mediated glucose disposal and defe ctive fatty acid metabolism in isolated adipocytes (Collison et al. [Diabet es 49:2222-2226, 20001). In this study, we have examined skeletal muscle an d cultured skeletal muscle myoblasts for defects in insulin action in the m ale SHRSP rat model compared with the normotensive, insulin-sensitive contr ol strain, Wistar-Kyoto (W-KY). We show that skeletal muscle from SHRSP ani mals exhibits a marked decrease in insulin-stimulated glucose transport com pared with WKY animals (fold increase in response to insulin: 1.4 +/- 0.15 in SHRSP, 2.29 +/- 0.22 in WKY; n = 4, P = 0.02), but the stimulation of gl ucose transport in response to activation of AMP-activated protein kinase w as similar between the two strains. Similar reductions in insulin-stimulate d glucose transport were also evident in myoblast cultures from SHRSP compa red with WKY cultures. These differences were not accounted for by a reduct ion in cellular GLUT4 content. Moreover, analysis of the levels and subcell ular distribution of insulin receptor substrates 1 and 2, the p85 alpha sub unit of phosphatidylinositol 3 ' -kinase, and protein kinase B (PKB)/cAKT i n skeletal muscle did not identify any differences between the two strains; the insulin-dependent activation of PICB/cAK-T was not different between t he two strains. However, the total cellular levels of caveolin and flotilli n, proteins implicated in insulin signal transduction/compartmentalization, were markedly elevated in skeletal muscles from SHRSP compared with WKY an imals. Increased cellular levels of the soluble N-ethylmaleimide attachment protein receptor (SNARE) proteins syntaxin 4 and vesicle-associated membra ne protein (VAMP)-2 were also observed in the insulin-resistant SHRSP strai n. Taken together, these data suggest that the insulin resistance observed in the SHRSP is manifest at the level of skeletal muscle, that muscle cell glucose transport exhibits a blunted response to insulin but unchanged resp onses to activation of AMP-activated protein kinase, that alterations in ke y molecules in both GLUT4 trafficking and insulin signal compartmentalizati on may underlie these defects in insulin action, and that the insulin resis tance of these muscles appears to be of genetic origin rather than a paracr ine or autocrine effect, since the insulin resistance is also observed in c ultured myoblasts over several passages.