Calorie restriction increases cell surface GLUT-4 in insulin-stimulated skeletal muscle

Reduced calorie intake [calorie restriction (CR); 60% of ad libitum (AL)] l eads to enhanced glucose transport without altering total GLUT-4 glucose tr ansporter abundance in skeletal muscle. Therefore, we tested the hypothesis that CR (20 days) alters the subcellular distribution of GLUT-I. Cell surf ace GLUT-4 content was higher in insulin-stimulated epitrochlearis muscles from CR vs. AL rats. The magnitude of this increase was similar to the CR-i nduced increase in glucose transport, and GLUT-4 activity (glucose transpor t rate divided by cell surface GLUT-4) was unaffected by diet. The CR effec t was specific to the insulin-mediated pathway, as evidenced by the observa tions that basal glucose transport and cell surface GLUT-4 content, as well as hypoxia-stimulated glucose transport, were unchanged by diet. CR did no t alter insulin's stimulation of insulin receptor substrate (IRS)-1-associa ted phosphatidylinositol 3-kinase (PI3K) activity. Muscle abundance of IRS- 2 and p85 subunit of PI3K were unaltered by diet, but IRS-1 content was low er in CR vs. AL. These data demonstrate that, despite IRS-1-PI3K activity s imilar to AL, CR specifically increases insulin's activation of glucose tra nsport by enhancing the steady-state proportion of GLUT-4 residing on the c ell surface.