Effects of hormone therapy on insulin signaling proteins in skeletal muscle of cynomolgus monkeys

We have previously shown that hormone therapy (HT) with medroxyprogesterone acetate (MPA) alone or in combination with conjugated equine estrogens (CEE) impairs insulin sensitivity. In the current study, we sought to determine if the effect of MPA on whole body insulin sensitivity is associated with alterations in insulin signaling proteins in skeletal muscle. Ovariectomized cynomolgus monkeys were treated for 2 years with either no hormones ( n=10), CEE (0.625 mg/day human equivalent, n=11) or CEE+MPA (2.5 mg/day human equivalent, n=12). At the end of the study, biopsies of rectus femoris muscle were flash frozen in the basal and insulin-stimulated (10 min post-intravenous insulin injection) state. Immunoblotting revealed that CEE+MPA-treated monkeys had significantly less glucose transporter 4 (GLUT4) expression (ANOVA P=0.001), but there was no significant treatment effect on expression of insulin receptor, insulin receptor substrate (IRS)-1, IRS-2, or the p85 subunit of phosphatidylinositol 3-kinase (PI 3-K). There was a tendency for decreased insulin receptor tyrosine phosphorylation with CEE+MPA treatment (ANOVA P=0.14). These deficiencies in skeletal muscle insulin signaling likely contribute to the unfavorable changes in whole body insulin sensitivity associated with CEE+MPA treatment.