Adipose tissue plays a central role in determining whole body
insulin sensitivity. Several aspects of adipose cell function are regulated by
androgens. Given that high
androgen levels and
insulin resistance are linked in women, we proposed that
androgens may influence
insulin-mediated
glucose metabolism in adipose cells. Preadipocytes harvested from s.c. adipose tissue of healthy women aged 37 +/- 5 years were differentiated in vitro, then treated with
testosterone (T) and/or
androgen receptor (AR) antagonists (
cyproterone acetate,
flutamide) for 48 h. Maximal
insulin-stimulated
glucose uptake (
insulin 10 nM) and increment following
insulin stimulation were significantly impaired in cells treated with T 10 and 100 nmol/l. This defect was abolished by
cyproterone acetate and partially reversed by
flutamide. The effect of T could not be accounted for by altered differentiation status of the adipocytes. In the
glucose metabolic pathway of
insulin signaling, treatment of cells with T 10 nmol/l did not alter
insulin-stimulated phosphorylation of
insulin receptor substrate-1 or Akt, but
insulin-stimulated phosphorylation of
protein kinase C (PKC) zeta was impaired.
Insulin signaling via the mitogenic/gene regulatory pathway, as assessed by
extracellular signal-regulated kinase phosphorylation, was unchanged. We conclude that (1) T, or an androgenic metabolite of T, induces
insulin resistance in adipocytes of women, selective for metabolic signaling pathways; (2) this defect is via AR; and (3) the defect in signaling is independent of
phosphatidylinositol 3-kinase activation and involves impaired phosphorylation of PKCzeta. These findings are relevant to understanding the pathogenesis of
insulin resistance in hyperandrogenic women.