Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women.
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.
Corbould
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Prince Henry's Institute of Medical Research, Monash Medical Centre, Block E, Level 4, Clayton Road, Clayton, Victoria 3168, Australia. anne.corbould@princehenrys.org
D017667:Adipocytes / Q000378:metabolism*; D000328:Adult; D000704:Analysis of Variance; D001692:Biological Transport / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D017373:Cyproterone Acetate / Q000494:pharmacology; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011085:Polycystic Ovary Syndrome / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050151:Subcutaneous Fat / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology*; D000099221:Protein Kinase C zeta
D017373:Cyproterone Acetate; D005485:Flutamide; D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D013739:Testosterone; D000099221:Protein Kinase C zeta; C526292:IRS1 protein, human