Virilizing doses of testosterone decrease insulin levels and upregulate transcript levels of insulin signaling proteins in liver and adipose tissue of females

Abstract

Transgender men undergoing hormone therapy are at risk for cardiovascular disease and insulin resistance. However, how initiation of virilizing testosterone therapy affects serum insulin and tissues in control of peripheral insulin sensitivity in transgender men is unknown. This study assessed the effect of acute, virilizing testosterone on serum insulin concentrations and insulin signaling in liver, skeletal muscle, and white adipose tissue (WAT) of female pigs as a translational model for transgender men. Females received three doses of intramuscular testosterone cypionate (TEST females; 50mg/day/pig) or corn oil (control) each spaced six days apart starting on estrus (D0). Fasting blood was collected on D0, 3, 5, 11, and 13 and females were euthanized on D13. On D13 post-treatment, TEST females had virilizing concentrations of serum testosterone with normal concentrations of serum estradiol. Moderate serum testosterone concentrations (D3) were associated with increased serum insulin and C-peptide concentrations. However, virilizing serum testosterone concentrations (D13) were associated with decreased serum insulin and C-peptide concentrations. Blood glucose concentrations were not altered by testosterone treatment. Virilizing concentrations of testosterone down-regulated AR and ESR1 in subcutaneous WAT and upregulated transcript levels of insulin signaling pathway proteins in WAT and liver. Virilizing testosterone concentrations had minimal effect on protein kinase B and forkhead box protein 1 levels in WAT. These results suggest that female pigs are less insulin sensitive when their serum testosterone concentrations are moderately high but become more insulin sensitive, specifically with respect to WAT and liver, when their serum testosterone is at a virilizing concentration.