Testosterone Increases the Expression and Phosphorylation of AMP kinase α in Men with Hypogonadism and Type 2 Diabetes.

CONTEXT: Adenosine 5'-monophosphate-activated protein kinase-alpha (AMPKalpha) is a mediator of exercise-induced glucose uptake in skeletal muscle. OBJECTIVE: We evaluated whether AMPKalpha expression and phosphorylation are reduced in skeletal muscle and adipose tissue of patients with hypogonadotropic hypogonadism (HH), and whether testosterone replacement therapy results in restoration of the expression and phosphorylation of AMPKalpha. DESIGN: This is a secondary analysis of a previously completed trial that showed an insulin-sensitizing effect of testosterone therapy in men with type 2 diabetes and HH. SETTING: Clinical research center at university. PATIENTS: Thirty-two men with HH and 32 eugonadal men were compared at baseline. INTERVENTIONS: Men with HH were treated with intramuscular injections of testosterone or placebo every 2 weeks for 22 weeks. Quadriceps muscle biopsies and subcutaneous abdominal fat biopsies were obtained before and after 4-hour euglycemic hyperinsulinemic clamp, prior to and after testosterone or placebo therapy. OUTCOME MEASURES AND RESULTS: mRNA expression of AMPKalpha in hypogonadal men was lower by 37% in adipose tissue and 29% in skeletal muscle, respectively, compared with levels in eugonadal men, while phosphorylated AMPKalpha was lower by 22% and 28%, respectively. Following testosterone replacement, the expression of AMPKalpha did not alter in the fasting state but increased markedly by 41% and 46% in adipose tissue and muscle, respectively, after the clamp. In contrast, phosphorylated AMPKalpha increased by 69% in muscle after testosterone therapy but did not change following the clamp. CONCLUSIONS: Testosterone modulates the expression of AMPKalpha and phosphorylated AMPKalpha. These effects may contribute to the improved insulin sensitivity following testosterone therapy.