Insulin Sensitivity Improves with Testosterone Therapy in Men with Type 2 Diabetes and Hypogonadism

About a third of men with type 2 diabetes (T2D) also have hypogonadotropic hypogonadism (HH). This comorbidity makes that subgroup more insulin resistant, with increased adiposity and less lean mass, according to research published recently in The Journal of Clinical Endocrinology & Metabolism.

A team led by Paresh Dandona, BSc, MB, BS, DPhil, FRCP, of the State University of New York at Buffalo, in Williamsville, N.Y., has previously demonstrated that testosterone therapy improves insulin sensitivity in this population. Adding this to the facts that exercise induces adenosine 5′-monophosphate-activated protein kinase-α (AMPKα) to increase glucose uptake and that testosterone increases muscle mass, the team hypothesized that AMPKα expression and phosphorylation may be decreased in these men. Would testosterone therapy reverse these effects?

In “Testosterone Increases the Expression and Phosphorylation of AMP Kinase α in Men with Hypogonadism and Type 2 Diabetes,” Dandona and team compared two groups of men with stable type 2 diabetes, 32 men ages 30 to 65 years: Group 1 of 32 men had HH and underwent intervention; group 2 of 32 men had normal gonadal function and received no intervention. Group 1 received intramuscular injections of testosterone or placebo every two weeks for 22 weeks.

The researchers took biopsies from the quadriceps muscles and from subcutaneous abdominal fat both before and after placement of a hyperinsulinemic clamp and before and after testosterone or placebo administration. Following the treatment period, in men receiving testosterone, free testosterone concentration increased by 7.8, and fat mass decreased while lean mass increased. Moreover, AMPKα expression increased by 41% and 46% in adipose tissue and muscle, respectively, after the clamp (but not in the fasting state), whereas phosphorylated AMPKα increased by 69% in muscle (with no change after the clamp).

Testosterone and insulin, therefore, modulate the expression and phosphorylation of AMPKα. In men with HH, testosterone therapy has insulin-sensitizing effects. “The increase in AMPKα expression following combined insulin and testosterone administration is perhaps a reflection of their synergistic anabolic effects on muscle protein synthesis and growth,” write the authors.

This work was supported by a National Institute of Diabetes and Digestive and Kidney Diseases grant.


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