A notable randomized, placebo-controlled trial performed by Dhindsa and colleagues examined metabolic changes following testosterone therapy in men with type 2 diabetes.¹ Results showed a 3.4 kg increase in lean body mass and -3.3 kg decrease in body fat mass. This was accompanied by a 31% increased insulin sensitivity (measured by glucose infusion rate during a clamp test). Dhindsa’s group sought to find out if the improved insulin sensitivity was a direct effect of testosterone or mediated via other effects of testosterone. Analysis of mRNA expression of insulin signaling mediators (IR, IR S-1, GLUT-4, Akt-2) in adipose tissue showed an increase after testosterone therapy. It was also found that testosterone increases AMP kinase activity in muscle. Furthermore, the testosterone treated men had a significant reduction in inflammation (CRP, TNF-alpha).

Dhindsa and colleagues additionally investigated the mechanisms behind the testosterone-induced muscle growth. In testosterone treated men they found an increase in serum IGF-1 as well as FGF-2, which is an important stimulatory modulator of satellite cells in the skeletal muscle, which play a cardinal role in muscle growth and repair. In other words, testosterone therapy activates muscle stem cells that turn into muscle cells.

These are clearly beneficial effects of testosterone. But what do they mean in clinical practice?

Dr. Dhindsa answers this question by presenting “real-life” data from a registry study where 229 men with hypogonadism and prediabetes were treated with testosterone undecanoate injections for 8 years. The main outcomes were progression to frank type 2 diabetes and resolution of prediabetes (in other words, restoration of normoglycemia). The study included a group of 87 untreated men, which served as a control group. It was found that among testosterone treated men, no subject progressed to frank type 2 diabetes, whereas in the control group 40% of men progressed to develop type 2 diabetes. In addition, 90% of testosterone treated men achieved restoration of normoglycemia (HbA_1c < 5.7%), and no longer had prediabetes. No subject in the control group achieved restoration of normoglycemia.

Long-term “real life” testosterone therapy has also been reported to result in resolution of type 2 diabetes. In a registry study of 152 hypogonadal men with type 2 diabetes who were treated with testosterone undecanoate injections for up to 12 years, 51 patients (33.6%) were in remission at the last measurement.

Accumulating data are also showing that long-term testosterone therapy reduces mortality in men with type 2 diabetes. In a diabetes clinic chart review, men who had been treated with testosterone therapy for up to 6 years had a mortality rate of 9% (same as in eugonadal men), while men who did not receive testosterone therapy has a mortality rate of 20%.

Dr Dhindsa concludes:

• Low testosterone levels are common in obesity, type 2 diabetes and metabolic syndrome.
• Testosterone has an important role in glucose, fat, protein metabolism.
• Testosterone is not merely a “sexual” or “lifestyle hormone”. Testosterone is a “metabolism hormone” with critical clinical implications.