No Benefits from Testosterone Therapy in Obese Men with Diabetes

Researchers in Australia who conducted a randomized trial of testosterone therapy in men with low testosterone levels and type 2 diabetes mellitus (T2D) reported they observed some reductions in body fat among the study population but no improvements in glucose metabolism.

Researchers at several Australian universities randomized 88 men with glycated hemoglobin (HbA1C) levels of 8.5% or less and testosterone levels of 12.0 nmol/L or less to 40 weeks of either placebo (43 men) or intramuscular testosterone undecanoate (45 men).

When treated men were compared to the placebo group, the mean adjusted difference (MAD) for homeostatic model assessment insulin resistance (HOMA-IR) was −0.08 (95% CI -0.31 to 0.47; P = 0.23) MAD for HbA1C levels was .36% (0.0 to 0.7); P= 0.05.

These findings, which were published this month online in Diabetes Care, were particularly disappointing given that the testosterone therapy did help patients improve their body compositions.

Treated men, when compared to the placebo group, were found to have lost body fat (MAD -2.38 kg [-3.10 to -1.66]; P<0.001) and gained lean mass (MAD 2.08 kg [1.52-2.64]; P < 0.001). The researchers also noted that patients who received testosterone tended to lose subcutaneous (but not visceral) abdominal adipose tissue.

Before the study, the researchers had seen several reasons to hypothesize that testosterone therapy might significantly improve glucose metabolism.

Observational studies consistently show that 30% to 50% of men with T2D have low circulating testosterone levels. That’s considerably more than chance would predict, even after accounting for age and obesity.

Further studies show that those low testosterone levels in men with T2D are independently associated with insulin resistance.

“However,” the study authors wrote, “it is not known whether low testosterone levels are a cause or a consequence of T2D or its associated clinical features.”

The paper cited several prior bits of evidence that suggest low testosterone levels might cause insulin resistance, evidence that ranged from testosterone’s tendency to reduce body fat to the observation that prostate cancer victims who undergo androgen deprivation therapy often develop insulin resistance.

What’s more, the paper noted, experimental evidence suggests that testosterone “not only promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into adipocytes but also regulates the metabolic action of mature adipocytes and myocytes in ways that reduce insulin resistance.”

Similar studies of the effects of testosterone therapy on insulin metabolism have reached inconsistent conclusions, though the authors note that the largest such previous study largely agreed with theirs.

Overall, they wrote, their trial had a number of strengths that included not only the randomized patient selection but also a long duration and a low drop-out rate. (Just 13 patients failed to complete the trial and, of them, 8 left because their condition worsened to the point that they needed to increase their oral medications or begin taking insulin.)

As for the fact that fat loss did not improve glucose metabolism, the researchers speculated that “this dissociation may have occurred because testosterone treatment did not decrease visceral adipose tissue, the fat compartment most closely related with insulin resistance.”

Overall, the authors wrote, the indications for testosterone therapy in men with T2D should be no different than in other men.