What's the Story with Testosterone Replacement Therapy and Diabetes?

Just weeks after Australian researchers published data suggesting that testosterone replacement therapy does not ameliorate type 2 diabetes among hypogonadal men, a team of American researchers has unveiled a second study that suggests just the opposite.

A team led by SUNY Buffalo’s Manav Batra, MD, recruited 41 diabetic men with hypogonadotropic hypogonadism (HH) and randomized them between testosterone and placebo groups.

The first group received intramuscular testosterone injections every 2 weeks for 6 months. (Doses started at 250 mg and were then adjusted to achieve free testosterone levels in the mid-normal range for healthy young men.) The second group received intramuscular injections of saline on the same schedule.

Hyperinsulinemic euglycemic clamps performed on fasting blood samples taken at baseline and 6 months showed a 30% increase in glucose infusion rates among patients in the testosterone group — an observation consistent with a reversal of insulin resistance.

The same test found no significant change among patients in the placebo group. Looking at other tests, adipose tissue expression of insulin resistance increased by 63% (±15%) among members of the testosterone group, while insulin receptor substrate increased 54% (±17%) and glucose transporter increased 59% (±14%).

Men who received testosterone also experienced significant drops in two compounds that interfere with insulin signaling. Protein-tyrosine phosphatase fell by 23% (±8%) and toll-like receptor 4 fell by 21% (±11%). Testosterone users, moreover, saw mononuclear cells’ expression of suppressor of cytokine signaling-3 drop 27%. Plasma concentrations of free fatty acids fell 35% and C-reactive protein fell 26%, (P<0.05).

Members of the placebo group experienced none of these changes.

Batra, who just presented the team’s findings at annual meeting of the American Association of Clinical Endocrinologists, said that several of the findings were significant. "Our data shows, for the first time, that men with type 2 diabetes and hypogonadotropic hypogonadism are more insulin resistant than men who have normal testosterone,” he told the audience in Las Vegas.

"This hypogonadotropic hypogonadism is associated with lower expression of mediators of insulin signaling in adipose tissue as compared to men who have normal testosterone. Following the testosterone replacement in these men, however, the expression of mediators of insulin signaling increases, and there is a reduction in expression of mediators interfering with insulin signaling that improves insulin sensitivity," he said.

The Australian study measured slightly different things. Researchers randomized 88 men with a 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 for homeostatic model assessment insulin resistance 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.

The Australian authors saw no reason why men with diabetes should feel greater impetus to begin testosterone therapy than other men with low testosterone.

Batra and his team, however, concluded that testosterone therapy should be strongly considered for hypogonadal diabetics as its tendency to increase insulin sensitivity might improve cardiovascular outcomes. They also called for long-term studies into the issue.