In the JournalsPerspective

Insulin sensitivity increases with testosterone therapy in men with type 2 diabetes

Testosterone treatment increased insulin sensitivity and lean body mass and decreased subcutaneous fat in men with type 2 diabetes and hypogonadotropic hypogonadism, according to study findings.

“This is the first definitive evidence that testosterone is an insulin sensitizer and, hence, a metabolic hormone,” Paresh Dandona, MD, PhD, an Endocrine Today Editorial Board member and chief of endocrinology, diabetes and metabolism in the department of medicine in the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo, said in a press release.

Paresh Dandona

Paresh Dandona

Dandona and colleagues evaluated 94 men with type 2 diabetes to determine the effect of testosterone replacement on insulin resistance.

“We hypothesized that testosterone may be an anti-inflammatory and insulin-sensitizing agent since it has been known for some time that testosterone reduces adiposity and increases skeletal muscle,” Dandona said in the release. “Our previous work has shown that obesity is associated with oxidative stress and inflammation, and inflammatory mediators are known to interfere with insulin signaling.”

Fifty participants were eugonadal (controls), and 44 had hypogonadotropic hypogonadism. Participants with hypogonadotropic hypogonadism were randomly assigned to intramuscular testosterone (250 mg) or placebo every 2 weeks for 24 weeks. Eugonadal men had higher subcutaneous and visceral fat mass compared with men with hypogonadism, whereas men with hypogonadism had 36% lower glucose infusion rate.

In men with hypogonadism, glucose infusion rate increased by 32% after 24 weeks with testosterone therapy compared with no change after placebo (P = .03). After testosterone treatment, the expression of insulin-signaling genes were significantly upregulated in adipose tissue. Concentrations of free fatty acids, C-reactive protein, interleukin-1 beta, tumor necrosis factor-alpha and leptin significantly fell after testosterone treatment (P < .05 for all).

“Testosterone treatment for men, where indicated, will improve sexual function and increase skeletal muscle strength and bone density,” Dandona said in the release. – by Amber Cox

Disclosure : Dandona reports receiving research support, honorarium and/or grants from Abbott Laboratories, Allergan, Bristol-Myers Squibb, Conjuchem, the CDC, the Citrus Industry of Florida, Dannipon Pharmaceuticals, Eli Lilly, GlaxoSmithKline, Merck, the Millard Fillmore Foundation, Mitsubishi, the NIH, Novartis, Novo Nordisk, the Oishei Foundation, Proctor & Gamble Pharmaceuticals, Quigley Pharma, Sankyo Pharmaceuticals North America, Sanofi, Solvay Pharmaceuticals, Takeda Pharmaceuticals, ToleRx, Transition Therapeutics and the William G. McGowan Charitable Fund. Please see the full study for a list of all other authors’ relevant financial disclosures.

Testosterone treatment increased insulin sensitivity and lean body mass and decreased subcutaneous fat in men with type 2 diabetes and hypogonadotropic hypogonadism, according to study findings.

“This is the first definitive evidence that testosterone is an insulin sensitizer and, hence, a metabolic hormone,” Paresh Dandona, MD, PhD, an Endocrine Today Editorial Board member and chief of endocrinology, diabetes and metabolism in the department of medicine in the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo, said in a press release.

Paresh Dandona

Paresh Dandona

Dandona and colleagues evaluated 94 men with type 2 diabetes to determine the effect of testosterone replacement on insulin resistance.

“We hypothesized that testosterone may be an anti-inflammatory and insulin-sensitizing agent since it has been known for some time that testosterone reduces adiposity and increases skeletal muscle,” Dandona said in the release. “Our previous work has shown that obesity is associated with oxidative stress and inflammation, and inflammatory mediators are known to interfere with insulin signaling.”

Fifty participants were eugonadal (controls), and 44 had hypogonadotropic hypogonadism. Participants with hypogonadotropic hypogonadism were randomly assigned to intramuscular testosterone (250 mg) or placebo every 2 weeks for 24 weeks. Eugonadal men had higher subcutaneous and visceral fat mass compared with men with hypogonadism, whereas men with hypogonadism had 36% lower glucose infusion rate.

In men with hypogonadism, glucose infusion rate increased by 32% after 24 weeks with testosterone therapy compared with no change after placebo (P = .03). After testosterone treatment, the expression of insulin-signaling genes were significantly upregulated in adipose tissue. Concentrations of free fatty acids, C-reactive protein, interleukin-1 beta, tumor necrosis factor-alpha and leptin significantly fell after testosterone treatment (P < .05 for all).

“Testosterone treatment for men, where indicated, will improve sexual function and increase skeletal muscle strength and bone density,” Dandona said in the release. – by Amber Cox

Disclosure : Dandona reports receiving research support, honorarium and/or grants from Abbott Laboratories, Allergan, Bristol-Myers Squibb, Conjuchem, the CDC, the Citrus Industry of Florida, Dannipon Pharmaceuticals, Eli Lilly, GlaxoSmithKline, Merck, the Millard Fillmore Foundation, Mitsubishi, the NIH, Novartis, Novo Nordisk, the Oishei Foundation, Proctor & Gamble Pharmaceuticals, Quigley Pharma, Sankyo Pharmaceuticals North America, Sanofi, Solvay Pharmaceuticals, Takeda Pharmaceuticals, ToleRx, Transition Therapeutics and the William G. McGowan Charitable Fund. Please see the full study for a list of all other authors’ relevant financial disclosures.

    Perspective
    Adrian Sandra Dobs

    Adrian Sandra Dobs

    It has been observed for about a decade that men with type 2 diabetes mellitus are more likely to have reduced circulating testosterone levels. The mechanisms to explain this are likely multifactorial and likely due to increased aromatization from adiposity and increased inflammation, leading to reduced testosterone synthesis. Testosterone therapy has been found to improve some of the pathophysiology of diabetes, but its mechanism is not clear.  have both direct and indirect effects. Dhinsa and colleagues have written an important manuscript where they describe the metabolic effects that occur with testosterone therapy. Using hyperglycemic clamp studies, DXA and MRI scans, and gene studies, they report that testosterone therapy reduces adiposity and increased lean body mass. That is expected.  But they also observed several direct effects on factors which affect glucose metabolism. Testosterone therapy reduced the pro-inflammatory factors observed in diabetes and increased the expression of genes related to insulin signal transduction and the suppression of genes interfering with the action of insulin.  Thus, testosterone therapy may benefit glucose metabolism and insulin sensitivity both indirectly via improved lean body mass, but also directly by reducing inflammation and increasing the expression of insulin sensitizing genes.  This tantalizing result suggests that testosterone therapy may have an important role in men with diabetes and testosterone deficiency to improve glucose control.   

    • Adrian Sandra Dobs, MD, MHS
    • Professor of Medicine and Oncology, The Johns Hopkins University School of Medicine

    Disclosures: Dobs reports no relevant financial disclosures.